Viridal Duo 40 micrograms / ml,Powder and Solvent for Solution for Injection.

1. Name Of The Medicinal Product

Viridal Duo 40 microgram/ml, Powder and Solvent for Solution for Injection

2. Qualitative And Quantitative Composition

Alprostadil 40 micrograms (used as a 1:1 clathrate complex with alfadex)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and Solvent for Solution for Injection.

The powder is odourless and white, and the isotonic sodium chloride solution is clear. The powder dissolves immediately to yield a clear solution.

4. Clinical Particulars 4.1 Therapeutic Indications

As an adjunct to the diagnostic evaluation of erectile dysfunction in adult males.

Treatment of erectile dysfunction in adult males.

4.2 Posology And Method Of Administration

The drug solution should be prepared shortly before the injection.

Prior to injection the needle should be screwed onto the tip of the injector. After disinfecting the tip of the cartridge with one of the alcohol swabs, the cartridge should then be inserted into the injector. By screwing the thread part clockwise, the cartridge is fixed in the injector. Then, the dry substance, which is inside the front chamber of the cartridge, is reconstituted with 1 ml sterile sodium chloride solution 0.9% in the bottom chamber. While holding the device in a vertical position with the needle upwards, the thread part should be screwed slowly until it will not go any further. The solvent will by-pass the upper stopper into the front chamber and dissolve the dry substance within a few seconds. As soon as the dry substance is reconstituted, the larger external and the smaller inner protective cap have to be removed from the needle. The air should then be expelled out of the cartridge and the prescribed dose adjusted precisely.

Unused solution must be discarded immediately.

Viridal Duo is injected into either the right or the left cavernous body of the penile shaft. Once the needle is in the cavernous body, the injection should be done within 5 to 10 seconds and is very easy without much resistance if the needle is in the correct position.

The development of an erection will start approximately 5 – 15 minutes after the injection.

Dosage for injection in the clinic

Injections for diagnostic evaluation and dose titration must be performed by the attending physician. He will determine an individual dose suitable to produce an erectile response for diagnostic purposes.

The recommended starting dose is 2.5 mcg Viridal Duo in patients with primary psychogenic or neurogenic origin of erectile dysfunction. In all other patients with erectile dysfunction 5 mcg Viridal Duo should be used as a starting dose. Dose adjustments may be performed in increments of about 2.5 mcg to 5 mcg Viridal Duo. Most of the patients require between 10 and 20 mcg per injection. Some patients may need to be titrated to higher doses. Doses exceeding 20 mcg should be prescribed with particular care in patients with cardiovascular risk factors. The dose per injection should never exceed 40 mcg.

Dosage for self-injection therapy at home

Before starting treatment at home, each patient or the patient's partner has to be taught by a physician how to prepare the drug and perform the injection. In no cases should the injection therapy be started without precise instructions by the physician. The patient should only use his optimum individual dosage which has been pre-determined by his physician using the above-mentioned procedure. This dose should allow the patient to have an erection at home which should not last longer than one hour. If he experiences prolonged erections beyond 2 hours but less than 4 hours, the patient is recommended to contact his physician to re-establish the dose of the drug. Maximum injection frequency recommended is 2 or 3 times a week with an interval of at least 24 hours between the injections.

Follow-up

After the first injections and at regular intervals, e.g. every three months, the physician should re-evaluate the patient. Any local adverse reaction, e.g. haematoma, fibrosis or nodules should be noted and controlled. Following discussion with the patient, an adjustment of dosage may be necessary.

4.3 Contraindications

Hypersensitivity to the active substances or to any other ingredients.

Patients with diseases causing priapism e.g. sickle-cell disease, leukaemia and multiple myeloma or patients with anatomical deformation of the penis as cavernosal fibrosis or Peyronie's disease. Patients with penis implants should not use Viridal Duo.

Viridal Duo should not be used in men for whom sexual activity is contraindicated.

4.4 Special Warnings And Precautions For Use

The physician should carefully select patients suitable for self-injection therapy.

Sexual stimulation and intercourse can lead to cardiac and/or pulmonary events in patients with coronary heart disease, congestive heart failure or pulmonary disease.

Viridal Duo should be used with care in these patient groups and patients should be examined and cleared for stress resistance by a cardiologist before treatment.

Viridal Duo should be used with care in patients who have experienced transient ischaemic attacks.

Patients who experience a prolonged erection lasting longer than four hours should contact their physician immediately. Therefore it is recommended that the patient has an emergency telephone number of his attending physician or of a clinic experienced in therapy of erectile dysfunction. Prolonged erection may damage penile erectile tissue and lead to irreversible erectile dysfunction.

A benefit-risk evaulation is neccesary before using Viridal Duo in patients with pre-existing scarring, e.g. nodules of the cavernous body or pre-existing penile deviation or Peyronie's disease or clinically relevant phimosis, e.g. phimosis with risk of paraphimosis these patients should be treated with particular care, e.g. more frequent re-evaluation of the patient's condition.

Patients who have to be treated with alpha-adrenergic drugs due to prolonged erections (see: overdose) may in the case of concomitant therapy with monoamino-oxidase-inhibitors, develop a hypertensive crisis.

Other intracavernous drugs e.g. smooth muscle relaxing agents or alpha-adrenergic blocking agents may lead to prolonged erection and must not be used concomitantly.

The effects of a combination therapy of alprostadil with oral, intraurethral or topical medicinal products for erectile dysfunction are currently unknown.

Patients with blood clotting disorders or patients on therapy influencing blood clotting parameters should be carefully selected for treatment by the treating physician and treated with special care, e.g. monitoring of the clotting parameters, patients should be thoroughly educated by the prescriber about the associated risks and advised to exercise sufficient manual pressure on the injection site. This is because of the increased risk of bleeding.

To prevent abuse, self-injection therapy with Viridal Duo should not be used by patients with drug addiction and/or disturbances of psychological or intellectual development.

In cases of excessive use, e.g. higher frequencies than recommended, an increased risk of penile scarring cannot be excluded.

Use of intracavernous alprostadil offers no protection from the transmission of sexually transmitted diseases. Individuals who use alprostadil should be counselled about the protective measures that are necessary to guard against the spread of sexually transmitted diseases, including the human immunodeficiency virus (HIV). In some patients, injection of Viridal Duo can induce a small amount of bleeding at the injection site. In patients infected with blood borne diseases, this could increase the transmission of such diseases to the partner. For this reason we recommend that a condom is used for intercourse after injecting Viridal Duo.

Viridal Duo is for intracavernous injection. Subcutaneous injection or injections at areas of the penis other than the cavernous body should be avoided.

The injection should be performed under hygienic conditions to avoid infections. In any condition that precludes safe self-injection like poor manual dexterity, poor visual acuity or morbid obesity, the partner should be trained in the injection technique and should perform the injection.

Up to now, there is no clinical experience in patients under 18 and over 75 years of age.

Viridal Duo does not interfere with ejaculation and fertility.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of smooth muscle relaxing drugs like papaverine or other drugs inducing erection like alpha-adrenergic blocking agents may lead to prolonged erection and should not be used in parallel with Viridal Duo.

Risks exist when using alpha-adrenergic drugs to terminate prolonged erections in patients with cardiovascular disorders or receiving MAO inhibitors.

The effects of blood pressure lowering and vasodilating drugs may be increased.

4.6 Pregnancy And Lactation

The natural amount of PGE1 present in the sperm may be increased by the PGE1 present in Viridal Duo. In case the partner is pregnant, a condom should be used in order to avoid irritation of the vagina and a risk for the foetus.

4.7 Effects On Ability To Drive And Use Machines

Viridal Duo may rarely induce a transient drop of blood pressure with subsequent impairment of reactivity that could interfere with patient's ability to drive or operate machinery.

4.8 Undesirable Effects

Undesirable effects frequencies are defined as:

Very common (

Common (

Uncommon (

Rare (

Very rare (< 1/10,000).

During administration of Viridal Duo the following undesirable effects may be observed:

General disorders and administration site condition

Common: burning sensation during injection and after the injection, sensation of tension in the penis and pain of mostly mild intensity at the site of injection.

Uncommon: spotlike haemorrhage/ spotlike bruises at the site of puncture, haemosiderin deposits, reddening and swellings at the site of injection, swellings of the preputium or the glans, and headache.

Reproductive system and breast disorders

Common: fibrotic alterations (e.g. fibrotic nodules, plaques at the site of injection or in the corpus cavernosum) can occur during long-term treatment.

Uncommon: fibrotic alterations associated with slight penile axis deviations. Prolonged erections of more than 4 hours' duration are uncommon (mainly seen during dose titration).

Rare: fibrotic changes of the cavernous body during a long term treatment lasting up to 4 years.

Cardiac disorders

Rare: circulatory effects such as short periods of hypotension and/or vertigo or dizziness.

Immune system disorders

Rare: allergic reactions ranging from cutaneous hypersensitivity such as rash, erythema, urticaria to anaphylactic/anaphylactoid reactions.

4.9 Overdose

Symptoms

Full rigid erections lasting more than four hours.

If the patient experiences a prolonged erection, he is advised to contact his attending physician or a urologic clinic nearby immediately.

Treatment strategy

Treatment of prolonged erection should be done by a physician experienced in the field of erectile dysfunction. If prolonged erection occurs, the following is recommended:

If the erection has lasted less than six hours:

? observation of the erection because spontaneous flaccidity frequently occurs.

If the erection has lasted longer than six hours:

? cavernous body injection of alpha-adrenergic substances (e.g. phenylephrine or epinephrine (adrenaline)). Risks exist when using drugs in patients with cardiovascular disorders or receiving MAO inhibitors. All patients should be monitored for cardiovascular effects when these drugs are used to terminate prolonged erections.

or

? aspiration of blood from the cavernous body.

Accidental systemic injection of high doses

Single dose rising tolerance studies in healthy volunteers indicated that single intravenous doses of alprostadil from 1 to 120 mcg were well tolerated. Starting with a 40 mcg bolus intravenous dose, the frequency of drug-related adverse events increased in a dose-dependent manner, characterised mainly by facial flushing.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC Code: Other urologicals G04BX 05

Alprostadil [Prostaglandin E1 (PGE1)], the active ingredient of Viridal Duo, is an endogenous compound derived from the essential fatty acid dihomogammalinolenic acid. Alprostadil is a potent smooth muscle relaxant that produces vasodilation and occurs in high concentrations in the human seminal fluid. Pre-contracted isolated preparations of the human corpus cavernosum, corpus spongiosum and cavernous artery were relaxed by alprostadil, while other prostanoids were less effective. Alprostadil has been shown to bind to specific receptors in the cavernous tissue of human and non-human primates.

The binding of alprostadil to its receptors is accompanied by an increase in intracellular cAMP levels. Human cavernosal smooth muscle cells respond to alprostadil by releasing intracellular calcium. Since relaxation of smooth muscle is associated with a reduction of the cytoplasmic free calcium concentration, this effect may contribute to the relaxing activity of this prostanoid.

Intracavernous injection of alprostadil in healthy monkeys resulted in penile elongation and tumescence without rigidity. The cavernous arterial blood flow was increased for a mean duration of 20 min. In contrast, intracavernous application of alprostadil to rabbits and dogs caused no erectile response.

Systemic intravascular administration of alprostadil leads to a vasodilation and reduction of systemic peripheral vascular resistance. A decrease in blood pressure can be observed after administration of high doses. Alprostadil has also been shown in animal and in vitro tests to reduce platelet reactivity and neutrophil activation. Additional alprostadil activity has been reported: increase in fibrinolytic activity of fibroblasts, improvement of erythrocyte deformability and inhibition of erythrocyte aggregation; inhibition of the proliferative and mitotic activity of non-striated myocytes; inhibition of cholesterol synthesis and LDL-receptor activity; and an increase in the supply of oxygen and glucose to ischaemic tissue along with improved tissue utilisation of these substrates.

5.2 Pharmacokinetic Properties

After reconstitution, alprostadil (PGE1) dissociates from the ?-cyclodextrin clathrate, and the two components have independent fates.

In symptomatic volunteers, systemic mean endogenous PGE1 venous plasma concentrations measured before intracavernous injection are approximately 1 pg/ml. After injection of 20 mcg of alprostadil, the PGE1 venous plasma concentrations increase rapidly to concentrations of about 10-20 pg/ml. The PGE1 plasma concentrations return to concentrations close to the baseline within a few minutes. Approximately 90% of PGE1 found in plasma is protein-bound.

Metabolism

Enzymatic oxidation of the C15-hydroxy group and reduction of the C13,14 double bond produce the primary metabolites, 15-keto-PGE1, PGEo (13,14-dihydro-PGE1) and 15-keto-PGEo. Only PGEo and 15-keto-PGEo have been detected in human plasma. Unlike the 15-keto metabolites, which are less pharmacologically active than the parent compound, PGEo has a potency similar to that of PGE1 in most respects.

In symptomatic volunteers, the mean endogenous PGEo venous plasma concentrations measured before an intracavernous injection are approximately 1 pg/ml. After the injection of 20 mcg of alprostadil, the PGEo plasma concentrations increase to concentrations of about 5 pg/ml.

Excretion

After further degradation of the primary metabolites by beta and omega oxidation, the resulting, more polar metabolites are excreted primarily with the urine (88%) and the faeces (12%) and there is no evidence of tissue retention of PGE1 or its metabolites.

5.3 Preclinical Safety Data

Studies on local tolerance following single and repeated intracavernous injections of alprostadil or alprostadil alfadex in rabbits and/or monkeys, in monkeys up to 6 months with daily injection revealed in general good local tolerance. Possible adverse effects like haematomas and inflammations are more likely related to the injection procedure.

Within the 6 months study in male monkeys, there were no adverse effects of alprostadil alfadex on male reproductive organs.

Alprostadil did not cause any adverse effects on fertility or general reproductive performance in male and female rats treated with 40-200 mcg/kg/day. The high dose of 200 mcg/kg/day is about 300 times the maximum recommended human dose on a body weight basis (MHRD < 1 mcg/kg).

Alprostadil was not fetotoxic or teratogenic at doses up to 5000 mcg/kg/day (7500 times the MHRD) in rats, 200 mcg/kg/day (300 times the MHRD) in rabbits and doses up to 20 mcg/kg/day (30 times the MHRD) in guinea pigs or monkeys.

Mutagenicity studies with alprostadil alfadex revealed no risk of mutagenicity.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Powder for injection:

Lactose monohydrate

Alfadex

Diluent:

Sodium chloride

Water for injection.

6.2 Incompatibilities

It is not intended that this medicinal product be mixed with other medicinal products. Therefore in the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Shelf life for the product as packaged for sale: 4 years.

Shelf life after reconstitution: for immediate use only.

6.4 Special Precautions For Storage

Do not store above 25°C.

Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

Administration devices:

1 reusable injector (starter kit)

1 double-chamber cartridge with dry substance and 1 ml 0.9% sterile sodium chloride solution.

1 injection needle 29G x ? (0.33 mm x 12.7 mm)

1 alcohol swab to be obtained for each injection.

1. Cartons containing one colourless glass double-chamber cartridge, one injection needle 29 G x ? (0.33 mm x 12.7 mm) and one reusable injector (starter kit).

2. Cartons containing two colourless glass double-chamber cartridges, two injection needles 29 G x ? (0.33 mm x 12.7 mm) and one reusable injector (starter kit).

3. Cartons containing one, two or six colourless glass double-chamber cartridges and corresponding number of injection needles 29 G x ? (0.33 mm x 12.7 mm) without reusable injector.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Fix the injection needle onto the front part of the injector.

Disinfect the tip of the cartridge with one of the alcohol swabs. Insert the cartridge into the reusable injector and fix it by screwing the thread part. Dissolve the drug substance in the front chamber of the cartridge by completely screwing the thread-part into the injector thus moving both rubber stoppers to the top of the cartridge and allowing the solvent in to the bottom chamber to reach the dry substance via the bypass of the cartridge. Shake slightly until a clear solution is produced.

Expel the air and adjust the prescribed dosage precisely prior to intracavernous injection.

After preparation of the solution, the injection must be performed using aseptic procedures into either the left or right cavernous body of the penile shaft. Care should be taken not to inject into penile vessels or nerves on the upper side of the penis and into the urethra on the under side. The injection should be completed within 5 to 10 seconds and manual pressure should be applied to the injection site for 2 to 3 minutes.

Unused solution must be discarded immediately.

Advice

The content of the front chamber of the cartridge consists of a white, dry powder, which forms a compact layer, approximately 8 mm in height. The layer may show cracks and crumble slightly.

In case of damage to the cartridge, the usually dry content of the front chamber becomes moist and sticky and extensively loses volume. Viridal Duo must not be used in this case.

The bottom chamber contains the clear, colourless sodium chloride solvent solution.

The dry substance dissolves immediately after addition of the sodium chloride solution. Initially after reconstitution the solution may appear slightly opaque due to the presence of bubbles. This is of no relevance and disappears within a short time to give a clear solution.

Disposal of needle: disable needle then dispose of in a sharps container.

Disposal of cartridge: no special requirements.

7. Marketing Authorisation Holder

UCB Pharma Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

United Kingdom

8. Marketing Authorisation Number(S)

PL 00039/0753

9. Date Of First Authorisation/Renewal Of The Authorisation

3rd September 2010

10. Date Of Revision Of The Text

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Read all of this leaflet carefully before you start using this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet 1. What Octreotide Mayne is and what it is used for 2. Before you use Octreotide Mayne 3. How to use Octreotide Mayne 4. Possible side effects 5. How to store Octreotide Mayne 6. Further information What Octreotide Mayne is and what it is used for

Octreotide Mayne is a synthetic version of a hormone that occurs naturally in the body, called somatostatin. Octreotide inhibits the release of growth hormone and some gut hormones and secretions.

Octreotide Mayne is used:

To treat the symptoms that occurs with hormone producing gastrointestinal tumours. These symptoms are associated with the over-production of some of the body's natural substances which may result in an imbalance of your natural hormone levels. This imbalance may cause a variety of symptoms in the stomach, pancreas or intestines (gut). To reduce the levels of growth hormone and Insulin-like growth factor number 1 (IGF-1) if you have acromegaly and to improve symptoms that you may have due to over-production of these hormones. Prior to having an operation on the pancreas, to prevent further complications. Before you use Octreotide Mayne Octreotide Mayne should not be used if you are: allergic to octreotide or any of the ingredients in Octreotide Mayne (see Section 6). Special care will be taken: as Octreotide may affect your blood sugar levels. You or your doctor should closely monitor your blood sugar levels. if you have a tumour (growth) that produces insulin (insulinoma). You or your doctor should closely monitor your blood sugar levels. if you have any thyroid problems if you have gallstones if you have liver disease if you are pregnant or planning to become pregnant. If you do become pregnant, tell your doctor immediately. if you are breast-feeding Taking other medicines:

Please tell your doctor if you are taking any of the following medicines;

ciclosporin (a drug used after a transplant) cimetidine (a drug used to reduce stomach acid) bromocriptine (a drug used in Parkinson's disease or in acromegaly or to suppress breast milk) terfenadine (to relieve allergic symptoms) carbamazepine (a drug used in psychiatric disorders, epilepsy, trigeminal neuralgia and neuropathy) digoxin (medicine for certain heart problems) warfarin (a drug used to thin the blood)

Other medicines that are metabolised by the liver can also be affected, so tell your doctor or pharmacist about all the medicines you are taking.

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Ask your doctor or pharmacist for advice before taking any medicine. You should not use Octreotide if you are pregnant, unless you have been told by your doctor that it is absolutely necessary for you to do so.

You should not breastfeed your infant whilst receiving treatment with Octreotide, unless you have been told to do so.

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Always use Octreotide exactly as your doctor has told you. You should check with your doctor or pharmacist if you are unsure of anything.

A doctor or nurse will usually give you this medicine.

The medicine will be given to your either as a subcutaneous injection (underneath the skin) or as a slow intravenous injection (via a drip into the vein).

The usual dosages are given below; however your doctor will decide what dosage to give to you, as this depends on the nature of your treatment, your age and your medical condition:

To treat the symptoms that occur with hormone producing gastrointestinal tumours: 50 micrograms each 24 hours or each 12 hours, depending on your response, the dose may be increased to 100 to 200 micrograms every 8 hours. The usual recommended maximum daily dosage is 600 micrograms. If you have acromegaly: initial doses of 50 to 100 micrograms, every 8 hours. For most patients the dosage is 200 to 300 micrograms per day and the maximum daily dosage is 1500 micrograms. Prior to having an operation on the pancreas: 100 micrograms every 8 hours for 7 days, starting on the day of the operation.

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If you use more Octreotide Mayne than advised: if you think you have had too much Octreotide, tell your doctor or nurse immediately.

Octreotide Mayne Side Effects

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These are very serious side effects. You may need urgent medical attention. These side effects are rare (occur in less than 1 in 1000 patients but more than 1 in 10,000).

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Common (occurs in less than 1 in 10 patients but more than 1 in 100):

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severe loss of appetite (anorexia) being sick epigastric pain (pain in upper part of stomach)

Rare (occurs in less than 1 in 1000 patients but more than 1 in 10,000):

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Medicines should not be disposed of via wastewater or household waste. These measures will help to protect the environment.

Other information

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The vials also contain Glacial Acetic Acid, Sodium Acetate Trihydrate, Sodium Chloride and Water for Injections. The multi-dose vials additionally contain Phenol (a preservative).

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The vials may be overwrapped with a protective plastic to minimise the risk of spillage if the vials break; these vials are referred to as ONCO-TAIN.

Marketing authorisation holder and manufacturer: Mayne Pharma Plc Queensway Royal Leamington Spa Warwickshire CV31 3RW United Kingdom

This leaflet was last approved in June 2007

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Pegvisomant

Read all of this leaflet carefully before you start using this medicine. Keep this leaflet. You may need to read it again If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What SOMAVERT is and what it is used for 2. Before you use SOMAVERT 3. How to use SOMAVERT 4. Possible side effects 5. How to store SOMAVERT 6. Further information What Somavert Is And What It Is Used For

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SOMAVERT is a product of biotechnology. The active substance in SOMAVERT, pegvisomant is known as a growth hormone receptor antagonist. These substances decrease the action of GH and levels of IGF-I circulating in the blood.

Before You Use Somavert Do not use SOMAVERT If you are allergic (hypersensitive) to pegvisomant or to any of the other ingredients of SOMAVERT. Take special care with SOMAVERT: If you experience disturbed vision or headaches while using SOMAVERT you must contact your doctor immediately. Your doctor or nurse will monitor the levels of IGF-I (Insulin-like growth factors) circulating in the blood and adjust the dose of SOMAVERT if necessary. Your doctor should also monitor your adenoma (benign tumour). Your doctor or nurse will monitor the level of liver enzymes in the blood every 4-6 weeks for the first six months of treatment with SOMAVERT. Administration of SOMAVERT should be discontinued if signs of liver disease persist. If you are diabetic, your doctor may need to adjust the amount of insulin or other medicines you are using. Female patients should use adequate contraception as fertility may be increased. See also the section about Pregnancy below. Using other medicines

You must tell your doctor if you have previously used other medicines for the treatment of acromegaly or medicines for the treatment of diabetes.

Please tell your doctor or pharmacist if you are using or have recently used any other medicines, including medicines obtained without a prescription.

As part of your treatment you may be given other medicines. It is important to keep using all your medicines as well as SOMAVERT unless you are told otherwise by your doctor or pharmacist.

Pregnancy and breast-feeding:

The effects of SOMAVERT in pregnant women are not known, and so the use of SOMAVERT in pregnant women is not recommended. You are advised to not become pregnant while taking SOMAVERT therapy. In case you become pregnant, you must consult your doctor. Ask your doctor or pharmacist for advice before taking any medicine.

It is not known if SOMAVERT passes into breast milk. You should not breast-feed while taking SOMAVERT unless your doctor has discussed this with you.

Driving and using machines:

No studies on the effects on the ability to drive and use machines have been performed.

Important information about some of the ingredients of SOMAVERT

This medicinal product contains less than 1 mmol sodium (23 mg) per 10 mg dose, less than 1 mmol sodium (23 mg) per 15 mg dose, or less than 1 mmol sodium (23 mg) per 20 mg dose i.e. essentially ‘sodium-free’.

How To Use Somavert

Always inject SOMAVERT exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

A starting dose of 80 mg of SOMAVERT will be given subcutaneously (just under the skin) by your doctor. Following this, the usual daily dose of SOMAVERT is 10 mg, which is given by subcutaneous injection (just under the skin).

Every four to six weeks your doctor will make appropriate dose adjustments, made in increments of 5 mg pegvisomant/day, based on your so-called serum IGF-I levels to maintain an optimal therapeutic response.

Method and route of administration

SOMAVERT is injected under the skin. The injection can be self-administered or given by another person, for example your doctor or his/her assistant. The detailed instructions on injection procedure provided at the end of this leaflet must be followed. You should continue to inject SOMAVERT for as long as instructed by your doctor.

SOMAVERT must be dissolved before use. The injection must not be mixed in the same syringe or vial as any other medicine.

Fatty tissue of the skin can build-up at the site of injection. To avoid this, use a slightly different place for your injection each time, as described in Step 2 of the ‘Instructions for Preparing and Giving an Injection of Somavert’ section of this leaflet. This gives your skin and the area under your skin time to recover from one injection before it receives another one in the same place.

If you have the impression that the effect of SOMAVERT is too strong or too weak, talk to your doctor or pharmacist.

If you inject more SOMAVERT than you should

If you accidentally inject more SOMAVERT than told to by your doctor it is unlikely to be serious, but you should contact your doctor or pharmacist immediately.

If you forget to use SOMAVERT

If you forget to give yourself an injection you should inject the next dose as soon as you remember and then continue to inject SOMAVERT as prescribed by your doctor. Do not inject a double dose to make up for forgotten individual doses

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines SOMAVERT can cause side effects, although not everybody gets them

Common side effects (likely to occur in fewer than 1 in 10 patients) include: Headache, dizziness, sleepiness, uncontrolled trembling. Diarrhoea, constipation, feeling sick, being sick, feeling bloated, indigestion, gas. Sweating, itching, rash. Joint pain, muscle pain, swelling of the extremities. Increased blood cholesterol, weight gain, increased blood glucose, increased appetite. Increased blood pressure. Bruising or bleeding at injection site, soreness or swelling at injection site, build up of fat below the surface of the skin at injection site. Flu-like illness, fatigue. Increased levels of substances that measure the function of the liver. These can be seen in the results of blood tests. Abnormal dreams, problems sleeping. Uncommon side effects (likely to occur in fewer than 1 in 100 patients) include: Decreased platelets in the blood, increased or decreased white cells in the blood, tendency to bleed. Decreased sense of touch, abnormal sense of taste, migraine. Eyestrain, eye pain, inner ear problems. Shortness of breath. Dry mouth, increased saliva, tooth problems, hemorrhoids. Blood in the urine, protein in the urine, increased urine, kidney problems. Facial swelling, dry skin, tendency to bruise, night sweats. Arthritis. Increased fatty substances in the blood, decreased blood glucose. Fever, weakness, feeling abnormal, impaired healing. Anger, lack of interest, feeling confused, increased sex drive, panic attack, loss of memory.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

About 17% of patients will develop antibodies to growth hormone during treatment. The antibodies do not seem to stop SOMAVERT from working.

How To Store Somavert

Keep out of the reach and sight of children

Do not use SOMAVERT after the expiry date which is stated on the vial and the carton after EXP. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C) Do not freeze. Keep the vials in the outer carton in order to protect from light.

After preparing the SOMAVERT solution it must be used immediately. Carefully dispose of any SOMAVERT solution that has not been injected.

Do not use SOMAVERT if you notice that the solution is cloudy or contains particulate matter.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment

Further Information What SOMAVERT contains The active substance is pegvisomant. One vial of powder contains either10 mg, 15 mg, or 20 mg. After reconstitution with 1 ml of solvent, 1 ml of the clear solution contains either 10 mg, 15 mg, or 20 mg pegvisomant. The other ingredients are glycine, mannitol (E421), sodium phosphate dibasic anhydrous and sodium phosphate monobasic monohydrate. The solvent is water for injections. One vial of solvent contains 8 ml water for injections. What SOMAVERT looks like and contents of the pack

SOMAVERT is presented as a powder and a solvent for injection, in a vial. Powder in a vial (either10 mg, 15 mg, or 20 mg pegvisomant) and solvent in a vial (8 ml). Pack sizes of 1 and 30. Not all pack sizes are marketed. The powder is white and the solvent is clear and colourless.

Marketing Authorisation holder: Pfizer Limited Sandwich Kent CT13 9NJ United Kingdom Manufacturer: Pfizer Manufacturing Belgium NV Rijksweg 12 2870 Puurs Belgium

For any information about this medicine product, please contact the local representative of the Marketing Authorisation Holder.

United Kingdom Pfizer Limited Tel:+44 (0)1737 331111

This leaflet was last approved on: December 2007

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.europa.eu. There are also links to other websites about rare diseases and treatments

Instructions For Preparing And Giving An Injection Of Somavert Introduction

The following instructions explain how to prepare and inject SOMAVERT. Please read the instructions carefully and follow them step by step. You will be instructed by your doctor or his/her assistant on the technique of self-injection. Do not attempt to self-inject until you are sure that you understand how to prepare and give an injection.

The powder must be dissolved with the solvent before use.

This injection should not be mixed in the same syringe or vial with any other medicine.

Step 1. Choosing The Method For Preparing The Somavert Solution

There are 2 methods for preparing the SOMAVERT solution. Please discuss with your healthcare professional which method is best for you:

a) The Vial Adapter Method (MIXJECT), b) The Non-Vial Adapter Method. a) VIAL ADAPTER METHOD (MIXJECT)

GETTING STARTED

Wash your hands thoroughly. Collect: 1 vial of powder (SOMAVERT), 1 vial of solvent (Water for Injections), 1 luer-lock syringe of 1ml (for both reconstituting the SOMAVERT solution and giving the injection) is recommended. However, other sizes and types of syringes can be used for the preparation and injection of SOMAVERT. Please consult your healthcare professional for further information. 2 MIXJECT vial adapters, 1 detachable needle (25 to 30 gauge), Alcohol or antiseptic swabs and a proper disposal container for used needles and syringes. Inspect the expiry dates on both the vial label and the syringe label. They should not be used after the month and year shown.

After reconstitution with 1 ml of solvent, 1 ml of the clear solution contains either 10 mg, 15 mg, or 20 mg pegvisomant.

PREPARING THE SOMAVERT DOSE FOR INJECTION

1. Remove the protective plastic caps from the tops of both vial of solvent and vial of SOMAVERT (Fig. 1). Take care not to touch the rubber vial stoppers. At this point, the stoppers are clean. If the stoppers are touched or otherwise contaminated, you must clean them with an antiseptic or alcohol swab before inserting a vial adapter through the stopper.
2. Open only one of the vial adapters by peeling back the protective cover. Leave the adapter in the plastic packaging and do not touch the spike of the adapter. 3. While holding the plastic adapter packaging, place the adapter over the solvent vial and insert the piercing spike of the vial adapter all the way in through the rubber stopper of the solvent vial, using a pushing motion. (Fig. 2). Remove the plastic packaging from the vial adapter and discard. 4. Remove the syringe from the protective packaging. Pull the plunger of the syringe out to the 1 ml mark. Hold the solvent vial, placed on a flat surface, with one hand and connect the tip of the syringe to the vial adapter by twisting the syringe on the vial adapter clockwise (Fig. 3). Gently push the plunger until the air is injected into the vial.

ADDING SOLVENT

5. Securely grasp the solvent vial, adapter and syringe assembly. Carefully turn the vial, adapter and syringe assembly upside down. Bring to eye level (Fig. 4).
6. Slide one hand carefully down the solvent vial so that with your thumb and forefinger you can securely grasp the neck of the vial, and with your other fingers, the upper part of the syringe. With the other hand, slowly pull the syringe plunger down to slightly past the 1 ml mark.

Examine the solution in the syringe for air bubbles. If bubbles are present, tap the syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger up to eject only the air bubbles back into the vial. Recheck that 1 ml of solvent remains in the syringe.

Carefully turn the solvent vial, adapter and syringe assembly and place them upright on a clean surface. Do not remove the syringe from the adapter at this point.

7. As explained for the first vial adapter, open now the second vial adapter by peeling back the protective cover. Do not touch the vial adapter. Do not remove the adapter from the plastic packaging. While holding the plastic adapter packaging, place the adapter over the SOMAVERT vial and insert the piercing spike of the vial adapter all the way in through the rubber stopper of the SOMAVERT vial, using a pushing motion (Fig. 5). Remove the plastic packaging from the vial adapter and discard. 8. Disconnect the syringe from the solvent vial adapter and attach it to the vial adapter on the vial of SOMAVERT. Tilt the vial of SOMAVERT, adapter and syringe assembly to the side and gently inject the solvent down the inner side of the vial of SOMAVERT (Fig 6). Discard the solvent vial as directed by your healthcare provider. 9. Hold the vial of SOMAVERT with the adapter and syringe still attached upright between your hands and gently roll it to dissolve the powder (Fig. 7). DO NOT SHAKE THE VIAL. The solution should be clear after the powder is dissolved. If the solution is cloudy or hazy, do not inject it. Notify your pharmacy and request a replacement vial. Do not throw the vial away because the pharmacy may request that you return it.

PREPARING THE INJECTION

10. Securely grasp the vial containing the SOMAVERT reconstituted solution, vial adapter and syringe assembly. Carefully turn the vial, adapter and syringe assembly upside down. Bring to eye level. 11. As before, slide one hand carefully down the vial so that with your thumb and forefinger you can securely grasp the neck of the vial, and with your other fingers, the upper portion of the syringe. With the other hand, slowly pull the syringe plunger down to withdraw the full contents of the vial (1 ml). (Fig.8).

Visually inspect the syringe for air bubbles. If bubbles are present, tap the syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger up to eject only the air bubbles back into the vial. Recheck that 1 ml of the solution remains in the syringe. Carefully turn the vial containing the SOMAVERT reconstituted solution, adapter and syringe assembly and place them upright on a clean surface. Do not remove the syringe from the adapter at this point.

12. Open the needle packaging so that only the end of the needle to be connected to the syringe is exposed. The needle should be partially left in its protective packaging. Lay the needle with its protective packaging on the tabletop. Disconnect the syringe from the vial. Discard the protective packaging and attach the needle to the syringe. Keep the plastic cap on the needle while preparing the site for injection (Fig. 9). Once reconstituted, SOMAVERT should be used immediately. Please proceed to “STEP 2. GIVING THE INJECTION” b) NON VIAL ADAPTER METHOD

Getting Started

Wash your hands thoroughly. Collect one vial of powder (SOMAVERT) and one vial of solvent (Water for Injections), one 3-ml syringe with a 21-gauge, 1-inch detachable needle, one standard 1 ml insulin syringe, alcohol or antiseptic swabs and a proper disposal container for used needles. Inspect the expiry dates on both the vial label and the syringe label. They should not be used after the month and year shown.

After reconstitution with 1 ml of solvent, 1 ml of the clear solution contains either 10 mg, 15 mg, or 20 mg pegvisomant.

Preparing the SOMAVERT dose for injection

Remove the protective plastic caps from the tops of both vials. Take care not to touch the rubber vial stoppers. At this point, the stoppers are clean. If the stoppers are touched or otherwise contaminated, you must clean them with an antiseptic or alcohol swab before inserting a needle through the stopper.

Carefully remove the cap from the needle of the larger syringe (3 ml) and set the cap aside. This is the solvent syringe.

1. Pull the plunger of the solvent syringe down to the 1 ml mark. With one hand, securely hold the vial of solvent and, with the other hand, insert the needle of the solvent syringe straight through the center of the rubber stopper and deep into the vial. Gently push the plunger until the air is injected into the vial. (Fig. 1)

ADDING SOLVENT

2. Securely grasp the solvent vial and syringe assembly, with the needle still deeply inserted into the vial. Carefully turn the vial and syringe assembly upside down. Bring to eye level. (Fig. 2) 3. Slide one hand carefully down the solvent vial so that with your thumb and forefinger you can securely grasp the neck of the vial, and with your other fingers, the upper part of the syringe. With the other hand, slowly pull the syringe plunger down to slightly past the 1 ml mark.

Examine the solution in the syringe for air bubbles. If bubbles are present, tap the syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger up to eject only the air bubbles back into the vial. Recheck that 1 ml of solvent remains in the syringe, then withdraw the needle from the vial. (Fig 3)

4. Insert the needle of the solvent syringe straight through the stopper of the vial with the powder (SOMAVERT). Tilt the syringe to the side and gently inject the solvent down the inner side of the vial of SOMAVERT. When the solvent syringe is empty, withdraw it from the vial. Discard the solvent vial, syringe, and needle as directed by your healthcare provider. To minimise accidental injury, recap the needle only if instructed to do so by your healthcare provider, and in the manner demonstrated to you by your healthcare provider. (Fig 4) 5. Hold the vial of SOMAVERT upright between your hands and gently roll it to dissolve the powder. DO NOT SHAKE THE VIAL. The solution should be clear after the powder is dissolved. If the solution is cloudy or hazy, do not inject it. Notify your pharmacy and request a replacement vial. Do not throw the vial away because the pharmacy may request that you return it. Inject SOMAVERT immediately. (Fig. 5)

PREPARING THE INJECTION

6. Clean the rubber stopper of the vial of SOMAVERT with an antiseptic or alcohol swab. Remove the cap from the syringe (1 ml). Pull the syringe plunger down to the 1-ml mark. With one hand, securely hold the vial. With the other hand, insert the needle straight through the center of the rubber stopper and deep into the vial. Gently push the plunger until the air is injected into the vial. Securely grasp the vial and syringe assembly, with the needle still deeply inserted into the vial. Carefully turn the vial and syringe assembly upside down. Bring to eye level. (Fig. 6) 7. As before, slide one hand carefully down the vial so that with your thumb and forefinger you can securely grasp the neck of the vial, and with your other fingers, the upper portion of the syringe. With the other hand, slowly pull the syringe plunger down to withdraw the full contents of the vial (1 ml). To keep the needle tip within the liquid, you may have to slowly back it out of the stopper as you draw out the liquid.

Visually inspect the syringe for air bubbles. If bubbles are present, tap the syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger up to eject only the air bubbles back into the vial. Recheck that 1 ml of the solution remains in the syringe, then withdraw the needle from the vial.

Recap the needle as directed by your health care provider to minimise accidental injury while preparing the site for injection. (Fig. 7)

GIVING THE INJECTION

Choose an injection site on the upper arm, upper thigh, abdomen or buttocks. Always move on to a different area with each day’s injection. It may be helpful to keep a record of each day’s injection site as you take your daily dose of SOMAVERT. Do not use an area that has a rash or broken skin, or is bruised or lumpy.

Clean the site with an antiseptic or alcohol swab, let the skin dry before injecting the product. Uncap the needle if previously recapped.

8. With one hand, gently pinch up the skin at the site of injection. Hold the syringe with the other hand, and in a single, smooth motion, push the needle completely into the skin straight down (at a 90-degree angle). (Fig. A) 9. Be sure to keep the needle all the way into the skin while you slowly push the syringe plunger down until the barrel is empty.

Release the pinched skin and pull the needle straight out. (Fig. B)

10. Do not rub the injection area. A small amount of bleeding may occur. If necessary, apply a clean, dry cotton swab over the area and press gently for 1 or 2 minutes, or until the bleeding has stopped. (Fig. C) Disposing of Supplies

The syringe and needle should NEVER be reused. Dispose of the needle and syringe as instructed by your doctor, nurse or pharmacist.

All questions should be handled by a doctor, nurse or pharmacist familiar with SOMAVERT.

Read More:

Metalyse 8,000 units

Metalyse

8,000 units powder and solvent for solution for injection

Tenecteplase

Read all of this leaflet carefully before you start receiving this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet:

1. What METALYSE is and what it is used for
2. Before you receive METALYSE
3. How is METALYSE administered
4. Possible side effects
5. How to store METALYSE
6. Further information

What Metalyse Is And What It Is Used For

METALYSE is a powder and solvent for solution for injection. This means that each pack contains:

one vial of 8,000 units METALYSE powder and one pre-filled syringe containing 8 ml water for injections.

Before use, the solvent (water for injections) is added to the powder to form a solution that is given by injection.

METALYSE belongs to a group of medicines called thrombolytic agents. These medicines help to dissolve blood clots. Tenecteplase is a recombinant fibrin-specific plasminogen activator.

METALYSE is used to treat myocardial infarctions (heart attacks) within 6 hours after the onset of symptoms and helps to dissolve the blood clots that have formed in the blood vessels of the heart. This helps to prevent the damage caused by heart attacks and has been shown to save lives.

Before You Receive Metalyse

METALYSE will not be prescribed and given by your doctor

if you have previously had a sudden life-threatening allergic reaction (severe hypersensitivity) to the active ingredient tenecteplase, to gentamicin (a trace residue from the manufacturing process) or any of the other ingredients of METALYSE. If treatment with Metalyse is nevertheless considered to be necessary, facilities for reanimation should be immediately available in case of need; if you have, or have recently had, an illness that increases your risk of bleeding (haemorrhage), including: a bleeding disorder or tendency to bleed (haemorrhage) stroke (cerebrovascular event) very high, uncontrolled blood pressure a head injury severe liver disease a stomach ulcer (peptic ulcer) varicose veins in the gullet (oesophageal varices) abnormality of the blood vessels (e.g. an aneurysm) certain tumours inflammation of the lining around the heart (pericarditis); inflammation or infection of the heart valves (endocarditis); if you are taking tablets/capsules used to “thin” the blood, such as warfarin or coumarin (anti-coagulants); if you have an inflamed pancreas (pancreatitis); if you have recently had major surgery including surgery to your brain or spine; if you have been given cardiopulmonary resuscitation (chest compressions) for more than 2 minutes duration, in the last two weeks. Your doctor will take special care with METALYSE if you have had any allergic reaction other than a sudden life-threatening allergic reaction (severe hypersensitive) to the active substance tenecteplase, to gentamicin (a trace residue from the manufacturing process), or to any of the other ingredients of Metalyse (see section 6: “Further information”); if you have high blood pressure; if you have problems with circulation of blood in the brain (cerebrovascular disease); if you have had gastrointestinal (gut) or genitourinary bleeding within the last ten days (this may cause blood in stools or urine); if you have a heart valve abnormality (e.g. mitral stenosis) with an abnormal heart rhythm (e.g. atrial fibrillation); if you have had an intramuscular injection in the last two days; if you are aged over 75 years; if you weigh less than 60 kg. Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Ask your doctor for advice before you are given METALYSE.

How Is Metalyse Administered

The doctor calculates your dose of METALYSE according to your bodyweight, based on the following scheme:

Bodyweight less than 60kg 6,000 units

Bodyweight 60 to 70kg 7,000 units

Bodyweight 70 to 80kg 8,000 units

Bodyweight 80 to 90kg 9,000 units

Bodyweight above 90kg 10,000 units

Your doctor will give you medication to prevent blood clotting in addition to METALYSE, as soon as possible after your chest pain starts.

METALYSE is given by a single injection into a vein by a doctor who is experienced in the use of this type of drug.

Your doctor will give METALYSE as soon as possible after your chest pain starts as a single dose.

Repetition is not recommended.

Possible Side Effects

Like all medicines, METALYSE can cause side effects, although not everybody gets them.

Evaluation of side effects is based on the following frequencies:

very common: affects more than 1 user in 10

common: affects 1 to 10 users in 100

uncommon: affects 1 to 10 users in 1,000

rare: affects 1 to 10 users in 10,000

very rare: affects less than 1 user in 10,000

not known: frequency cannot be estimated from the available data

The side effects described below have been experienced by people given METALYSE:

Very Common:

bleeding

Common:

bleeding at the injection or puncture site nosebleeds genitourinary bleeding (you may notice blood in your urine) bruising gastro-intestinal bleeding (e.g. bleeding from the stomach or bowel)

Uncommon:

irregular heart beat (reperfusion arrhythmias), sometimes leading to cardiac arrest internal bleeding in the abdomen (retroperitoneal bleeding) bleeding in the brain (cerebral haemorrhage). Death or permanent disability may occur following bleeding in the brain or other serious bleeding events bleeding in the eyes (eye haemorrhage)

Rare:

low blood pressure (hypotension) bleeding in the lungs (pulmonary haemorrhage) hypersensitivity (anaphylactoid reactions) e.g. rash, hives (urticaria), swelling of the throat bleeding into the area surrounding the heart (haemopericardium) blood clot in the lung (pulmonary embolism) and in the vessels of other organ systems (thrombotic embolisation)

Not known :

fat embolism (clots consisting of fat) nausea vomiting body temperature increased (fever) blood transfusions as consequence of bleedings

As with other thrombolytic agents, the following events have been reported as sequelae of myocardial infarction and/or thrombolytic administration:

Very common:

Low blood pressure (hypotension) Irregular heart beat Chest pain (angina pectoris)

Common:

Further heart attack (recurrent ischaemia) Heart failure Shock due to heart failure Inflammation of the lining around the heart Fluid in the lungs (pulmonary oedema)

Uncommon:

Heart arrest Problem with the heart valve or heart lining (mitral valve incompetence, pericardial effusion) Blood clot in the veins (venous thrombosis) Fluid between the heart lining and the heart (cardiac tamponade) Rupture of the heart muscle (myocardial rupture)

Rare:

Blood clot in the lung (pulmonary embolism)

These cardiovascular events can be life-threatening and may lead to death.

In case of bleeding in the brain events related to the nervous system have been reported e.g. drowsiness (somnolence), speech disorders, palsy of parts of the body (hemiparesis) and fits (convulsions).

Tell your doctor immediately if you think you are experiencing any of these side effects.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Metalyse

Keep out of the reach and sight of children.

Do not store above 30°C.

Keep the container in the outer carton in order to protect from light.

Once METALYSE has been reconstituted it may be stored for 24 hours at 2-8°C and 8 hours at 30°C. However, for microbiological reasons your doctor will normally use the reconstituted solution for injection immediately.

Do not use METALYSE after the expiry date which is stated on the label/carton.

Further Information What METALYSE contains The active substance is tenecteplase. One vial contains 8,000 units of tenecteplase. One pre-filled syringe contains 8 ml of water for injections. The other ingredients are L-arginine, phosphoric acid and polysorbate 20. The METALYSE solvent is water for injections. Gentamicin is contained as trace residue from the manufacturing process. What METALYSE looks like and contents of the pack

The folding box contains one vial with a lyophilised powder, one ready for use syringe with a solvent, one vial adapter and one needle.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH Binger Strasse 173 D-55216 Ingelheim am Rhein Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG Birkendorfer Strasse 65 D-88397 Biberach/Riss Germany

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

United Kingdom Boehringer Ingelheim Ltd. Tel:+44 1344 424 600

This leaflet was last approved in 06/2010

Detailed information on this medicine is available on the European Medicines Agency (EMA) web site: http://www.ema.europa.eu

74366-01

Read More:

Simulect 10mg powder and solvent for solution for injection or infusion

Simulect 10 mg powder and solvent for solution for injection or infusion

Basiliximab

Read all of this leaflet carefully before you are given this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor, nurse or pharmacist. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist. In this leaflet: 1. What Simulect is and what it is used for 2. Before you are given Simulect 3. How Simulect is given to you 4. Possible side effects 5. How to store Simulect 6. Further information What Simulect Is And What It Is Used For

Simulect belongs to a group of medicines called immunosuppressants. It is given in hospital to adults, adolescents and children who are having a kidney transplant. Immunosuppressants reduce the body’s response to anything that it sees as "foreign" – which includes transplanted organs. The body’s immune system thinks a transplanted organ is a foreign body and will try to reject it. Simulect works by stopping the immune cells that attack transplanted organs.

You will only be given two doses of Simulect. These will be given in hospital, around the time of your transplant operation. Simulect is given to stop your body from rejecting the new organ during the first 4 to 6 weeks after the transplant operation, when rejection is most likely. You will be given other medicines to help protect your new kidney during this time, such as ciclosporin and corticosteroids and after you leave hospital.

Before You Are Given Simulect

Follow your doctor’s instructions carefully. If you are unsure about anything, ask your doctor, nurse or pharmacist.

You must not be given Simulect if you are allergic (hypersensitive) to basiliximab or any of the other ingredients of Simulect listed in section 6 under "What Simulect contains". Tell your doctor if you suspect you may have had an allergic reaction to any of these ingredients in the past. if you are pregnant or breast-feeding. Take special care with Simulect if you have previously received a transplant that failed after only a short time or, if you have previously been in the operating theatre for a transplantation that in the end was not performed.

In this situation, you may have received Simulect. Your doctor will check this for you and discuss with you the possibility of repeated treatment with Simulect.

Using other medicines

Please tell your doctor, nurse or pharmacist if you are using or have recently used any other medicines, including medicines obtained without a prescription.

Older patients (aged 65 years and over)

Simulect can be given to older patients, but the information available is limited. Your doctor may discuss this with you before you are given Simulect.

Children and adolescents (aged 1 to 17 years)

Simulect can be given to children and adolescents. The dose for children who weigh less than 35 kg will be smaller than the dose usually given to adults.

Pregnancy and breast-feeding

It is very important to tell your doctor before your transplant if you are pregnant or you think that you may be pregnant. You must not be given Simulect if you are pregnant. You must use adequate contraception to prevent pregnancy during treatment and up to 4 months after receiving the last dose of Simulect. If you become pregnant during this time, despite the use of contraceptive measures, you should tell your doctor immediately.

You should also tell your doctor if you are breast-feeding. Simulect may harm your baby. You must not breast-feed after being given Simulect or up to 4 months after the second dose.

Ask your doctor, nurse or pharmacist for advice before taking any medicine while you are pregnant or breast-feeding.

Driving and using machines

There is no evidence to indicate that Simulect has an effect on your ability to drive a car or use machines.

How Simulect Is Given To You

You will only be given Simulect if you are receiving a new kidney. Simulect is given twice, in hospital, either slowly through a needle in your vein as an infusion lasting 20–30 minutes or as an intravenous injection using a syringe.

If you have experienced a severe allergic reaction to Simulect or if you had complications after your surgery such as graft loss, the second dose of Simulect should not be given to you.

The first dose is given just before the transplant operation, and the second dose 4 days after the operation.

Usual dose for children and adolescents (aged 1 to 17 years) For children and adolescents who weigh less than 35 kg, the dose of Simulect given in each infusion or injection is 10 mg. For children and adolescents who weigh 35 kg or more, the dose of Simulect given in each infusion or injection is 20 mg. Usual dose for adults

The usual dose for adults is 20 mg in each infusion or injection.

If you are given too much Simulect

An overdose of Simulect is not likely to cause side effects straight away, but it may weaken your immune system for longer. Your doctor will watch out for any effects on your immune system and treat them if necessary.

Possible Side Effects

Like all medicines, Simulect can cause side effects, although not everybody gets them.

Tell your doctor or nurse as soon as possible if you get any unexpected symptoms while you are being given Simulect, or during the 8 weeks afterwards, even if you do not think that they are related to the medicine.

Sudden severe allergic reactions have been reported in patients treated with Simulect. If you notice sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, fast heart beat, dizziness, light headedness, shortness of breath, wheezing or trouble breathing or flu-like symptoms, tell your doctor or nurse immediately.

In children, the most commonly reported side effects were constipation, excessive growth of normal hair, runny or blocked nose, fever, high blood pressure, and various kinds of infections.

In adults, the most commonly reported side effects were constipation, nausea, diarrhoea, weight increase, headache, pain, swelling of hands, ankles or feet, high blood pressure, anaemia, changes in blood chemistry (e.g. potassium, cholesterol, phosphate, creatinine), surgical wound complications, and various kinds of infections.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse.

How To Store Simulect

Store in a refrigerator (2°C - 8°C).

Keep out of the reach and sight of children.

Further Information What Simulect contains The active substance is basiliximab. Each vial contains 10 mg of basiliximab. The other ingredients are: potassium dihydrogen phosphate; disodium phosphate, anhydrous; sodium chloride; sucrose; mannitol (E421); glycine. What Simulect looks like and contents of the pack

Simulect comes as a white powder in a colourless glass vial containing 10 mg of basiliximab. It is supplied in a pack with a colourless glass ampoule containing 5 ml sterile water for injections. 2.5 ml of the sterile water is used to dissolve the powder before it is given to you.

Simulect is also available in vials with 20 mg basiliximab.

Marketing Authorisation Holder Novartis Europharm Limited Wimblehurst Road Horsham West Sussex RH12 5AB United Kingdom Manufacturer Novartis Pharma S.A.S. 26, rue de la Chapelle F-68333 Huningue France

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

United Kingdom Novartis Pharmaceuticals UK Ltd. Tel:+44 1276 698370

This leaflet was last approved in 10 / 2008

Read More:

ACWY Vax Vaccine

1. Name Of The Medicinal Product

ACWY Vax - powder and solvent for solution for injection in a pre-filled syringe

Meningococcal polysaccharide groups A, C, Y and W135 vaccine

2. Qualitative And Quantitative Composition

After reconstitution, 1 dose (0.5 ml) contains:

 

Neisseria meningitidis group A polysaccharide

50 µg

Neisseria meningitidis group C polysaccharide

50 µg

Neisseria meningitidis group Y polysaccharide

50 µg

Neisseria meningitidis group W135 polysaccharide

50 µg

For a full list of excipients, see section 6.1.

  3. Pharmaceutical Form

Powder and solvent for solution for injection in a pre-filled syringe.

The powder is white. The solvent is clear and colourless.

4. Clinical Particulars 4.1 Therapeutic Indications

Active immunisation of children older than 2 years, adolescents and adults against invasive meningococcal disease caused by meningococci of groups A, C, W135 and Y.

ACWY Vax should be used in accordance with available official recommendations.

4.2 Posology And Method Of Administration

Posology

One dose of 0.5 ml.

Subjects who remain at increased risk of invasive meningococcal disease may be revaccinated at intervals (see persistence of immune response in Section 5.1). Intervals should be in accordance with available official recommendations.

Method of administration

ACWY Vax is for deep subcutaneous injection only.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients.

Hypersensitivity after previous administration of ACWY Vax.

As with other vaccines, the administration of ACWY Vax should be postponed in subjects suffering from acute severe febrile illness. The presence of a minor infection, such as a cold, is not a contra-indication for immunisation.

4.4 Special Warnings And Precautions For Use

As with all injectable vaccines, appropriate medical treatment should always be readily available in case of anaphylactic reactions following the administration of the vaccine.

Vaccination should be preceded by a review of the medical history (especially with regard to previous vaccination and possible occurrence of undesirable events) and a clinical examination.

ACWY Vax should under no circumstances be administered intravascularly or intradermally.

ACWY Vax will only confer protection against Neisseria meningitidis groups A, C, W135 and Y. Protection cannot be guaranteed in every individual vaccinated.

The vaccine may not elicit a protective immune response in subjects with impaired immune systems.

Group C, W135 and Y polysaccharides are poorly immunogenic in children less than 24 months of age. Group A polysaccharide induces an antibody response in children from the age of 6 months. However, the response is lower than that observed in older subjects and may be transient.

Group C polysaccharide may induce immunological hyporesponsiveness to further doses of polysaccharide C or to meningococcal group C conjugate vaccine. The clinical relevance of this phenomenon remains unknown.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There are no data on concomitant administration of ACWY Vax and other vaccines.

Different injection sites should be used when concomitant administration with other injectable vaccines can not be avoided.

4.6 Pregnancy And Lactation

Pregnancy

Adequate human data on use during pregnancy and adequate animal reproduction studies are not available.

Nevertheless, vaccination during pregnancy may be considered when there is an increased risk for meningococcal disease.

Lactation

Adequate data on the administration of ACWY Vax to women who are breast-feeding are not available.

However, ACWY Vax may be administered to breast-feeding women when there is an increased risk of meningococcal disease.

4.7 Effects On Ability To Drive And Use Machines

The vaccine is unlikely to produce an effect on the ability to drive and use machines.

4.8 Undesirable Effects

In recent clinical studies, ACWY Vax was administered to 502 subjects.

The most commonly reported adverse reactions were pain at the injection site and redness at the injection site.

Adverse reactions occurring during these studies were mostly reported within 48 hours following vaccination.

Adverse reactions considered as being at least possibly related to vaccination have been categorised by frequency as follows.

Frequencies are reported as:

Very common: (

Common: (

Uncommon: (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders:

Very Common: headache

Common: drowsiness

Uncommon: dizziness

Gastrointestinal disorders:

Common: gastrointestinal symptoms e.g. nausea, vomiting and diarrhoea

Skin and subcutaneous tissue disorders:

Uncommon: urticaria, rash

Metabolism and nutrition disorders:

Common: loss of appetite

General disorders and administration site conditions:

Very common: pain, redness at the injection site, fatigue

Common: fever, swelling at the injection site

Psychiatric disorders:

Common: irritability

In a WHO study conducted in Ghana, ACWY Vax was administered to 177 adults. The following adverse reactions were observed in this trial:

Very common: tenderness at injection site

Common: induration at injection site.

In addition, the following adverse reactions have been reported during post-marketing surveillance:

Skin and subcutaneous tissue disorders:

Angioneurotic oedema

Musculoskeletal and connective tissue disorders:

Arthralgia, musculoskeletal stiffness

General disorders and administration site conditions:

Influenza-like symptoms, chills

Immune system disorders:

Allergic reactions, including anaphylactic and anaphylactoid reactions

4.9 Overdose

Cases of overdose (up to 10 times the recommended dose) have been reported during post-marketing surveillance. Adverse events reported following overdosage were similar to those reported with normal vaccine administration.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Bacterial vaccines, ATC code: J07AH04

Immunogenicity data

ACWY Vax induces bactericidal antibodies against meningococci of groups A, C, W135 and Y.

The current formulation of ACWY Vax was shown immunologically non-inferior to the previous formulation of the vaccine in a trial conducted in Lebanon in 161 subjects aged 2-30 years.

The immunogenicity of the previous formulation of ACWY Vax was evaluated in four clinical studies conducted in Belgium, Lebanon, Poland and Taiwan (N =341) in subjects aged 2-30 years.

Antibody titres were measured with the serum bactericidal assay (SBA).

Vaccine response was defined as seroconversion for initially seronegative subjects (with SBA titre below 1:8) or as four-fold increase in SBA titre from pre to post vaccination for initially seropositive subjects.

The percentage of vaccine responders observed in the four clinical studies conducted with the previous formulation were as follows:

In children aged 2-5 years: Group A - 69.1%, Group C - 93.1%, Group W135 - 89.3%, Group Y - 79.2%.

In subjects aged 6-30 years: Group A - 72.2%, Group C - 95.4%, Group W135 - 92.3%, Group Y -81.2%.

In initially seronegative subjects seroconversion rates were 100% for Group A and Y, and at least 92.9% for Group C and W135.

The risk of meningococcal disease is much higher in individuals with late complement component deficiency (LCCD) because of their inability to kill meningococci via the classical and alternative pathways. However, ACWY Vax induces anti-capsular polysaccharide antibodies against each of the four groups in LCCD subjects. In spite of the complement deficiency, killing of meningococci A, C, W135 and Y is observed when sera from LCCD subjects vaccinated with ACWY Vax are incubated with human neutrophils.

Efficacy data

In response to a meningococcal disease epidemic in Burkina Faso, a mass vaccination campaign with Mencevax ACW was performed in more than 1.68 million children and adults aged from 2 to 29 years. The vaccine effectiveness against group A and W135 disease was 95.8% (95% CI: 81.8%-99.0%) for persons with reported vaccination.

Persistence of immune response

Literature data supports the persistence of vaccine induced antibody response for at least 3 years.

An ongoing clinical study has demonstrated that 100% of subjects aged 18-25 years had bactericidal antibody titres 135 and Y and 96% for group C two years after vaccination.

In a study conducted in Ghana in 177 subjects aged 15-34 years, 100%, 88.4% and 93.5% of subjects had SBA titres 135, respectively at approximately one year after vaccination with ACWY Vax.

In studies conducted among complement-deficient subjects, the antibodies persisted for 3 years post vaccination with ACWY Vax and the revaccination restored antibody concentrations.

5.2 Pharmacokinetic Properties

Evaluation of pharmacokinetic properties is not required for vaccines.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on general safety tests performed in animals.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Powder :

Sucrose

Trometamol

Solvent:

Sodium chloride

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

3 years.

After reconstitution, the vaccine should be used immediately. However, chemical and physical in-use stability has been demonstrated for 8 hours at 2-8°C.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

Powder in a vial (type I glass) with a stopper and solvent (0.5 ml) in a pre-filled syringe (type I glass) with a stopper with or without needles– pack size of 1.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The vaccine should be inspected visually for any foreign particulate matter and/or other coloration prior to administration. In the event of either being observed, discard the vaccine.

ACWY Vax must be reconstituted by adding the entire content of the supplied container of solvent to the vial containing the powder. The powder should be completely dissolved in the solvent.

The reconstituted vaccine is a clear colourless solution.

7. Marketing Authorisation Holder

SmithKline Beecham plc

Trading as:

GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex UB11 1BT

8. Marketing Authorisation Number(S)

PL 10592/0301

9. Date Of First Authorisation/Renewal Of The Authorisation

23/06/2008

10. Date Of Revision Of The Text

09/02/2011

POM

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Cetrotide 0.25 mg

1. Name Of The Medicinal Product

Cetrotide 0.25 mg powder and solvent for solution for injection

2. Qualitative And Quantitative Composition

Each vial contains 0.25 mg cetrorelix (as acetate).

After reconstitution with the solvent provided, each ml of the solution contains 0.25 mg cetrorelix.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

Appearance of the powder: white lyophilisate

Appearance of the solvent: clear and colourless solution

The pH of the reconstituted solution is 4.0 – 6.0

4. Clinical Particulars 4.1 Therapeutic Indications

Prevention of premature ovulation in patients undergoing a controlled ovarian stimulation, followed by oocyte pick-up and assisted reproductive techniques.

In clinical trials Cetrotide was used with human menopausal gonadotropin (HMG), however, limited experience with recombinant follicule-stimulating hormone (FSH) suggested similar efficacy.

4.2 Posology And Method Of Administration

Cetrotide should only be prescribed by a specialist experienced in this field.

The first administration of Cetrotide should be performed under the supervision of a physician and under conditions where treatment of possible allergic/pseudo-allergic reactions (including life-threatening anaphylaxis) is immediately available. The following injections may be self-administered as long as the patient is made aware of the signs and symptoms that may indicate hypersensitivity, the consequences of such a reaction and the need for immediate medical intervention.

The contents of 1 vial (0.25 mg cetrorelix) are to be administered once daily, at 24 h intervals, either in the morning or in the evening. Following the first administration, it is advised that the patient be kept under medical supervision for 30 minutes to ensure there is no allergic/pseudo-allergic reaction to the injection.

Cetrotide is for subcutaneous injection into the lower abdominal wall.

The injection site reactions may be minimised by rotating the injection sites, delaying injection at the same site and injecting the product in a slow rate to facilitate the progressive absorption of the product.

Administration in the morning: Treatment with Cetrotide should commence on day 5 or 6 of ovarian stimulation (approximately 96 to 120 hours after start of ovarian stimulation) with urinary or recombinant gonadotropins and is to be continued throughout the gonadotropin treatment period including the day of ovulation induction.

Administration in the evening: Treatment with Cetrotide should commence on day 5 of ovarian stimulation (approximately 96 to 108 hours after start of ovarian stimulation) with urinary or recombinant gonadotropins and is to be continued throughout the gonadotropin treatment period until the evening prior to the day of ovulation induction.

Additional information on special populations:

There is no relevant indication for the use of Cetrotide in children or geriatric populations.

For instructions for preparation, see section 6.6.

4.3 Contraindications

• Hypersensitivity to the active substance or any structural analogues of gonadotropin-releasing hormone (GnRH), extrinsic peptide hormones or to any of the excipients.

• Pregnancy and lactation.

• Postmenopausal women.

• Patients with moderate and severe renal and hepatic impairment.

4.4 Special Warnings And Precautions For Use

Special care should be taken in women with signs and symptoms of active allergic conditions or known history of allergic predisposition. Treatment with Cetrotide is not advised in women with severe allergic conditions.

During or following ovarian stimulation an ovarian hyperstimulation syndrome can occur. This event must be considered as an intrinsic risk of the stimulation procedure with gonadotropins.

An ovarian hyperstimulation syndrome should be treated symptomatically, e.g. with rest, intravenous electrolytes/colloids and heparin therapy.

Luteal phase support should be given according to the reproductive medical centre?s practice.

There is limited experience up to now with the administration of Cetrotide during a repeated ovarian stimulation procedure. Therefore Cetrotide should be used in repeated cycles only after a careful risk/benefit evaluation.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro investigations have shown that interactions are unlikely with medicinal products that are metabolised by cytochrome P450 or glucuronised or conjugated in some other way. However, though there has been no evidence of drug-interactions, especially with commonly used medicinal products, gonadotropins or products that may induce histamine release in susceptible individuals, the possibility of an interaction cannot be totally excluded.

4.6 Pregnancy And Lactation

Cetrotide is not intended to be used during pregnancy and lactation (see section 4.3).

Studies in animals have indicated that cetrorelix exerts a dose related influence on fertility, reproductive performance and pregnancy. No teratogenic effects occurred when the medicinal product was administered during the sensitive phase of gestation.

4.7 Effects On Ability To Drive And Use Machines

Cetrotide has no or negligible influence on the ability to drive or use machines.

4.8 Undesirable Effects

The most commonly reported side effects are local injection site reactions such as erythema, swelling and pruritus that are usually transient in nature and mild in intensity. In clinical trials, these effects were observed with a frequency of 9.4% following multiple injections of Cetrotide 0.25 mg.

Mild to moderate ovarian hyperstimulation syndrome (OHSS) (WHO grade I or II) have been commonly reported and should be considered as an intrinsic risk of the stimulation procedure. Inversely, severe OHSS remains uncommon.

Uncommonly, cases of hypersensitivity reactions including pseudo-allergic/anaphylactoid reactions have been reported.

The adverse reactions reported below are classified according to frequency of occurrence as follows:

Very Common

Common

Uncommon

Rare

Very rare

< 1/10,000

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Immune system disorders

Uncommon

Systemic allergic/pseudo-allergic reactions including life-threatening anaphylaxis.

Nervous system disorders

Uncommon

Headache

Gastrointestinal disorders

Uncommon

Nausea

Reproductive system and breast disorders

Common

Mild to moderate ovarian hyperstimulation syndrome (WHO grade I or II) can occur which is an intrinsic risk of the stimulation procedure (see section 4.4).

 

 

Uncommon

Severe ovarian hyperstimulation syndrome (WHO grade III)

General disorders and administration site conditions

Common

Local reactions at the injection site (e.g. erythema, swelling and pruritus) have been reported. Usually they were transient in nature and of mild intensity. The frequency as reported in clinical trials was 9.4% following multiple injections of 0.25 mg cetrorelix.

4.9 Overdose

Overdosage in humans may result in a prolonged duration of action but is unlikely to be associated with acute toxic effects.

In acute toxicity studies in rodents non-specific toxic symptoms were observed after intraperitoneal administration of cetrorelix doses more than 200 times higher than the pharmacologically effective dose after subcutaneous administration.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: anti-gonadotropin-releasing hormones, ATC code: H01CC02.

Cetrorelix is a luteinising hormone releasing hormone (LHRH) antagonist. LHRH binds to membrane receptors on pituitary cells. Cetrorelix competes with the binding of endogenous LHRH to these receptors. Due to this mode of action, cetrorelix controls the secretion of gonadotropins (LH and FSH).

Cetrorelix dose-dependently inhibits the secretion of LH and FSH from the pituitary gland. The onset of suppression is virtually immediate and is maintained by continuous treatment, without initial stimulatory effect.

In females, cetrorelix delays the LH surge and consequently ovulation. In women undergoing ovarian stimulation the duration of action of cetrorelix is dose dependent. Following a single dose of 3 mg of cetrorelix a duration of action of at least 4 days has been evaluated. On day 4 the suppression was approximately 70%. At a dose of 0.25 mg per injection repeated injections every 24 hours will maintain the effect of cetrorelix.

In animals as well as in humans, the antagonistic hormonal effects of cetrorelix were fully reversible after termination of treatment.

5.2 Pharmacokinetic Properties

The absolute bioavailability of cetrorelix after subcutaneous administration is about 85%.

The total plasma clearance and the renal clearance are 1.2 ml x min-1 x kg-1 and 0.1 ml x min-1 x kg-1, respectively. The volume of distribution (Vd) is 1.1 l x kg-1. The mean terminal half-lives following intravenous and subcutaneous administration are about 12 h and 30 h, respectively, demonstrating the effect of absorption processes at the injection site. The subcutaneous administration of single doses (0.25 mg to 3 mg cetrorelix) and also daily dosing over 14 days show linear kinetics.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

No target organ toxicity could be observed from acute, subacute and chronic toxicity studies in rats and dogs following subcutaneous administration of cetrorelix. No signs of medicinal product-related local irritation or incompatibility were noted in dogs after intravenous, intra-arterial and paravenous injection when cetrorelix was administered in doses clearly above the intended clinical use in man.

Cetrorelix showed no mutagenic or clastogenic potential in gene and chromosome mutation assays.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Powder:

Mannitol

Solvent:

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

2 years.

The solution should be used immediately after preparation.

6.4 Special Precautions For Storage

Do not store above 25 °C. Keep the vial(s) in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

Packs with 1 or 7 Type I glass vials sealed with a rubber stopper.

Additionally for each vial the packs contain:

1 pre-filled syringe (Type I glass cartridge closed with rubber stoppers) with 1 ml solvent for parenteral use

1 injection needle (20 gauge)

1 hypodermic injection needle (27 gauge)

2 alcohol swabs.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Cetrotide should only be reconstituted with the solvent provided, using a gentle, swirling motion. Vigorous shaking with bubble formation should be avoided.

The reconstituted solution is without particles and clear. Do not use if the solution contains particles or if the solution is not clear.

Withdraw the entire contents of the vial. This ensures a delivery to the patient of a dose of at least 0.23 mg cetrorelix.

The solution should be used immediately after reconstitution.

7. Marketing Authorisation Holder

Merck Serono Europe Limited

56 Marsh Wall

London E14 9TP

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/99/100/001

EU/1/99/100/002

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 13 April 1999

Date of first renewal: 15 April 2004

Date of latest renewal: March 2009

10. Date Of Revision Of The Text

03/2010

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Cobalin-H Injection (Amdipharm Plc)

1. Name Of The Medicinal Product

Cobalin-H

2. Qualitative And Quantitative Composition

Anhydrous hydroxocobalamin 1000mcg/ml.

3. Pharmaceutical Form

Injection

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of Addisonian pernicious anaemia.

Prophylaxis and treatment of other macrocytic anaemias due to vitamin B12 deficiency.

Treatment of tobacco amblyopia.

Treatment of Leber's atrophy.

4.2 Posology And Method Of Administration

The following dosages are suitable for children and adults.

Addisonian pernicious anaemia and other macrocytic anaemias without neurological involvement:

Initially:

250 micrograms to 1000 micrograms intramuscularly on alternate days for one or two weeks then 250 micrograms weekly until blood count is normal.

Maintenance:

1000 micrograms every two or three months.

Addisonian pernicious anaemia and other macrocytic anaemias with neurological involvement:

Initially:

1000 micrograms on alternate days as long as improvement continues.

Maintenance:

1000 micrograms every two months.

Prophylaxis of macrocytic anaemias associated with vitamin B12 deficiency resulting from gastrectomy, ileal resection, certain ma/absorption states and vegetarianism:

1000 micrograms every two or three months.

Tobacco amblyopia and Leber's optic atrophy:

Initially:

1000 micrograms daily by intramuscular injection for two weeks then twice weekly as long as improvement is maintained.

Maintenance:

1000 micrograms every three months or as required.

4.3 Contraindications

Sensitivity to hydroxocobalamin / vitamin B12.

4.4 Special Warnings And Precautions For Use

Cobalin-H should not be given before a megaloblastic marrow has been demonstrated. Regular monitoring of the blood is advisable. Doses of hydroxocobalamin greater than 10 micrograms daily may produce a haematological response in patients with folate deficiency. Indiscriminate use may mask the exact diagnosis. Cardiac arrhythmias secondary to hypokalaemia have been reported during initial therapy and plasma potassium should, therefore, be monitored during this period.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The serum concentration of hydroxocobalamin may be reduced by concurrent administration of oral contraceptives. Chlorphenicol-treated patients may respond poorly to hydroxocobalamin. Vitamin B12 assays by microbiological techniques are invalidated by antimetabolites and most antibiotics.

4.6 Pregnancy And Lactation

Hydroxocobalamin should not be used to treat megaloblastic anaemia of pregnancy.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

The following effects have been reported and are listed below by body system:

Disorders of the immune system:

 

Rare:

Allergic hypersensitivity reactions

Very rare:

Anaphylaxis

Gastro intestinal disorders:

 

Frequency Not Known:

Nausea

General disorders:

 

Frequency Not Known:

Fever, dizziness, Injection site disorders

Neurological disorders:

 

Frequency Not Known:

Headache

4.9 Overdose

Treatment is unlikely to be needed in cases of overdosage.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Vitamin B12

ATC classification: B03B A03

5.2 Pharmacokinetic Properties

Vitamin B12 is extensively bound to specific plasma proteins called transcobalamins; transcobalamin II appears to be involved in the rapid transport of the cobalamins to tissues. It is stored in the liver, excreted in the bile, and undergoes enterohepatic recycling; part of a dose is excreted in the urine, most of it in the first 8 hours.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium dihydrogen orthophosphate

Sodium chloride

Water for Injections

6.2 Incompatibilities

None stated.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Protect from light. Store below 25°C.

6.5 Nature And Contents Of Container

Cobalin-H is supplied in clear 1ml Type I glass ampoules in cartons of 5 or 10.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

AMDIPHARM PLC

REGENCY HOUSE

MILES GRAY ROAD

BASILDON

ESSEX

SS14 3AF

UNITED KINGDOM

8. Marketing Authorisation Number(S)

PL 20072/0217

9. Date Of First Authorisation/Renewal Of The Authorisation

18th June 1993 / 6th November 1998

10. Date Of Revision Of The Text

18/05/2011

Read More:

Dacarbazine 200 mg, powder for solution for injection (Hospira UK Ltd)

DACARBAZINE 200 mg POWDER FOR SOLUTION FOR INJECTION

Read all of this leaflet carefully before you start using this medicine

Keep this leaflet. You may need to read it again.

If you have any further questions ask your doctor.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

In this leaflet: 1. What Dacarbazine Powder for Solution for Injection is and what it is used for 2. Before you use Dacarbazine Powder for Solution for Injection 3. How to use Dacarbazine Powder for Solution for Injection 4. Possible side effects 5. How to store Dacarbazine Powder for Solution for Injection 6. Further information What Dacarbazine Powder For Solution For Injection Is And What It Is Used For

Dacarbazine Powder for Solution for Injection is an anti-cancer medicine, in the form of a powder for solution for injection. Treatment with an anti-cancer medicine is sometimes called cancer chemotherapy.

Dacarbazine Powder for Solution for Injection may be used for the treatment of some types of cancer, for example: metastatic malignant melanoma (a type of skin cancer that has spread) and Hodgkin’s disease and some types of cancer in soft tissues.

Before You Use Dacarbazine Powder For Solution For Injection Do not use Dacarbazine Powder for Solution for Injection if you have shown signs of hypersensitivity (severe allergy) to dacarbazine on previous occasions if you have severe liver or kidney diseases in combination with yellow fever vaccine and some other types of vaccines (live attenuated) in combination with phenytoin (a medicine used to prevent convulsions). Taking/using other medicines

Special care should be taken if you are taking other medicinal products which could interact with Dacarbazine:

ciclosporin or tacrolimus (medicines used after having a transplant) fotemustine (a medicine used in cancer treatment) medicines which could damage your liver warfarin (a medicine used to thin the blood). Your doctor may need to do your blood test (INR) more often

Please tell your doctor if you are taking, or have recently taken, any other medicines, including medicines obtained without a prescription.

Pregnancy and breast feeding

Do not use Dacarbazine:

if you are pregnant or trying to become pregnant if you are breast feeding Driving and using machines

Dacarbazine may influence the ability to drive or operate machinery because of nausea and vomiting or rare adverse reactions affecting the nervous system.

Important information about one of the ingredients of Dacarbazine Powder for Solution for Injection

This medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium free’.

How To Use Dacarbazine Powder For Solution For Injection

This medicinal product is for intravenous use (injection into a vein).

Your treatment will usually be given to you in hospital.

You will be given Dacarbazine as an infusion (slow injection via a drip) into a vein or a slow intravenous injection(injection into a vein).

Tell your doctor or nurse at once if you notice any pain at the injection site during or shortly after treatment. Pain around the injection site could mean the needle has not been properly inserted into the vein.

The dose of dacarbazine will depend on the illness for which you are being treated. The dose is calculated according to your body surface area (expressed as mg/m2).

Depending on your illness, dosing is typically between 200 and 850 mg/m2 of dacarbazine.

As this medicine will be given to you whilst you are in hospital it is unlikely that you will be given too little or too much. However, tell your doctor or pharmacist if you have any concerns.

Possible Side Effects

Like all medicines Dacarbazine Powder for Solution for Injection can have side effects although not everybody gets them.

If any of the following happen, tell your doctor immediately: severe allergic reaction - you may experience a sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth and throat (which may cause difficulty in swallowing or breathing), and you may feel you are going to faint.

This is a very serious side effect. You may need urgent medical attention. This very serious side effect is rare.

If you experience any of the following tell your doctor as soon as possible:

Common (less than 1 in 10 patients but more than 1 in 100):

pallor (anaemia) loss of appetite nausea/vomiting

Uncommon (Less than 1 in 100 patients but more than 1 in 1000):

confusion fits (seizures) numbness of the skin or pins and needles sensation in the face (paraesthesia) headache blurred vision facial flushing hair loss (alopecia) transient rash an influenza (‘flu’) type syndrome of fever, muscle pain (myalgia) and generally feeling unwell (malaise) which may start approximately one week after treatment and may last for up to three weeks tiredness and weakness (lethargy)

Rare (less than 1 in 1000 patients but more than 1 in 10,000)

diarrhoea bruising increased sensitivity of the skin to sunlight (photosensitivity)

Very rare (less than 1 in 10,000)

redness of the skin/rash itching

Blood samples will be taken to check for changes in blood cells levels, which is a common side effect of Dacarbazine treatment. Blood and urine tests will be performed to check for changes in kidney function. Blood tests may be performed to check that your liver is working properly. Kidney and liver problems are uncommon.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

HOW TO STORE DACARBAZINE 200 mg POWDER FOR SOLUTION FOR INJECTION

Keep out of the reach and sight of children

The vials should be stored at 2 - 8°C with the vials kept in the outer carton (in order to protect from light).

This medicine should not be used after the expiry date printed on the vial label.

Further Information What Dacarbazine Powder for Solution for Injection contains

The medicine is presented in glass containers called vials containing 200 mg dacarbazine. Each pack contains 1 vial.

The active substance is dacarbazine The other ingredients are citric acid monohydrate, mannitol and sodium hydroxide What Dacarbazine Powder for Solution for Injection looks like and contents of the pack

The powder is a white or pale yellow solid.

The vial containing the powder is a glass container with a rubber stopper.

Each single-dose vial contains 200 mg of Dacarbazine. When reconstituted each ml of solution contains 10 mg of dacarbazine.

The 200 mg presentation of Dacarabazine is sold in packs containing 1 vial of powder

Marketing Authorisation Holder and Manufacturer

The Marketing authorisation holder and company responsible for batch release in the European Union is

Mayne Pharma Plc Queensway Royal Leamington Spa Warwickshire CV31 3RW UK

The Manufacturer is

Mayne Pharma Pty Ltd Lexia Place Mulgrave Victoria 3170 Australia

This leaflet was last approved in

08/2006

Read More:

AVONEX 30 micrograms powder and solvent for solution for injection

AVONEX 30 micrograms powder and solvent for solution for injection

(Interferon beta-1a)

BIO-SET Presentation

Read all of this leaflet carefully before you start using this medicine.

Even if you have used Avonex before, some of the information may have changed.

Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or your pharmacist This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,please tell your doctor or pharmacist.

(Notes information)

Latest issue: 12/2008

This leaflet is changed from time to time.

Please check every time you get your prescription refilled to see if the leaflet has been updated.

In this leaflet: 1. What AVONEX is and what it is used for 2. Before you use AVONEX 3. How to use AVONEX 4. Possible side effects 5. How to store AVONEX 6. Further information 7. How to inject AVONEX What Avonex Is And What It Is Used For What AVONEX is

The active ingredient in Avonex is a protein called interferon beta-1a. Interferons are natural substances made in your body to help protect you from infections and diseases. The protein in Avonex is made up of exactly the same ingredients as interferon beta that is found in the human body.

What AVONEX is used for

Avonex is used to treat Multiple Sclerosis (MS). Treatment with Avonex can help to prevent you from getting worse, although it will not cure MS.

Everyone has their own set of MS symptoms. These can include:

feeling off-balance or light headed, walking problems, stiffness and muscle spasms, tiredness, numbness in the face, arms or legs acute or chronic pain, bladder and bowel problems, sexual problems and problems seeing things difficulty in thinking and concentrating, depression.

MS also tends to flare up from time to time: this is called a relapse.

(Notes information)

Avonex works best when you use it at the same time, once a week, on a regular basis.

Do not stop your Avonex treatment without speaking to your neurologist.

Avonex can help to reduce the number of relapses that you have and slow down the disabling effects of MS. Your doctor will advise you for how long you can use Avonex or when to stop.

How AVONEX works

Multiple sclerosis is linked to nerve (brain or spinal cord) damage. In MS, your body’s defence system reacts against it’s own myelin – the ‘insulation’ that surrounds nerve fibres. When myelin is damaged, the messages between the brain and other parts of the body are disrupted. This is what causes the symptoms of MS. Avonex seems to work by stopping your body’s defence system from attacking the myelin.

Before You Use Avonex Do not use AVONEX if you are allergic (hypersensitive) to interferon beta, human serum albumin or any of the other ingredients in Avonex if you are pregnant, do not start using Avonex if you have severe depression or think about committing suicide.

Talk to a doctor straight away if any of these apply to you.

(Notes information)

Avonex and allergic reactions. Because Avonex is based on a protein, there is a small chance of an allergic reaction.

More about depression. If you have severe depression or thoughts about suicide, you must not use Avonex.

If you have depression, your doctor may still prescribe Avonex for you, but it's important to let your doctor know if you have had depression or any similar problems affecting your moods.

Take special care with AVONEX

Talk to your doctor first:

If you have or have had in the past:

depression or problems affecting your moods thoughts about committing suicide.

Changes to your mood, thoughts about suicide, feeling unusually sad, anxious or worthless, should be reported to your doctor immediately.

epilepsy or other seizure disorders not controlled by medication serious kidney or liver problems a low number of white blood cells or platelets, which can cause an increased risk of infection, bleeding or anaemia heart problems, which can cause symptoms such as chest pain (angina), particularly after any activity; swollen ankles, shortness of breath (congestive heart failure); or an irregular heartbeat (arrhythmias).

Talk to your doctor if you have any of these conditions, or if they worsen whilst taking Avonex.

Tell your doctor you are using AVONEX: if you are having a blood test. Avonex may interfere with the results.

(Notes information)

Sometimes you will need to remind other medical staff that you are being treated with Avonex. For example, if you are prescribed other medicines, or if you have a blood test, Avonex may affect the other medicines or the test result.

Using other medicines

If you are using other medicines, especially those used to treat epilepsy or depression. Avonex may affect other medicines or be affected by them. This includes any other medicines including medicines obtained without a prescription.

Pregnancy and breastfeeding

If you are pregnant, do not start using Avonex.

If you could get pregnant, you need to use contraception while you use Avonex. If you are planning a baby or if you become pregnant while you are using Avonex, tell your doctor. You and your doctor can discuss if you should carry on with treatment. If you are already pregnant, or think that you might be, talk to a doctor as soon as you can. If you want to breastfeed talk to your doctor first. Driving and using machines

If you feel dizzy, do not drive. Avonex makes some people feel dizzy. If this happens to you, or if you get any other side effects that could affect your ability, do not drive or use machines.

Important information about some of the ingredients of AVONEX

This medicine is essentially ‘sodium-free’. It contains less than 23 mg (1 mmol) sodium in each weekly dose.

How To Use Avonex

The usual dose for adults and adolescents aged 12 years and over

One injection of Avonex, once a week.

Try to use Avonex at the same time on the same day each week.

Not for children

Avonex is not to be used in children below the age of 12 years.

Injecting yourself

You can inject Avonex yourself without the help of your doctor, if they have trained you to do this. The instructions on how to inject yourself are at the end of this leaflet (see section 7, How to inject AVONEX).

If you have trouble handling the syringe, ask your doctor who may be able to help.

(Notes information)

There are more details on how to inject Avonex at the end of this leaflet.

Alternate needle:

Your pack of Avonex already includes a needle for injection. It may be possible for your doctor to prescribe you a shorter and thinner needle, depending on your body type. Talk to your doctor to see if this is appropriate for you.

If you have problems handling the syringe, talk to your doctor about using a syringe grip. This is a specially designed holder to help you with injecting Avonex.

How long to use AVONEX

Your doctor will tell you how long you need to keep using Avonex. It is important to continue using Avonex regularly. Do not make changes unless your doctor tells you.

If you inject too much

You should only have one injection of Avonex, once a week. If you have used more than one injection of Avonex in a three-day period, contact your doctor or pharmacist straight away for advice.

If you miss an injection

If you miss your usual weekly dose, inject a dose as soon as you can. Then leave a week before using Avonex again. Continue injecting on this new day every week. If you have a preferred day for using Avonex, talk to your doctor about managing the dose, to get back to your preferred day.

Do not use two injections to make up for a missed injection.

Possible Side Effects

Like all medicines, Avonex can cause side effects, although not everyone gets them.

(Notes information)

Although the list of possible side effects can seem worrying, it’s possible that you may not have any of them.

Serious side effects: get medical help

Serious allergic reactions

If you get any of these:

swelling of the face, lips or tongue difficulty breathing a rash.

Call a doctor immediately. Do not use any more Avonex until you have spoken to a doctor.

Depression

If you get any symptoms of depression:

feeling unusually sad, anxious or worthless.

Call a doctor immediately.

Liver problems

If you get any of these symptoms:

yellowing of your skin or the whites of your eyes (jaundice) itching all over feeling sick, being sick (nausea and vomiting) easy bruising of the skin.

Call a doctor immediately as they may be signs of a possible liver problem.

Side effects seen in clinical trials

(Notes information)

Side effects seen in clinical trials. These are the side effects that people reported when Avonex was being tested. The figures are based on how many people said they’d had them. It gives you an idea how likely you are to get similar side effects.

Very common side effects
(at least 1 in 10 people are affected)

flu-like symptoms – headache, muscle aches, chills or a fever: see Flu-like symptoms, below headache.

Common side effects
(less than 1 in 10 people are affected)

loss of appetite feeling weak and tired difficulty sleeping depression flushing runny nose diarrhoea (loose stools) feeling or being sick (nausea or vomiting) numbness or tingling of skin rash, bruising of the skin increased sweating, night sweats pain in your muscles, joints, arms, legs or neck muscle cramps, stiffness in the joints and muscles pain, bruising and redness at the injection site changes to blood tests. Symptoms you might notice are tiredness, repeated infection, unexplained bruising or bleeding.

Uncommon side effects
(less than 1 in 100 people affected)

hair loss changes to your monthly period burning feeling at the site of injection.

Rare side effects
(less than 1 in 1,000 people affected)

difficulty breathing.

If any of the effects trouble you, talk to your doctor.

Other side effects

(Notes information)

These effects have been seen in people using Avonex, but we do not know how likely they are to happen.

an underactive or overactive thyroid nervousness or anxiety, emotional instability, irrational thoughts or hallucinations (seeing or hearing things that are not real), confusion or suicide numbness, dizziness, seizures or fits and migraines an awareness of your heartbeat (palpitations), a rapid or irregular heartbeat, or heart problems which would have the following symptoms: a reduced ability to exercise, inability to lie flat in bed, shortness of breath or swollen ankles liver problems as described above nettle rash or blister-like rash, itching, worsening of psoriasis if you have it swelling or bleeding at the site of injection, or chest pain after an injection gaining or losing weight changes to test results, including changes to liver function tests.

If any of the effects trouble you, talk to your doctor.

Effects of the injection Feeling faint: Your first injection of Avonex may be given by your doctor. It may make you feel faint. You may even actually faint. This is unlikely to happen again. Just after an injection, your muscles may feel tense or very weak – as though you are having a relapse. This is rare. It only happens when you inject and the effects soon pass. They may happen any time after starting on Avonex. If you notice any irritation or skin problems after an injection, talk to your doctor.

Flu-like symptoms

(Notes information)

Three simple ways to help reduce the impact of flu-like symptoms:

1. Use your Avonex injection just before bedtime. This may allow you to sleep through the effects. 2. Take paracetamol or ibuprofen half an hour before your Avonex injection and continue taking it for up to a day. Speak to your doctor or pharmacist about a suitable dose. 3. If you have a fever, drink plenty of water to keep you hydrated.

Some people find that after injecting Avonex, they feel like they have flu. Signs are:

headache muscle aches chills or a fever.

These symptoms are not really flu.

You can’t pass it on to anyone else. They are more common when you first start using Avonex. As you keep using your injections, the flu-like symptoms gradually decrease.

How To Store Avonex

Keep out of the reach and sight of children.

Do not use after the expiry date stated on the label.

Store below 25 °C.

Once prepared in the syringe use as soon as possible. However, the prepared syringe can be stored in the fridge (between 2 °C and 8 °C) for up to 6 hours before you inject. Do not freeze.

Bring it out half an hour before injecting.

Do NOT use AVONEX if you notice:

The seal of the cap of the BIO-SET device is broken. The sealed plastic tray is damaged or opened. The liquid in the vial obtained after reconstitution is not colourless or slightly yellow in colour or you can see particles floating in it.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information Ingredients

The active ingredient is: Interferon-beta 1a 30 micrograms

The other ingredients are: Human serum albumin, sodium chloride, dibasic sodium phosphate and monobasic sodium phosphate.

What is in your Avonex pack

A box of Avonex Bioset has four doses of Avonex.

Each dose comes in a sealed plastic tray and has a white to off-white coloured powder in a glass container (vial) and an injection syringe filled with water. These are mixed together to make up the injection you take (solution for injection). A separate needle to give the injection is also included in the tray.

Marketing Authorisation Holder is: Biogen Idec Limited Innovation House 70 Norden Road Maidenhead Berkshire SL6 4AY United Kingdom Avonex is made by: Biogen Idec BV Robijnlaan 8 NL-2132 WX Hoofddorp The Netherlands Biogen Idec Denmark Manufacturing ApS Biogen Idec All? 1 DK-3400 Hiller?d Denmark

You can get a larger print version of this leaflet by calling the local representatives.

For any further information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

United Kingdom Biogen Idec Limited Tel:+44 (0) 1628 50 1000

This leaflet was last approved in 12/2008

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.europa.eu

How To Inject Avonex

You should have had training in how to inject Avonex.

These notes are a reminder. If there’s anything you’re not sure about, check with your doctor or pharmacist.

Where to inject Avonex is injected into a muscle, for example, the upper thigh muscle. Injection of Avonex into the buttocks is not recommended. Use a different injection site each week. This means less risk of irritation to your skin and muscle. Do not use any area of skin that is bruised, sore, or infected, or if there is an open wound. A Getting ready 1. Take a tray out of the box.

Check the expiry date on the lid of the tray. Do not use it if it is out-of-date.

Peel back the paper lid completely. Check the blister tray contains:

one BIO-SET (vial + base + cap) one syringe one injection needle (see picture “Contents of the plastic tray”). 2. Wash your hands thoroughly with soap and water and dry them. 3. Prepare alcohol wipes and sticking plasters (not supplied) if you need them. 4. Find a clean, hard surface to lay out the items needed for your injection. Lay the tray down on it. B. Preparing the injection 1 Remove cap off the vial
Twist, then pull cap off.
Do not touch the connection port. 2 Pull the cap off the syringe
Hold the base of the syringe. Pull the cap off.
Do not touch the connection port.
Do not push on the plunger. 3 Line up the syringe and vial
Place the Bio-Set on a flat surface.
Line up the two connection ports so that they are in a straight line.
Hold the syringe by the base. Screw it firmly clockwise into the vial. 4 Push the syringe down until it clicks
Keep the Bio-Set on the flat surface and hold the syringe by the base.
Keep them in a straight line.
Tip: If the syringe is at an angle to the Bio-Set, it will leak.
Push the syringe until it clicks. 5 Mix the water and powder
Slowly inject all the water from the syringe into the vial.
Tip: Don’t push the plunger quickly. This turns the solution to foam that can’t be drawn into the syringe.
Push the plunger right down to get air out of the syringe. 6 Dissolve the powder fully
Pick up the vial and the syringe, keeping them attached and straight.
Gently swirl the vial until all the powder has dissolved.
Do not shake: this will make froth. 7 Fill the syringe
Turn the syringe and vial upside down, still in a straight line.
Tip: If the syringe is at an angle to the Bio-Set, it will leak.
Slowly pull the plunger until all the liquid is in the syringe. 8 Separate syringe and vial
Hold the filled syringe by the base. Turn it anti-clockwise to remove it from the Bio-Set vial.
Do not touch the connection port on the syringe. C: Giving the injection 1 Check the liquid in the syringe
It should be clear and colourless.
If the solution is any colour except colourless or slightly yellow, or if you can see particles floating in it, do not inject. 2 Fit the needle
Unwrap the needle to expose the connection port. Keep the cover on.
Push and twist the needle clockwise onto the syringe.
Now pull off the plastic needle cover.
Do not twist it.
Tip: If you twist the needle cover to remove it, you may accidentally remove the needle as well. 3 Remove any air
To remove air, point the syringe needle upwards. Gently tap to bring air bubbles to the top.
Push the plunger carefully to remove the air. Don’t let more than a small drop of liquid escape. 4 Clean and stretch the injection site
If you need to, use an alcohol wipe to clean the skin at the injection site you’ve chosen. Allow the skin to dry.
With one hand, stretch the skin around the injection site.
Relax your muscle. 5 Make the injection
Insert the injection needle with a quick dart-like thrust at right angles to the skin, into the muscle
The needle must go all the way in.
Press the plunger slowly until the syringe is empty. 6 Pull the needle out
Keep the skin stretched tightly or squeeze the skin around the injection site, and pull out the needle.
If you use alcohol wipes, hold one on the injection site.
Put a plaster over the site of injection if you need to.
Dispose of the rubbish properly
After you have finished each injection, put the needle, syringe and vial into a special container (such as a sharps bin), not in ordinary rubbish. Waste paper and used wipes can be put in an ordinary rubbish bin.

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MiraLax Powder for Oral Solution

Pronunciation: pol-ee-ETH-il-een GLIE-col
Generic Name: Polyethylene Glycol-3350
Brand Name: Examples include GlycoLax and MiraLax
MiraLax Powder for Oral Solution is used for:

Treating occasional constipation.

MiraLax Powder for Oral Solution is a laxative. It works by softening the stool and increasing the frequency of bowel movements by retaining water in the stool.

Do NOT use MiraLax Powder for Oral Solution if: you are allergic to any ingredient in MiraLax Powder for Oral Solution you have blockage of the stomach or intestine (nausea, vomiting, stomach pain, or bloating); loss of strength in the intestinal muscles; chronic inflammation and ulceration of the bowel; holes in the intestine; or an enlarged colon

Contact your doctor or health care provider right away if any of these apply to you.

Before using MiraLax Powder for Oral Solution:

Some medical conditions may interact with MiraLax Powder for Oral Solution. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant, or are breast-feeding if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement if you have allergies to medicines, foods, or other substances

Some MEDICINES MAY INTERACT with MiraLax Powder for Oral Solution. However, no specific interactions with MiraLax Powder for Oral Solution are known at this time.

Ask your health care provider if MiraLax Powder for Oral Solution may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use MiraLax Powder for Oral Solution:

Use MiraLax Powder for Oral Solution as directed by your doctor. Check the label on the medicine for exact dosing instructions.

An extra patient leaflet is available with MiraLax Powder for Oral Solution. Talk to your pharmacist if you have questions about this information. Use the measuring cap that comes with MiraLax Powder for Oral Solution to measure your dose. Mix the medicine in 4 to 8 oz of liquid unless your doctor tells you otherwise. You may mix MiraLax Powder for Oral Solution in water, juice, soda, coffee, or tea. Do not use MiraLax Powder for Oral Solution for more than 2 weeks unless directed to do so by your doctor. If you miss a dose of MiraLax Powder for Oral Solution and you are taking it regularly, take it as soon as possible. If several hours have passed or if it is nearing time for the next dose, do not double the dose to catch up, unless advised by your health care provider. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use MiraLax Powder for Oral Solution.

Important safety information: It may take 2 to 4 days for MiraLax Powder for Oral Solution to work. Follow the diet and exercise program given to you by your health care provider to produce more regular bowel habits. The risk of abnormal blood electrolyte levels and dependence on laxatives may be greater if you take MiraLax Powder for Oral Solution in high doses or for a long time. Do NOT take more than the recommended dose or use for longer than 2 weeks without checking with your doctor. Do not take MiraLax Powder for Oral Solution with other laxatives or stool softeners, unless directed by your doctor. MiraLax Powder for Oral Solution should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed. PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using MiraLax Powder for Oral Solution while you are pregnant. It is not known if MiraLax Powder for Oral Solution is found in breast milk. If you are or will be breast-feeding while you use MiraLax Powder for Oral Solution, check with your doctor. Discuss any possible risks to your baby. Possible side effects of MiraLax Powder for Oral Solution:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Cramps; diarrhea; excessive or frequent bowel movements; gas; nausea; stomach bloating.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: MiraLax side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include severe or prolonged stomach cramps or diarrhea.

Proper storage of MiraLax Powder for Oral Solution:

Store MiraLax Powder for Oral Solution at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep MiraLax Powder for Oral Solution out of the reach of children and away from pets.

General information: If you have any questions about MiraLax Powder for Oral Solution, please talk with your doctor, pharmacist, or other health care provider. MiraLax Powder for Oral Solution is to be used only by the patient for whom it is prescribed. Do not share it with other people. If your symptoms do not improve or if they become worse, check with your doctor. Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about MiraLax Powder for Oral Solution. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012 Database Edition 12.1.1.002 Copyright © 2012 Wolters Kluwer Health, Inc. More MiraLax resources MiraLax Side Effects (in more detail)MiraLax Use in Pregnancy & BreastfeedingMiraLax Drug InteractionsMiraLax Support Group27 Reviews for MiraLax - Add your own review/rating Compare MiraLax with other medications Bowel PreparationConstipationConstipation, Acute

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Fasturtec

1. Name Of The Medicinal Product

Fasturtec 1.5 mg/ml powder and solvent for concentrate for solution for infusion.

2. Qualitative And Quantitative Composition

After reconstitution, 1 ml of Fasturtec concentrate contains 1.5 mg rasburicase.

Fasturtec is a recombinant urate-oxidase enzyme produced by genetically modified Saccharomyces cerevisiae strain. Rasburicase is a tetrameric protein with identical subunits of a molecular mass of about 34 kDa.

1 mg corresponds to 18.2 EAU*.

*One enzyme activity unit (EAU) corresponds to the enzyme activity that converts 1?mol of uric acid into allantoin per minute under the operating conditions described: +30°C±1°C TEA pH8.9 buffer.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for concentrate for solution for infusion.

The powder is an entire or broken white to off white pellet.

The solvent is a colourless and clear liquid.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment and prophylaxis of acute hyperuricaemia, in order to prevent acute renal failure, in patients with haematological malignancy with a high tumour burden and at risk of a rapid tumour lysis or shrinkage at initiation of chemotherapy.

4.2 Posology And Method Of Administration

Fasturtec should be administered under the supervision of a physician trained in chemotherapy of haematological malignancies.

Fasturtec is to be used immediately prior to and during the initiation of chemotherapy only, as at the present, there is insufficient data to recommend multiple treatment courses.

The recommended dose for Fasturtec is 0.20 mg/kg/day. Fasturtec is administered as a once daily 30 minute intravenous infusion in 50 ml of a sodium chloride 9 mg/ml (0.9%) solution (see section 6.6).

The duration of treatment with Fasturtec may be up to 7 days, the exact duration should be based upon adequate monitoring of uric acid levels in plasma and clinical judgment.

Administration of rasburicase does not require any change in the timing or schedule of initiation of cytoreductive chemotherapy.

Rasburicase solution should be infused over 30 minutes. Rasburicase solution should be infused through a different line than that used for infusion of chemotherapeutic agents to prevent any possible drug incompatibility. If use of a separate line is not possible, the line should be flushed out with saline solution between infusion of chemotherapeutic agents and rasburicase. For instruction on use, see section 6.6.

Because rasburicase may degrade uric acid in vitro, special precautions must be used during sample handling for plasma uric acid measurements, see section 6.6.

Additional information on special populations

Renally or hepatically impaired patients: No dose adjustment is necessary.

Paediatric patients: As no dose adjustment is necessary, the recommended dose is 0.20 mg/kg/day.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

G6PD deficiency and other cellular metabolic disorders known to cause haemolytic anaemia. Hydrogen peroxide is a by-product of the conversion of uric acid to allantoin. In order to prevent possible haemolytic anaemia induced by hydrogen peroxide, rasburicase is contraindicated in patients with these disorders.

4.4 Special Warnings And Precautions For Use

Rasburicase like other proteins, has the potential to induce allergic responses in humans. Clinical experience with Fasturtec demonstrates that patients should be closely monitored for the onset of allergic-type undesirable effects, especially severe hypersensitivity reactions including anaphylaxis (see section 4.8). In such cases, treatment should immediately and permanently be discontinued and appropriate therapy initiated.

Caution should be used in patients with a history of atopic allergies.

At present, there is insufficient data available on patients being retreated to recommend multiple treatment courses. Anti-rasburicase antibodies have been detected in treated patients and healthy volunteers administered rasburicase.

Methaemoglobinaemia has been reported in patients receiving Fasturtec. Fasturtec should immediately and permanently be discontinued in patients having developed methaemoglobinaemia, and appropriate measures initiated (see section 4.8).

Haemolysis has been reported in patients receiving Fasturtec. In such case, treatment should immediately and permanently be discontinued and appropriate measures initiated (see section 4.8).

Administration of Fasturtec reduces the uric acid levels to below normal levels and by this mechanism reduces the chance of development of renal failure due to precipitation of uric acid crystals in renal tubules as a consequence of hyperuricaemia. Tumour lysis can also result in hyperphosphataemia, hyperkalaemia and hypocalcaemia. Fasturtec is not directly effective in the treatment of these abnormalities. Therefore, patients must be monitored closely.

Fasturtec has not been investigated in the patients with hyperuricemia in the context of myeloproliferative disorders.

There is no data available to recommend the sequential use of Fasturtec and allopurinol.

To ensure accurate measurement of uric acid plasma level during treatment with Fasturtec, a strict sample handling procedure must be followed (see section 6.6).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No metabolism studies have been performed. Rasburicase being an enzyme itself, it would be an unlikely candidate for drug-drug interactions.

4.6 Pregnancy And Lactation

For rasburicase no clinical data on exposed pregnancies are available. Animal studies with respect to effects on parturition and postnatal development have not been performed (see section 5.3.). The potential risk for humans is unknown. Fasturtec should not be used during pregnancy or breast-feeding women.

It is unknown whether rasburicase is excreted in human milk.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

Fasturtec is concomitantly administered as supportive care to cytoreductive chemotherapy of advanced malignancies, the causality of adverse events is therefore difficult to assess due to the significant burden of adverse events expected from the underlying disease and its treatment.

The most significant drug-related adverse events were common allergic reactions, mainly rashes and urticaria. Cases of hypotension (< 1%), bronchospasm (< 1%), rhinitis (< 0.1%) and severe hypersensitivity reactions (< 1%), including anaphylaxis (< 0.1%) have also been attributed to Fasturtec.

In clinical trials, haematological disorders such as haemolysis, haemolytic anaemia and methaemoglobinaemia are uncommonly caused by Fasturtec. The enzymatic digestion of uric acid to allantoin by rasburicase produces hydrogen peroxide and haemolytic anaemia or methaemoglobinaemia have been observed in certain at risk populations such as those with G6PD deficiency.

In addition, grade 3 or 4 adverse reactions possibly attributable to Fasturtec and reported in the clinical trials, are listed below, by system organ class and by frequency. Frequencies are defined as: common (

 

Common

Uncommon

Nervous system disorders

 

Headache

Gastrointestinal disorders

 

Diarrhoea

Vomiting

Nausea

General disorders and administration site conditions

Fever

 

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

4.9 Overdose

In view of the mechanism of action of Fasturtec, an overdose will lead to low or undetectable plasma uric acid concentrations and increased production of hydrogen peroxide. Thus patients suspected of receiving an overdose should be monitored for haemolysis, and general supportive measures should be initiated as no specific antidote for Fasturtec has been identified.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment, ATC code: V03AF07.

In humans, uric acid is the final step in the catabolic pathway of purines. The acute increase in plasma levels of uric acid subsequent to the lysis of large numbers of malignant cells and during cytoreductive chemotherapy may lead to impairment of renal function and renal failure resulting from the precipitation of crystals of uric acid in renal tubules. Rasburicase is a highly potent uricolytic agent that catalyses enzymatic oxidation of uric acid into allantoin, a water soluble product, easily excreted by the kidneys in the urine.

The enzymatic oxidation of uric acid leads to stoichiometric formation of hydrogen peroxide. The increased of hydrogen peroxide over ambient levels can be eliminated by endogenous antioxidants and the only increased risk is for haemolysis in G6PD deficient and inherited anaemia patients.

In healthy volunteers, a marked dose-related decrease in plasma uric acid levels was observed across the dose range 0.05 mg/kg to 0.20 mg/kg of Fasturtec.

A randomised comparative phase III study, using the recommended dose, showed a significantly more rapid onset of action of Fasturtec in comparison with allopurinol. At 4 hours post first dose, there was a significant difference in the mean percentage change from baseline plasma uric acid concentration (p<0.0001) in the Fasturtec group (-86.0%) compared to that for the allopurinol group (-12.1%).

Time to first confirmation of normal levels of uric acid in hyperuricaemic patients is four hours for Fasturtec and 24 hours for allopurinol. In addition this rapid control of uric acid in this population is accompanied by improvements in renal function. In turn, this allows efficient excretion of the serum phosphate load preventing further deterioration of renal function from calcium/phosphorus precipitation.

Paediatric patients

In pivotal clinical studies, 246 patients (<18 years) were treated with rasburicase at doses of 0.15 mg/kg/day or 0.20 mg/kg/day for 1 to 8 days (mainly 5 to 7 days). Efficacy results on 229 evaluable patients showed an overall response rate (normalization of plasma uric acid levels) of 96.1%. Safety results on 246 patients were consistent with the adverse events profile in the overall population.

In long term safety studies, an analysis of data from 867 patients (< 18 years) treated with rasburicase at 0.20 mg/kg/day for 1 to 24 days (mainly 1 to 4 days) showed consistent findings with pivotal clinical studies in terms of efficacy and safety.

5.2 Pharmacokinetic Properties

After infusion of rasburicase at a dose of 0.20 mg/kg/day, steady state is achieved at day 2-3. No unexpected accumulation of rasburicase was observed. In patients, the volume of distribution ranged from 110 - 127 ml/kg, which is comparable to the physiological vascular volume. Clearance of rasburicase was ca. 3.5 ml/h/kg and the elimination half-life ca. 19 hours. The patients included in the pharmacokinetic studies were mainly children and adolescents. Based upon these limited data, it seems that clearance is increased (ca. 35%) in children and adolescents compared to adults, resulting in a lower systemic exposure.

Rasburicase is a protein, and therefore: 1) not expected to bind to proteins, 2) expected that metabolic degradation will follow the pathways of other proteins, i.e. peptide hydrolysis, 3) unlikely to be candidate for drug-drug interactions.

Renal elimination of rasburicase is considered to be a minor pathway for rasburicase clearance. As metabolism is expected to occur by peptide hydrolysis, an impaired liver function is not expected to affect the pharmacokinetics.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. The interpretation of the non-clinical studies is hampered due to the presence of endogenous urate oxidase in standard animal models.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Powder :

alanine

mannitol

disodium phosphate dodecahydrate

disodium phosphate dihydrate

sodium dihydrogen phosphate dihydrate

Solvent :

poloxamer 188

water for injection

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Rasburicase solution should be infused through a different line than that used for infusion of chemotherapeutic agents to prevent any possible drug incompatibility. If use of a separate line is not possible, the line should be flushed out with saline solution between chemotherapeutic agent infusions and rasburicase.

No filter should be used for infusion.

Do not use any glucose solution for dilution due to potential incompatibility.

6.3 Shelf Life

3 years

After reconstitution or dilution an immediate use is recommended. However, the in-use stability has been demonstrated for 24 hours between +2°C and 8°C.

6.4 Special Precautions For Storage

Powder in vial: store in a refrigerator (2°C – 8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions of the reconstituted or the diluted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Fasturtec is supplied as a pack of :

3 vials of 1.5 mg rasburicase and 3 ampoules of 1 ml solvent. The powder is supplied in 3 ml clear glass (type I) vial with a rubber stopper and the solvent in a 2 ml clear glass (type I) ampoule.

1 vial of 7.5 mg rasburicase and 1 ampoule of 5 ml solvent. The powder is supplied in 10 ml clear glass (type I) vial with a rubber stopper and the solvent in a 5 ml clear glass (type I) ampoule.

6.6 Special Precautions For Disposal And Other Handling

Rasburicase must be reconstituted with the entire volume of the supplied solvent ampoule (1.5 mg rasburicase vial to be reconstituted with the 1 ml solvent ampoule; 7.5 mg rasburicase vial to be reconstituted with the 5 ml solvent ampoule). Reconstitution results in a solution with a concentration of 1.5 mg/ml rasburicase to be further diluted with sodium chloride 9 mg/ml (0.9%) intravenous solution.

Reconstitution of the solution:

Add the content of one ampoule of solvent to one vial containing rasburicase and mix by swirling very gently under controlled and validated aseptic conditions.

Do not shake.

Inspect visually prior to use. Only clear and colourless solutions without particles should be used.

For single-use only, any unused solution should be discarded.

The solvent contains no preservative. Therefore the reconstituted solution should be diluted under controlled and validated aseptic conditions.

Dilution before infusion:

The required volume of the reconstituted solution depends on the patient's body weight. The use of several vials may be necessary to obtain the quantity of rasburicase required for one administration. The required volume of the reconstituted solution, taken from one or more vials, is to be further diluted with sodium chloride 9 mg/ml (0.9%) solution to make a total volume of 50 ml. The concentration of rasburicase in the final solution for infusion depends on the patient's body weight.

The reconstituted solution contains no preservative. Therefore the diluted solution should be infused immediately.

Infusion:

The final solution should be infused over 30 minutes.

Sample handling:

If it is necessary to monitor a patient's uric acid level, a strict sample-handling procedure must be followed to minimise ex vivo degradation of the analyte. Blood must be collected into pre-chilled tubes containing heparin anticoagulant. Samples must be immersed in an ice/water bath. Plasma samples should immediately be prepared by centrifugation in a pre-cooled centrifuge (4°C). Finally, plasma must be maintained in an ice/water bath and analysed for uric acid within 4 hours.

7. Marketing Authorisation Holder

sanofi-aventis

174, avenue de France

F - 75013 Paris, France

8. Marketing Authorisation Number(S)

EU/1/00/170/001-002

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 23 February 2001

Date of last renewal: 23 February 2006

10. Date Of Revision Of The Text

February 2009

Legal category: POM

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GONAL-f 1050 IU / 1.75 ml (77mcg / 1.75 ml)

1. Name Of The Medicinal Product

GONAL-f 1050 IU/1.75 ml (77 micrograms/1.75 ml) powder and solvent for solution for injection.

2. Qualitative And Quantitative Composition

Each vial contains 77 micrograms of follitropin alfa* equivalent to 1050 IU. Each ml of the reconstituted solution contains 600 IU.

* recombinant human follicle stimulating hormone (r-hFSH) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

Appearance of the powder: white lyophilised pellet.

Appearance of the solvent: clear colourless solution.

The pH of the reconstituted solution is 6.5-7.5.

4. Clinical Particulars 4.1 Therapeutic Indications

In adult women

• Anovulation (including polycystic ovarian syndrome) in women who have been unresponsive to treatment with clomiphene citrate.

• Stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer and zygote intra-fallopian transfer.

• GONAL-f in association with a luteinising hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level < 1.2 IU/l.

In adult men

• GONAL-f is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin (hCG) therapy.

4.2 Posology And Method Of Administration

Treatment with GONAL-f should be initiated under the supervision of a physician experienced in the treatment of fertility disorders.

Posology

The dose recommendations given for GONAL-f are those in use for urinary FSH. Clinical assessment of GONAL-f indicates that its daily doses, regimens of administration, and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. It is advised to adhere to the recommended starting doses indicated below.

Comparative clinical studies have shown that on average patients require a lower cumulative dose and shorter treatment duration with GONAL-f compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dose of GONAL-f than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation. See section 5.1.

Bioequivalence has been demonstrated between equivalent doses of the monodose presentation and the multidose presentation of GONAL-f.

The following table states the volume to be administered to deliver the prescribed dose:

Dose (IU)

Volume to be injected (ml)

75

0.13

150

0.25

225

0.38

300

0.50

375

0.63

450

0.75

The next injection should be done at the same time the next day.

Women with anovulation (including polycystic ovarian syndrome)

GONAL-f may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle.

A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and/or oestrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle.

When an optimal response is obtained, a single injection of 250 micrograms recombinant human choriogonadotropin alfa (r-hCG) or 5,000 IU, up to 10,000 IU hCG should be administered 24-48 hours after the last GONAL-f injection. The patient is recommended to have coitus on the day of, and the day following, hCG administration. Alternatively intrauterine insemination (IUI) may be performed.

If an excessive response is obtained, treatment should be stopped and hCG withheld (see section 4.4). Treatment should recommence in the next cycle at a dose lower than that of the previous cycle.

Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies.

A commonly used regimen for superovulation involves the administration of 150-225 IU of GONAL-f daily, commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum oestrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days).

A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours after the last GONAL-f injection to induce final follicular maturation.

Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, GONAL-f is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU GONAL-f are administered for the first 7 days. The dose is then adjusted according to the ovarian response.

Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter.

Women with anovulation resulting from severe LH and FSH deficiency.

In LH and FSH deficient women (hypogonadotrophic hypogonadism), the objective of GONAL-f therapy in association with lutropin alfa is to develop a single mature Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotropin (hCG). GONAL-f should be given as a course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time.

A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and oestrogen response.

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks.

When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last GONAL-f and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following, hCG administration.

Alternatively, IUI may be performed.

Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle.

Men with hypogonadotrophic hypogonadism

GONAL-f should be given at a dose of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis.

Special population

Elderly population

There is no relevant use of GONAL-f in the elderly population. Safety and effectiveness of GONAL-f in elderly patients have not been established.

Renal or hepatic impairment

Safety, efficacy and pharmacokinetics of GONAL-f in patients with renal or hepatic impairment have not been established.

Paediatric population

There is no relevant use of GONAL-f in the paediatric population.

Method of administration

GONAL-f is intended for subcutaneous administration. The first injection of GONAL-f should be performed under direct medical supervision. Self-administration of GONAL-f should only be performed by patients who are well motivated, adequately trained and have access to expert advice.

As GONAL-f multidose is intended for several injections, clear instructions should be provided to the patients to avoid misuse of the multidose presentation.

Due to a local reactivity to benzyl alcohol, the same site of injection should not be used on consecutive days.

Individual reconstituted vials should be for single patient use only.

For instructions on the reconstitution and administration of GONAL-f powder and solvent for solution for injection see section 6.6 and the package leaflet.

4.3 Contraindications

• hypersensitivity to the active substance follitropin alfa, FSH or to any of the excipients

• tumours of the hypothalamus or pituitary gland

• ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome

• gynaecological haemorrhages of unknown aetiology

• ovarian, uterine or mammary carcinoma

GONAL-f must not be used when an effective response cannot be obtained, such as:

• primary ovarian failure

• malformations of sexual organs incompatible with pregnancy

• fibroid tumours of the uterus incompatible with pregnancy

• primary testicular insufficiency

4.4 Special Warnings And Precautions For Use

GONAL-f is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of GONAL-f calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with measurement of serum oestradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women.

Porphyria

Patients with porphyria or a family history of porphyria should be closely monitored during treatment with GONAL-f. Deterioration or a first appearance of this condition may require cessation of treatment.

Treatment in women

Before starting treatment, the couple's infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and appropriate specific treatment given.

Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended GONAL-f dose and regimen of administration and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests.

In clinical trials, an increase of the ovarian sensitivity to GONAL-f was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments.

No direct comparison of GONAL-f/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with GONAL-f/LH is similar to that obtained with hMG.

Ovarian Hyperstimulation Syndrome (OHSS)

A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment.

In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities.

The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction.

Independent risk factors for developing OHSS include polycystic ovarian syndrome high absolute or rapidly rising serum oestradiol levels (e.g. > 900 pg/ml or > 3,300 pmol/l in anovulation; > 3,000 pg/ml or > 11,000 pmol/l in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of

Adherence to recommended GONAL-f dose and regimen of administration can minimise the risk of ovarian hyperstimulation (see sections 4.2 and 4.8). Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to early identify risk factors.

There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as serum oestradiol level > 5,500 pg/ml or > 20,200 pmol/l and/or

In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.

Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started.

Multiple pregnancy

In patients undergoing ovulation induction, the incidence of multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes.

To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age.

The patients should be advised of the potential risk of multiple births before starting treatment.

Pregnancy loss

The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction or ART than following natural conception.

Ectopic pregnancy

Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after ART, was reported to be higher than in the general population.

Reproductive system neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women.

Congenital malformation

The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies.

Thromboembolic events

In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however that pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events.

Treatment in men

Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to GONAL-f/hCG therapy. GONAL-f should not be used when an effective response cannot be obtained.

Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response.

Sodium content

GONAL-f contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of GONAL-f with other medicinal products used to stimulate ovulation (e.g. hCG, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of GONAL-f needed to elicit an adequate ovarian response. No other clinically significant medicinal product interaction has been reported during GONAL-f therapy.

4.6 Pregnancy And Lactation

Pregnancy

There is no indication for use of GONAL-f during pregnancy. Data on a limited number of exposed pregnancies (less than 300 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of follitropin alfa.

No teratogenic effect has been observed in animal studies (see section 5.3).

In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of GONAL-f.

Breastfeeding

GONAL-f is not indicated during breastfeeding.

Fertility

GONAL-f is indicated for use in infertility (see section 4.1).

4.7 Effects On Ability To Drive And Use Machines

GONAL-f is expected to have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

The most commonly reported adverse reactions are headache, ovarian cysts and local injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection).

Mild or moderate ovarian hyperstimulation syndrome (OHSS) has been commonly reported and should be considered as an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon (see section 4.4).

Thromboembolism may occur very rarely, usually associated with severe OHSS (see section 4.4).

The following definitions apply to the frequency terminology used hereafter:

Very common (

Common (

Uncommon (

Rare (

Very rare (< 1/10,000)

Treatment in women

Immune system disorders   Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Nervous system disorders   Very common: Headache Vascular disorders   Very rare: Thromboembolism, usually associated with severe OHSS (see section 4.4) Respiratory, thoracic and mediastinal disorders   Very rare: Exacerbation or aggravation of asthma Gastrointestinal disorders   Common: Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea Reproductive system and breast disorders   Very common: Ovarian cysts Common: Mild or moderate OHSS (including associated symptomatology) Uncommon: Severe OHSS (including associated symptomatology) (see section 4.4) Rare: Complication of severe OHSS General disorders and administration site conditions   Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection)

Treatment in men

Immune system disorders   Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock Respiratory, thoracic and mediastinal disorders   Very rare: Exacerbation or aggravation of asthma Skin and subcutaneous tissue disorders   Common: Acne Reproductive system and breast disorders   Common: Gynaecomastia, Varicocele General disorders and administration site conditions   Very common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Investigations   Common: Weight gain 4.9 Overdose

The effects of an overdose of GONAL-f are unknown, nevertheless, there is a possibility that OHSS may occur (see section 4.4).

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05.

In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the object of GONAL-f therapy is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.

Clinical efficacy and safety in women

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/l as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.

In clinical studies comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table below) and in ovulation induction, GONAL-f was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.

In ART, GONAL-f at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH.

Table: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of GONAL-f with urinary FSH in assisted reproduction technologies)

 

GONAL-f

(n = 130)

urinary FSH

(n = 116)

Number of oocytes retrieved

11.0 ± 5.9

8.8 ± 4.8

Days of FSH stimulation required

11.7 ± 1.9

14.5 ± 3.3

Total dose of FSH required (number of FSH 75 IU ampoules)

27.6 ± 10.2

40.7 ± 13.6

Need to increase the dose (%)

56.2

85.3

Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed.

Clinical efficacy and safety in men

In men deficient in FSH, GONAL-f administered concomitantly with hCG for at least 4 months induces spermatogenesis.

5.2 Pharmacokinetic Properties

Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 l and 0.6 l/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine.

Following subcutaneous administration, the absolute bioavailability is about 70 %. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity additional to that already stated in other sections of this SmPC.

In rabbits, the formulation reconstituted with 0.9 % benzyl alcohol and 0.9 % benzyl alcohol alone, both resulted in a slight haemorrhage and subacute inflammation after single subcutaneous injection or mild inflammatory and degenerative changes after single intramuscular injection respectively.

Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (

Given in high doses (

6. Pharmaceutical Particulars 6.1 List Of Excipients

Powder

Sucrose

Sodium dihydrogen phosphate monohydrate

Disodium phosphate dihydrate

Phosphoric acid, concentrated

Sodium hydroxide

Solvent

Water for injections

Benzyl alcohol

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

2 years.

The reconstituted solution is stable for 28 days at or below 25°C.

6.4 Special Precautions For Storage

Prior to reconstitution, do not store above 25°C. Store in the original package, in order to protect from light.

After reconstitution, do not store above 25°C. Do not freeze. Store in the original container, in order to protect from light.

6.5 Nature And Contents Of Container

GONAL f is presented as a powder and solvent for injection. The powder is presented in 3 ml vials (Type I glass), with rubber stopper (bromobutyl rubber) and aluminium flip-off cap. The solvent for reconstitution is presented in 2 ml pre-filled syringes (Type I glass) with a rubber stopper. The administration syringes made of polypropylene with a stainless steel pre-fixed needle are also provided.

The medicinal product is supplied as a pack of 1 vial of powder with 1 pre-filled syringe of solvent for reconstitution and 15 disposable syringes for administration graduated in FSH units.

6.6 Special Precautions For Disposal And Other Handling

GONAL-f 1050 IU/1.75 ml (77 micrograms/1.75 ml) must be reconstituted with the 2 ml solvent provided before use.

GONAL-f 1050 IU/1.75 ml (77 micrograms/1.75 ml) preparation must not be reconstituted with any other GONAL-f containers.

The solvent pre-filled syringe provided should be used for reconstitution only and then disposed of in accordance with local requirements. A set of administration syringes graduated in FSH units is supplied in the GONAL-f multidose box. Alternatively, a 1 ml syringe, graduated in ml, with pre-fixed needle for subcutaneous administration could be used (see section “How to prepare and use the GONAL-f powder and solvent” in the package leaflet).

The reconstituted solution should not be administered if it contains particles or is not clear.Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Merck Serono Europe Ltd.

56 Marsh Wall

London E14 9TP

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/95/001/021

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 20 October 1995.

Date of last renewal: 20 October 2010.

10. Date Of Revision Of The Text

May 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

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GONAL-f 450 IU / 0.75 ml (33 mcg / 0.75ml)

1. Name Of The Medicinal Product

GONAL-f 450 IU/0.75 ml (33 micrograms/0.75 ml) powder and solvent for solution for injection.

2. Qualitative And Quantitative Composition

Each vial contains 33 micrograms of follitropin alfa* equivalent to 450 IU. Each ml of the reconstituted solution contains 600 IU.

* recombinant human follicle stimulating hormone (r-hFSH) produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

Appearance of the powder: white lyophilised pellet.

Appearance of the solvent: clear colourless solution.

The pH of the reconstituted solution is 6.5-7.5.

4. Clinical Particulars 4.1 Therapeutic Indications

In adult women

• Anovulation (including polycystic ovarian syndrome) in women who have been unresponsive to treatment with clomiphene citrate.

• Stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra-fallopian transfer and zygote intra-fallopian transfer.

• GONAL-f in association with a luteinising hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level < 1.2 IU/l.

In adult men

• GONAL-f is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin (hCG) therapy.

4.2 Posology And Method Of Administration

Treatment with GONAL-f should be initiated under the supervision of a physician experienced in the treatment of fertility disorders.

Posology

The dose recommendations given for GONAL-f are those in use for urinary FSH. Clinical assessment of GONAL-f indicates that its daily doses, regimens of administration, and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing medicinal products. It is advised to adhere to the recommended starting doses indicated below.

Comparative clinical studies have shown that on average patients require a lower cumulative dose and shorter treatment duration with GONAL-f compared with urinary FSH. Therefore, it is considered appropriate to give a lower total dose of GONAL-f than generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation. See section 5.1.

Bioequivalence has been demonstrated between equivalent doses of the monodose presentation and the multidose presentation of GONAL-f.

The following table states the volume to be administered to deliver the prescribed dose:

Dose (IU)

Volume to be injected (ml)

75

0.13

150

0.25

225

0.38

300

0.50

375

0.63

450

0.75

The next injection should be done at the same time the next day.

Women with anovulation (including polycystic ovarian syndrome)

GONAL-f may be given as a course of daily injections. In menstruating women treatment should commence within the first 7 days of the menstrual cycle.

A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate, but not excessive, response. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and/or oestrogen secretion. The maximal daily dose is usually not higher than 225 IU FSH. If a patient fails to respond adequately after 4 weeks of treatment, that cycle should be abandoned and the patient should undergo further evaluation after which she may recommence treatment at a higher starting dose than in the abandoned cycle.

When an optimal response is obtained, a single injection of 250 micrograms recombinant human choriogonadotropin alfa (r-hCG) or 5,000 IU, up to 10,000 IU hCG should be administered 24-48 hours after the last GONAL-f injection. The patient is recommended to have coitus on the day of, and the day following, hCG administration. Alternatively intrauterine insemination (IUI) may be performed.

If an excessive response is obtained, treatment should be stopped and hCG withheld (see section 4.4). Treatment should recommence in the next cycle at a dose lower than that of the previous cycle.

Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies.

A commonly used regimen for superovulation involves the administration of 150-225 IU of GONAL-f daily, commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum oestrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU daily. In general adequate follicular development is achieved on average by the tenth day of treatment (range 5 to 20 days).

A single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG is administered 24-48 hours after the last GONAL-f injection to induce final follicular maturation.

Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. In a commonly used protocol, GONAL-f is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks of treatment with an agonist, 150-225 IU GONAL-f are administered for the first 7 days. The dose is then adjusted according to the ovarian response.

Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter.

Women with anovulation resulting from severe LH and FSH deficiency.

In LH and FSH deficient women (hypogonadotrophic hypogonadism), the objective of GONAL-f therapy in association with lutropin alfa is to develop a single mature Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotropin (hCG). GONAL-f should be given as a course of daily injections simultaneously with lutropin alfa. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time.

A recommended regimen commences at 75 IU of lutropin alfa daily with 75-150 IU FSH. Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and oestrogen response.

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5-75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks.

When an optimal response is obtained, a single injection of 250 micrograms r-hCG or 5,000 IU up to 10,000 IU hCG should be administered 24-48 hours after the last GONAL-f and lutropin alfa injections. The patient is recommended to have coitus on the day of, and on the day following, hCG administration.

Alternatively, IUI may be performed.

Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle.

Men with hypogonadotrophic hypogonadism

GONAL-f should be given at a dose of 150 IU three times a week, concomitantly with hCG, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued; current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis.

Special population

Elderly population

There is no relevant use of GONAL-f in the elderly population. Safety and effectiveness of GONAL-f in elderly patients have not been established.

Renal or hepatic impairment

Safety, efficacy and pharmacokinetics of GONAL-f in patients with renal or hepatic impairment have not been established.

Paediatric population

There is no relevant use of GONAL-f in the paediatric population.

Method of administration

GONAL-f is intended for subcutaneous administration. The first injection of GONAL--f should be performed under direct medical supervision. Self-administration of GONAL-f should only be performed by patients who are well motivated, adequately trained and have access to expert advice.

As GONAL-f multidose is intended for several injections, clear instructions should be provided to the patients to avoid misuse of the multidose presentation.

Due to a local reactivity to benzyl alcohol, the same site of injection should not be used on consecutive days.

Individual reconstituted vials should be for single patient use only.

For instructions on the reconstitution and administration of GONAL-f powder and solvent for solution for injection see section 6.6 and the package leaflet.

4.3 Contraindications

• hypersensitivity to the active substance follitropin alfa, FSH or to any of the excipients

• tumours of the hypothalamus or pituitary gland

• ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome

• gynaecological haemorrhages of unknown aetiology

• ovarian, uterine or mammary carcinoma

GONAL-f must not be used when an effective response cannot be obtained, such as:

• primary ovarian failure

• malformations of sexual organs incompatible with pregnancy

• fibroid tumours of the uterus incompatible with pregnancy

• primary testicular insufficiency

4.4 Special Warnings And Precautions For Use

GONAL-f is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of GONAL-f calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with measurement of serum oestradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women.

Porphyria

Patients with porphyria or a family history of porphyria should be closely monitored during treatment with GONAL-f. Deterioration or a first appearance of this condition may require cessation of treatment.

Treatment in women

Before starting treatment, the couple's infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and appropriate specific treatment given.

Patients undergoing stimulation of follicular growth, whether as treatment for anovulatory infertility or ART procedures, may experience ovarian enlargement or develop hyperstimulation. Adherence to recommended GONAL-f dose and regimen of administration and careful monitoring of therapy will minimise the incidence of such events. For accurate interpretation of the indices of follicle development and maturation, the physician should be experienced in the interpretation of the relevant tests.

In clinical trials, an increase of the ovarian sensitivity to GONAL-f was shown when administered with lutropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments.

No direct comparison of GONAL-f/LH versus human menopausal gonadotropin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate obtained with GONAL-f/LH is similar to that obtained with hMG.

Ovarian Hyperstimulation Syndrome (OHSS)

A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment.

In distinction to uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities.

The following symptomatology may be observed in severe cases of OHSS: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnoea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction.

Independent risk factors for developing OHSS include polycystic ovarian syndrome high absolute or rapidly rising serum oestradiol levels (e.g. > 900 pg/ml or > 3,300 pmol/l in anovulation; > 3,000 pg/ml or > 11,000 pmol/l in ART) and large number of developing ovarian follicles (e.g. > 3 follicles of

Adherence to recommended GONAL-f dose and regimen of administration can minimise the risk of ovarian hyperstimulation (see sections 4.2 and 4.8). Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to early identify risk factors.

There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as serum oestradiol level > 5,500 pg/ml or > 20,200 pmol/l and/or

In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation.

Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotropin treatment be stopped if still ongoing, and that the patient be hospitalised and appropriate therapy be started.

Multiple pregnancy

In patients undergoing ovulation induction, the incidence of multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancy, especially of high order, carries an increased risk of adverse maternal and perinatal outcomes.

To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient age.

The patients should be advised of the potential risk of multiple births before starting treatment.

Pregnancy loss

The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction or ART than following natural conception.

Ectopic pregnancy

Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after ART, was reported to be higher than in the general population.

Reproductive system neoplasms

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women.

Congenital malformation

The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies.

Thromboembolic events

In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however that pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events.

Treatment in men

Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to GONAL-f/hCG therapy. GONAL-f should not be used when an effective response cannot be obtained.

Semen analysis is recommended 4 to 6 months after the beginning of treatment as part of the assessment of the response.

Sodium content

GONAL-f contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of GONAL-f with other medicinal products used to stimulate ovulation (e.g. hCG, clomiphene citrate) may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dose of GONAL-f needed to elicit an adequate ovarian response. No other clinically significant medicinal product interaction has been reported during GONAL-f therapy.

4.6 Pregnancy And Lactation

Pregnancy

There is no indication for use of GONAL-f during pregnancy. Data on a limited number of exposed pregnancies (less than 300 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of follitropin alfa.

No teratogenic effect has been observed in animal studies (see section 5.3).

In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of GONAL-f.

Breastfeeding

GONAL-f is not indicated during breastfeeding.

Fertility

GONAL-f is indicated for use in infertility (see section 4.1).

4.7 Effects On Ability To Drive And Use Machines

GONAL-f is expected to have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

The most commonly reported adverse reactions are headache, ovarian cysts and local injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection).

Mild or moderate ovarian hyperstimulation syndrome (OHSS) has been commonly reported and should be considered as an intrinsic risk of the stimulation procedure. Severe OHSS is uncommon (see section 4.4).

Thromboembolism may occur very rarely, usually associated with severe OHSS (see section 4.4).

The following definitions apply to the frequency terminology used hereafter:

Very common (

Common (

Uncommon (

Rare (

Very rare (< 1/10,000)

Treatment in women

Immune system disorders

 

Very rare:

Mild to severe hypersensitivity reactions including anaphylactic reactions and shock

Nervous system disorders

 

Very common:

Headache

Vascular disorders

 

Very rare:

Thromboembolism, usually associated with severe OHSS (see section 4.4)

Respiratory, thoracic and mediastinal disorders

 

Very rare:

Exacerbation or aggravation of asthma

Gastrointestinal disorders

 

Common:

Abdominal pain, abdominal distension, abdominal discomfort, nausea, vomiting, diarrhoea

Reproductive system and breast disorders

 

Very common:

Ovarian cysts

Common:

Mild or moderate OHSS (including associated symptomatology)

Uncommon:

Severe OHSS (including associated symptomatology) (see section 4.4)

Rare:

Complication of severe OHSS

General disorders and administration site conditions

 

Very common:

Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection)

Treatment in men

 

Immune system disorders

 

Very rare:

Mild to severe hypersensitivity reactions including anaphylactic reactions and shock

Respiratory, thoracic and mediastinal disorders

 

Very rare:

Exacerbation or aggravation of asthma

Skin and subcutaneous tissue disorders

 

Common:

Acne

Reproductive system and breast disorders

 

Common:

Gynaecomastia, Varicocele

General disorders and administration site conditions

 

Very common:

Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection)

Investigations

 

Common:

Weight gain

4.9 Overdose

The effects of an overdose of GONAL-f are unknown, nevertheless, there is a possibility that OHSS may occur (see section 4.4).

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins, ATC code: G03GA05.

In women, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. In women with anovulation, the object of GONAL-f therapy is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.

Clinical efficacy and safety in women

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level < 1.2 IU/l as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.

In clinical studies comparing r-hFSH (follitropin alfa) and urinary FSH in ART (see table below) and in ovulation induction, GONAL-f was more potent than urinary FSH in terms of a lower total dose and a shorter treatment period needed to trigger follicular maturation.

In ART, GONAL-f at a lower total dose and shorter treatment period than urinary FSH, resulted in a higher number of oocytes retrieved when compared to urinary FSH.

Table: Results of study GF 8407 (randomised parallel group study comparing efficacy and safety of GONAL-f with urinary FSH in assisted reproduction technologies)

 

GONAL-f

(n = 130)

urinary FSH

(n = 116)

Number of oocytes retrieved

11.0 ± 5.9

8.8 ± 4.8

Days of FSH stimulation required

11.7 ± 1.9

14.5 ± 3.3

Total dose of FSH required (number of FSH 75 IU ampoules)

27.6 ± 10.2

40.7 ± 13.6

Need to increase the dose (%)

56.2

85.3

Differences between the 2 groups were statistically significant (p< 0.05) for all criteria listed.

Clinical efficacy and safety in men

In men deficient in FSH, GONAL-f administered concomitantly with hCG for at least 4 months induces spermatogenesis.

5.2 Pharmacokinetic Properties

Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 l and 0.6 l/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine.

Following subcutaneous administration, the absolute bioavailability is about 70 %. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotropin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity and genotoxicity additional to that already stated in other sections of this SmPC.

In rabbits, the formulation reconstituted with 0.9 % benzyl alcohol and 0.9 % benzyl alcohol alone, both resulted in a slight haemorrhage and subacute inflammation after single subcutaneous injection or mild inflammatory and degenerative changes after single intramuscular injection respectively.

Impaired fertility has been reported in rats exposed to pharmacological doses of follitropin alfa (

Given in high doses (

6. Pharmaceutical Particulars 6.1 List Of Excipients

Powder

Sucrose

Sodium dihydrogen phosphate monohydrate

Disodium phosphate dihydrate

Phosphoric acid, concentrated

Sodium hydroxide

Solvent

Water for injections

Benzyl alcohol

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

2 years.

The reconstituted solution is stable for 28 days at or below 25°C.

6.4 Special Precautions For Storage

Prior to reconstitution, do not store above 25°C. Store in the original package, in order to protect from light.

After reconstitution, do not store above 25°C. Do not freeze. Store in the original container, in order to protect from light.

6.5 Nature And Contents Of Container

GONAL f is presented as a powder and solvent for injection. The powder is presented in 3 ml vials (Type I glass), with rubber stopper (bromobutyl rubber) and aluminium flip-off cap. The solvent for reconstitution is presented in 1 ml pre-filled syringes (Type I glass) with a rubber stopper. The administration syringes made of polypropylene with a stainless steel pre-fixed needle are also provided.

The medicinal product is supplied as a pack of 1 vial of powder with 1 pre-filled syringe of solvent for reconstitution and 6 disposable syringes for administration graduated in FSH units.

6.6 Special Precautions For Disposal And Other Handling

GONAL-f 450 IU/0.75 ml (33 micrograms/0.75 ml) must be reconstituted with the 1 ml solvent provided before use.

GONAL-f 450 IU/0.75 ml (33 micrograms/0.75 ml) preparation must not be reconstituted with any other GONAL-f containers.

The solvent pre-filled syringe provided should be used for reconstitution only and then disposed of in accordance with local requirements. A set of administration syringes graduated in FSH units is supplied in the GONAL-f multidose box. Alternatively, a 1 ml syringe, graduated in ml, with pre-fixed needle for subcutaneous administration could be used (see section “How to prepare and use the GONAL-f powder and solvent” in the package leaflet).

The reconstituted solution should not be administered if it contains particles or is not clear.Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Merck Serono Europe Ltd.

56 Marsh Wall

London E14 9TP

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/95/001/031

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 20 October 1995.

Date of last renewal: 20 October 2010.

10. Date Of Revision Of The Text

May 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Read More:

Boots Dual Action Athlete's Foot Spray

Boots Dual Action Athlete’s Foot Spray

(Tolnaftate)

Effectively treats athlete’s foot

Relieves skin irritation

Fast drying

150 ml e

Read all of this label for full instructions.

What this medicine is for

An anti-fungal spray for the treatment and prevention of athlete’s foot. Also effective for other skin conditions where tenderness and sweating cause skin irritation, such as dhobie itch (groin ringworm), prickly heat.

Before you use this medicine Do not use: If you are allergic to any of the ingredients

You can use this medicine if you are pregnant or breastfeeding.

How to use this medicine

Shake well before use. Hold the can 15 cm (6 inches) from the skin before spraying.

Wash and thoroughly dry the affected area Spray the affected area liberally If suffering from athlete’s foot, spray the socks and inside of shoes with powder as well Adults and children of 2 years and over:

Apply morning and night.

Continue treatment for at least one week after the condition has cleared up, to stop it coming back.

For use on the skin only.

Avoid contact with eyes.

Do not use on children under 2 years, unless your doctor tells you to.

If symptoms worsen talk to your doctor.

If symptoms do not go away within 10 days, talk to your doctor.

Possible side effects

Most people will not have problems, but some may get some.

If you get any of these stop using the spray and see a doctor: Skin irritation Contact dermatitis (redness and swelling of the skin)

If you notice any side effect not listed here, please tell your pharmacist or doctor.

Do not store above 25°C.

Keep all medicines out of the sight and reach of children.

Use by the date on the base of can.

Active ingredients

This spray powder contains Tolnaftate 1% w/w.

Also contains: dimethyl ether, denatured alcohol, talc, disteardimonium hectorite.

PL 00014/0520

Text prepared 8/07

Manufactured for the Marketing Authorisation holder The Boots Company PLC Nottingham NG2 3AA

by

ColepCCL UK Limited Atkinson’s Way Foxhills Industrial Park Scunthorpe North Lincolnshire DN15 8QJ

Caution: Pressurised container. Protect from sunlight and do not expose to temperatures exceeding 50°C. Do not pierce or burn even when empty. Do not use in confined areas. Do not use near or place on painted or polished surfaces. Avoid inhalation.

EXTREMELY FLAMMABLE

SOLVENT ABUSE CAN KILL INSTANTLY

210

Э

Do not spray on or near naked flame or any incandescent material.

Keep away from sources of ignition. No smoking.

If you need more advice ask your pharmacist.

BTC29774 vA 14/04/08

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Remifentanil 5 mg powder for concentrate for solution for injection / infusion

1. Name Of The Medicinal Product

Remifentanil 5 mg powder for concentrate for solution for injection/infusion

2. Qualitative And Quantitative Composition

Remifentanil 5 mg powder for concentrate for solution for injection/infusion:

1 vial contains 5 mg remifentanil (as remifentanil hydrochloride).

After reconstitution the solution contains 1 mg/ml remifentanil (as hydrochloride), if prepared as recommended (see section 6.6)

Excipients: sodium 1.15 mg

3. Pharmaceutical Form

Powder for concentrate for solution for injection/infusion

Lyophilized white to slightly yellow cake or powdery mass.

4. Clinical Particulars 4.1 Therapeutic Indications

Remifentanil is indicated as an analgesic agent for use during induction and/or maintenance of general anaesthesia.

Remifentanil is indicated for provision of analgesia in mechanically ventilated intensive care patients of 18 years of age and older.

4.2 Posology And Method Of Administration

Remifentanil should be administered only in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by persons specifically trained in the use of anaesthetic drugs and the recognition and management of the expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include the establishment and maintenance of a patent airway and assisted ventilation.

Continuous infusions of remifentanil must be administered by a calibrated infusion device into a fast flowing IV line or via a dedicated IV line. This infusion line should be connected at, or close to, the venous cannula to minimise the potential dead space (see section 6.6 for additional information, including tables with examples of infusion rates by body weight to help titrate remifentanil to the patient's anaesthetic needs). Care should be taken to avoid obstruction or disconnection of infusion lines and to adequately clear the lines to remove residual remifentanil after use (see section 4.4). IV lines/infusion system should be removed after cessation of use to avoid inadvertent administration.

Remifentanil may be given by target-controlled infusion (TCI) with an approved infusion device incorporating the Minto pharmacokinetic model with covariates for age and lean body mass (LBM).

Congestion of the infusion drips or tearing off should be avoided, and the infusion drips should be sufficiently rinsed in order to remove residual Remifentanil after discontinuation of medication (see also section 4.4).

Remifentanil is for intravenous use only and must not be administered by epidural or intrathecal injection (see section 4.3).

Dilution

Remifentanil should not be administered without further dilution after reconstitution of the lyophilized powder. See section 6.3 for storage conditions and section 6.6 for recommended diluents and instructions on reconstitution / dilution of the product before administration.

For manually-controlled infusion [Invented name] can be diluted to concentrations of 20 to 250 micrograms /ml (50 micrograms /ml is the recommended dilution for adults and 20 to 25 micrograms /ml for paediatric patients aged 1 year and over).

For TCI the recommended dilution of Remifentanil is 20 to 50 micrograms /ml.

General Anaesthesia

The administration of Remifentanil must be individualised based on the patient's response.

Adults

Administration by manually-controlled infusion (MCI)

DOSING GUIDELINES FOR ADULTS

 

REMIFENTANIL BOLUS INJECTION

(micrograms /kg)

REMIFENTANIL CONTINUOUS INFUSION

(micrograms/kg/min)

 

Starting Rate

Range

     

1 (within at least 30 seconds)

0.5 to 1

_

 

Maintenance of anaesthesia in ventilated patients

   

• Nitrous oxide (66 %)

0.5 to 1

0.4

0.1 to 2

• Isoflurane (starting dose 0.5 MAC)

0.5 to 1

0.25

0.05 to 2

• Propofol (Starting dose 100 microtrams /kg/min)

0.5 to 1

0.25

0.05 to 2

When given by bolus injection at induction Remifentanil should be administered over not less than 30 seconds.

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil.

No data are available for dosage recommendations for simultaneous use of other hypnotics other than those listed in the table with remifentanil.

Induction of anaesthesia

Remifentanil should be co-administered with a hypnotic agent, such as propofol, thiopentone, or isoflurane, for the induction of anaesthesia. Administering Remifentanil after a hypnotic agent will reduce the incidence of muscle rigidity. Remifentanil can be administered at an infusion rate of 0.5 to 1 micrograms /kg/min, with or without an initial bolus injection of 1 micrograms /kg given over not less than 30 seconds. If endotracheal intubation is to occur more than 8 to 10 minutes after the start of the infusion of [Invented name], then a bolus injection is not necessary.

Maintenance of anaesthesia in ventilated patients

After endotracheal intubation, the infusion rate of Remifentanil should be decreased, according to anaesthetic technique, as indicated in the above table. Due to the fast onset and short duration of action of remifentanil, the rate of administration during anaesthesia can be titrated upward in 25% to 100% increments or downward in 25% to 50% decrements, every 2 to 5 minutes to attain the desired level of ?-opioid response. In response to light anaesthesia, supplemental bolus injections may be administered every 2 to 5 minutes.

Anaesthesia in spontaneously breathing patients

In spontaneously breathing anaesthetised patients with a secured airway respiratory depression is likely to occur. Therefore attention must be given to respiratory effects eventually combined with muscular rigidity. Special care is needed to adjust the dose to the patient requirements and ventilatory support may be required. Adequate facilities should be available for monitoring of patients administered remifentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression (intubation equipment must be available) and/or muscle rigidity (for more information see section 4.4).

The recommended starting infusion rate for supplemental analgesia in spontaneously breathing anaesthetised patients is 0.04 ?g/kg/min with titration to effect. A range of infusion rates from 0.025 to 0.1 ?g/kg/min has been studied.

Bolus injections are not recommended in spontaneously breathing anaesthetised patients.

Remifentanil should not be used as an analgesic in procedures where patients remain conscious or do not receive any airway support during the procedure.

Concomitant medication

Remifentanil decreases the amounts or doses of inhalational anaesthetics, hypnotics and benzodiazepines required for anaesthesia (see section 4.5).

Doses of the following agents used in anaesthesia: isoflurane, thiopentone, propofol and temazepam have been reduced by up to 75 % when used concurrently with remifentanil.

Guidelines for discontinuation/continuation during immediate postoperative period

Due to the very rapid offset of action of remifentanil no residual opioid activity will be present within 5 to 10 minutes after discontinuation. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of remifentanil. Sufficient time must be allowed to reach the maximum effect of the longer acting analgesic. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of post-operative care.

In case the longer acting analgesic has not reached the appropriate effect before the end of surgery, the administration of remifentanil can be continued to maintain analgesia during immediate postoperative period until the longer acting analgesic has reached the maximum effect.

If remifentanil is continued post-procedural, it should only be used in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function, under the close supervision of persons specifically trained in the recognition and management of the respiratory effects of potent opioids.

Furthermore it is recommended that patients should be closely monitored post-operatively for pain, hypotension and bradycardia.

Further information about the administration in mechanically ventilated intensive care patients is given in section 4.2.

In spontaneously breathing patients the initial infusion rate of remifentanil may be decreased to 0.1 µg/kg/min and thereafter can be increased or decreased every 5 min in steps of 0.025 µg/kg/min to balance the extent of analgesia against the degree of respiratory depression.

In spontaneously breathing patients bolus doses for analgesia are not recommended during postoperative period.

Administration by Target-Controlled Infusion (TCI)

Induction and maintenance of anaesthesia in ventilated patients

Remifentanil TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see table 1 above for manually controlled infusion). In association with these agents, adequate analgesia for induction of anaesthesia and surgery can generally be achieved with target blood remifentanil concentrations ranging from 3 to 8 ng/ml. Remifentanil should be titrated to individual patient response. For particularly stimulating surgical procedures target blood concentrations up to 15 ng/ml may be required.

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil (see table 1 above for manually controlled infusion).

The following table provides the equivalent blood remifentanil concentration using a TCI approach for various manually controlled infusion rates at steady state:

Remifentanil blood concentrations (nanograms/ml) estimated using the Minto (1997) pharmacokinetic model in a 70 kg, 170 cm, 40 year old male patient for various manually controlled infusion rates (micrograms/kg/min) at steady state

Remifentanil Infusion Rate

(micrograms /kg/min)

Remifentanil Blood Concentration

(nanograms/ml)

0.05

1.3

0.10

2.6

0.25

6.3

0.40

10.4

0.50

12.6

1.0

25.2

2.0

50.5

As there are insufficient data, the administration of remifentanil by TCI for spontaneous ventilation anaesthesia is not recommended.

Guidelines for discontinuation/continuation into the immediate post-operative period

At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the region of 1 to 2 ng/ml. As with manually controlled infusion, post-operative analgesia should be established before the end of surgery with longer acting analgesics (see also Guidelines for discontinuation / continuation during immediate postoperative period in section above for Manually Controlled Infusion).

As there are insufficient data, the administration of [Invented name] by TCI for the management of post-operative analgesia is not recommended.

Paediatric patients (1 to12 years of age)

Co-administration of remifentanil with induction agents has not been studied. The use of remifentanil for induction of anaesthesia by TCI in patients aged 1 to12 years is not recommended as there are no data available in this patient population.

Maintenance of anaesthesia

The following doses of remifentanil (see table) are recommended for maintenance of anaesthesia:

DOSING GUIDELINES FOR PAEDIATRIC PATIENTS (1 to12 years of age)

*CONCOMITANT ANAESTHETIC AGENT

REMIFENTANIL BOLUS INJECTION

(micrograms /kg)

REMIFENTANIL CONTINUOUS INFUSION

 

Starting Rate

(micrograms /kg/min)

Range for maintenance of anaesthesia

(micrograms /kg/min)

   

Halothane (starting dose 0.3 MAC)

1

0.25

0.05 to 1.3

Sevoflurane (starting dose 0.3 MAC)

1

0.25

0.05 to 0.9

Isoflurane (starting dose 0.5 MAC)

1

0.25

0.06 to 0.9

*co-administered with nitrous oxide/oxygen in a ratio of 2:1

When given by bolus injection, Remifentanil should be administered over not less than 30 seconds. Surgery should not commence until at least 5 minutes after the start of the Remifentanil infusion, if a simultaneous bolus dose has not been given.

For exclusive administration of nitrous oxide (70 %) and Remifentanil infusion rates for maintenance of anaesthesia should be between 0.4 und 3 micrograms/kg/min. Data gained from adults suggest that 0.4 micrograms/kg/min may be a convenient initial dose although specific studies are lacking.

Paediatric patients should be monitored and the dose titrated to the depth of analgesia appropriate for the surgical procedure.

Concomitant medication

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane, halothane and sevoflurane should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see in section above: Administration by Manually Controlled Infusion (MCI), Concomitant medication).

Guidelines for patient management in the immediate post-operative period

Establishment of alternative analgesia prior to discontinuation of Remifentanil:

Due to the very rapid offset of action of remifentanil, no residual activity will be present within 5 to 10 minutes after discontinuation. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of remifentanil. Sufficient time must be allowed to reach the therapeutic effect of the longer acting analgesic. The choice of agent(s), the dose and the time of administration should be planned in advance and individually tailored to be appropriate for the patient's surgical procedure and the level of post-operative care anticipated (see section 4.4).

Neonates/infants (aged less than 1 year):

The pharmacokinetic profile of remifentanil in neonates and infants (aged less than 1 year) is comparable to that seen in adults after correction for body weight differences. However, because there are insufficient clinical data, the administration of remifentanil is not recommended for this age group.

Special Patient groups

For dosage recommendations for special patient groups (elderly and obese patients, renally and hepatically impaired patients, patients undergoing neurosurgery and ASA III/IV patients; see section 4.2).

Cardiac Surgery

Administration by Manually-Controlled Infusion

For dosage recommendations in patients undergoing cardiac surgery see table below:

DOSING GUIDELINES FOR CARDIAC ANAESTHESIA

INDICATION

REMIFENTANIL BOLUS INJECTION

(micrograms /kg)

REMIFENTANIL CONTINUOUS INFUSION

(micrograms /kg/min)

 

Starting Rate

Typical infusion rates

   

Intubation

Not recommended

1

_

Maintenance of anaesthesia

     

• Isoflurane

(starting dose 0.4 MAC)

0.5 to 1

1

0.003 to 4

• Propofol

(Starting dose 50 micrograms /kg/min)

0.5 to 1

1

0.01 to 4.3

Continuation of post-operative analgesia, prior to extubation

Not recommended

1

0 to 1

Induction of anaesthesia

After administration of hypnotic to achieve loss of consciousness, Remifentanil should be administered at an initial infusion rate of 1 micrograms /kg/min. The use of bolus injections of Remifentanil during induction in cardiac surgical patients is not recommended. Endotracheal intubation should not occur until at least 5 minutes after the start of the infusion.

Maintenance period of anaesthesia

After endotracheal intubation the infusion rate of Remifentanil should be titrated according to the patient need. Supplemental bolus doses may also be administered as required. High risk cardiac patients, such as those undergoing valve surgery or with poor left ventricular function, should be administered a maximum bolus dose of 0.5 micrograms/kg.

These dosing recommendations also apply during hypothermic cardiopulmonary bypass (see section 5.2).

Concomitant medication

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil. No data are available for dosage recommendations for simultaneous use of other hypnotics with remifentanil (see in section above: Administration by Manually Controlled Infusion (MCI), Concomitant medication).

Guidelines for postoperative supply of patient

Continuation of Remifentanil post-operatively to provide analgesia prior to extubation

It is recommended that the infusion of Remifentanil is maintained at the final intra-operative rate during transfer of patients to the post-operative care area. The patient's level of analgesia and sedation should be closely monitored and the Remifentanil infusion rate adjusted to meet the individual patient's requirements (see Intensive care, below, for further information on management of intensive care patients.

Establishment of alternative analgesia prior to discontinuation of Remifentanil

Due to the very rapid offset of action of remifentanil, no residual opioid activity will be present within 5 to 10 minutes after discontinuation. Prior to discontinuation of Remifentanil, patients must be given alternative analgesic and sedative agents at a sufficient time in advance to allow the therapeutic effects of these agents to become established. It is therefore recommended that the choice of agent(s), the dose and the time of administration are planned, before weaning the patient from the ventilator.

Guidelines for discontinuation of Remifentanil

Due to the very rapid offset of action of Remifentanil, hypertension, shivering and aches have been reported in cardiac patients immediately following discontinuation of Remifentanil (see section 4.8 Undesirable effects). To minimise the risk of these events, adequate alternative analgesia must be established (as described above), before the Remifentanil infusion is discontinued. The infusion rate should be reduced by 25% decrements in at least 10-minute intervals until the infusion is discontinued.

During weaning from the ventilator the Remifentanil infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics. Haemodynamic changes such as hypertension and tachycardia should be treated with alternative agents as appropriate.

When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the patient must be carefully monitored. The benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.

Administration by Target-Controlled Infusion

Induction and maintenance of anaesthesia in ventilated patients

Remifentanil TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see the table in section 4.2 under Cardiac surgery/Administration by Manually-Controlled Infusion/Dosing guidelines for cardiac anaesthesia). In association with these agents, adequate analgesia for cardiac surgery is generally achieved at the higher end of the range of target blood remifentanil concentrations used for general surgical procedures. Following titration of remifentanil to individual patient response, blood concentrations as high as 20 nanograms /ml have been achieved in clinical studies.

At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects (hypotension and bradycardia) of remifentanil (see table in section 4.2 under Cardiac surgery/Administration by Manually-Controlled Infusion/Dosing guidelines for cardiac anaesthesia).

For information on blood remifentanil concentrations achieved with manually controlled infusion see Table 6

Guidelines for discontinuation/continuation into the immediate post-operative period

At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the range of 1 to 2 nanograms /ml. As with manually-controlled infusion, post-operative analgesia should be established before the end of surgery with longer acting analgesics (see section 4.2 under Cardiac surgery/Administration by Manually-Controlled Infusion/Guidelines for discontinuation of Remifentanil.

As there are insufficient data, the administration of Remifentanil by TCI for the management of post-operative analgesia is not recommended.

Intensive Care – Adults

Remifentanil can be used in mechanically ventilated intensive care patients. If required, additionally sedating drugs should be applied.

Remifentanil has been studied in intensive care patients in well controlled clinical trials for up to three days. As patients were not studied beyond three days, no evidence of safety and efficacy for longer treatment has been established. Therefore, a usage longer than three days is not recommended.

Due to the lack of data the administration of remifentanil by TCI is not recommended for ICU patients.

In adults, it is recommended that Remifentanil is initiated at an infusion rate of 0.1 micrograms /kg/min (6 micrograms /kg/h) to 0.15 micrograms /kg/min (9 micrograms /kg/h). The infusion rate should be titrated in increments of 0.025 micrograms /kg/min (1.5 micrograms /kg/h) to achieve the desired level of analgesia. A period of at least 5 minutes should be allowed between dose adjustments. The patient should be carefully monitored, regularly reassessed and the Remifentanil infusion rate adjusted accordingly. If an infusion rate of 0.2 micrograms /kg/min (12 micrograms /kg/h) is reached and the desired level of sedation is not achieved, it is recommended that dosing with an appropriate sedative agent is initiated (see below). The dose of the sedative agent should be titrated to obtain the desired level of sedation. Further increases to the [Invented name] infusion rate in increments of 0.025 micrograms /kg/min (1.5 micrograms /kg/h) may be made if additional analgesia is required.

The following table summarises the starting infusion rates and typical dose range for provision of analgesia in individual patients:

DOSING GUIDELINES FOR USE OF REMIFENTANIL WITHIN THE INTENSIVE CARE SETTING

CONTINUOUS INFUSION micrograms /kg/min (micrograms /kg/h)

 

Starting Rate

Range

0.1 (6) to 0.15 (9)

0.006 (0.36) to 0.74 (44.4)

Bolus doses of Remifentanil are not recommended in the intensive care setting.

The use of Remifentanil will reduce the dosage requirement of any concomitant sedative agents. Typical starting doses for sedative agents, if required, are given below.

RECOMMENDED STARTING DOSE OF SEDATIVE AGENTS, IF REQUIRED

Sedative Agent

Bolus (mg/kg)

Infusion rate (mg/kg/h)

Propofol

Up to 0.5

0.5

Midazolam

Up to 0.03

0.03

To allow separate titration of the respective agents, sedative agents should not be administered as an admixture.

Additional analgesia for ventilated patients undergoing painful procedures

An increase in the existing Remifentanil infusion rate may be required to provide additional analgesic cover for ventilated patients undergoing stimulating and/or painful procedures such as endotracheal suctioning, wound dressing and physiotherapy. It is recommended that a Remifentanil infusion rate of at least 0.1 micrograms /kg/min (6 micrograms /kg/h) is maintained for at least 5 minutes prior to the start of the stimulating procedure. Further dose adjustments may be made every 2 to 5 minutes in increments of 25%-50% in anticipation of, or in response to, additional requirement for analgesia. A mean infusion rate of 0.25 micrograms /kg/min (15 micrograms /kg/h), maximum 0.75 micrograms kg/min (44,4 micrograms /kg/h), has been administered for provision of additional analgesia during stimulating procedures.

Establishment of alternative analgesia prior to discontinuation of Remifentanil

Due to the very rapid offset of action of remifentanil, no residual opioid activity will be present within 5 to 10 minutes after discontinuation regardless of the duration of infusion. After administration of remifentanil the potential for the development of tolerance and hyperalgesia should be attended. Therefore, prior to discontinuation of remifentanil, patients must be given alternative analgesic and sedative agents at a sufficient time in advance to allow the therapeutic effects of these agents to become established and to prevent hyperalgesia and concomitant haemodynamic changes. It is therefore recommended that the choice of agent(s), the dose and the time of administration are planned prior to discontinuation of remifentanil. Long acting analgetics or intravenous or local analgetics, which can be controlled by the health care staff or the patient are alternative options for analgesia and should be chosen carefully according to the patients needs.

Prolonged administration of µ-opioid agonists may induce development of tolerance.

Guidelines for extubation and discontinuation of Remifentanil

In order to ensure a smooth emergence from a remifentanil-based regimen it is recommended that the infusion rate of Remifentanil is titrated gradually to 0.1 micrograms /kg/min (6 micrograms /kg/h) over a period up to 1 hour prior to extubation.

Following extubation, the infusion rate should be reduced by 25% decrements in at least 10-minute intervals until the infusion is discontinued. During weaning from the ventilator the Remifentanil infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics.

Upon discontinuation of Remifentanil, the IV cannula should be cleared or removed to prevent subsequent inadvertent administration.

When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the patient must be carefully monitored. The benefit of providing adequate analgesia must always be balanced against the potential risk of respiratory depression.

The following tables 1-5 give guidelines for infusion rates of Remifentanil for manually-controlled infusion:

Table 1: Remifentanil – Infusion rates (ml/kg/h)

Medicinal prodcuct delivery rate

(µg/kg/min)

Infusion delivery rate (ml/kg/h) for solution concentrations of

     

20 micrograms /ml

1 mg/50 ml

25 micrograms /ml

1 mg/40 ml

50 micrograms /ml

1 mg/20 ml

250 micrograms /ml

10 mg/40 ml

 

0.0125

0.025

0.05

0.075

0.1

0.15

0.2

0.25

0.5

0.75

1.0

1.25

1.5

1.75

2.0

0.038

0.075

0.15

0.23

0.3

0.45

0.6

0.75

1.5

2.25

3.0

3.75

4.5

5.25

6.0

0.03

0.06

0.12

0.18

0.24

0.36

0.48

0.6

1.2

1.8

2.4

3.0

3.6

4.2

4.8

0.015

0.03

0.06

0.09

0.12

0.18

0.24

0.3

0.6

0.9

1.2

1.5

1.8

2.1

2.4

Not recommended

Not recommended

0.012

0.018

0.024

0.036

0.048

0.06

0.12

0.18

0.24

0.3

0.36

0.42

0.48

Table 2: Remifentanil – Infusion rates (ml/h) for a 20 micrograms /ml solution

Infusion rate

(micrograms /kg/min)

Patient weight (kg)

           

5

10

20

30

40

50

60

 

0.0125

0.188

0.375

0.75

1.125

1.5

1.875

2.25

0.025

0.375

0.75

1.5

2.25

3.0

3.75

4.5

0.05

0.75

1.5

3.0

4.5

6.0

7.5

9.0

0.075

1.125

2.25

4.5

6.75

9.0

11.25

13.5

0.1

1.5

3.0

6.0

9.0

12.0

15.0

18.0

0.15

2.25

4.5

9.0

13.5

18.0

22.5

27.0

0.2

3.0

6.0

12.0

18.0

24.0

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Fibrogammin P

CSL Behring

FIBROGAMMIN P 250 IU

Powder and solvent for injection or infusion

Read all of this leaflet carefully before you start using this medicine.

Keep this leaflet. You may need to read it again. If you have further questions, please ask your doctor or your haemophilia nurse. This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.

In This Leaflet:

1. What Fibrogammin P is and what it is used for
2. Before you use Fibrogammin P
3. How to use Fibrogammin P
4. Possible side effects
5. Storing Fibrogammin P
6. Further information

What Fibrogammin P Is And What It Is Used For

Fibrogammin P (Factor XIII) is a product made from human plasma (this is the liquid part of the blood). It is used to prevent or stop the bleeding that you might get because of a lack of factor XIII in your blood, a condition that you have had from birth. Factor XIII is needed for the formation of blood clots which help bleeding to stop and helps slow healing wounds to heal more quickly.

Before You Use Fibrogammin P Do not use Fibrogammin P If you are allergic to any of the ingredients (see section 6). If you are unsure about this, ask your doctor. Take special care with Fibrogammin P If you experience any signs of an allergic reaction to Fibrogammin P (for example a rash, tight chest, wheezing or feeling dizzy), stop injecting the product immediately and contact your doctor. You should visit your doctor or haemophilia treatment centre regularly to ensure that your dose is correct. The doctor may wish to carry out some tests to make sure that you are getting the right amount. If your bleeding is not being controlled with Fibrogammin P, tell your doctor immediately. You may have developed an inhibitor (an antibody which can cancel out the effects of factor XIII) and your doctor may wish to carry out more tests to confirm this. If you have ever had a blood clot (thrombosis), you should ask your doctor for advice. Taking or using other medicines

There are no medicines that are known to react with Fibrogammin P. However, if you are taking another medicine and are concerned, please ask your doctor or haemophilia nurse.

Pregnancy and breast-feeding

If you are pregnant or planning a family soon, or if you are breast-feeding, ask your doctor for advice before using this product.

Driving and using machines

Fibrogammin P does not affect your ability to drive or use machines.

Important information about some of the ingredients of Fibrogammin P

Fibrogammin P contains up to 17 mg sodium per vial. Please take this into account if you are on a sodium (salt) controlled diet as you may need to cut down on the salt in your diet.

Fibrogammin P contains up to 24 mg glucose per vial. Please take this into account if you have diabetes.

Important safety information related to infections

When medicines are made from human blood, steps are taken to stop infections (e.g. HIV and Hepatitis) being passed on to the patient. This includes:

Careful selection of the blood donors Testing of each donation for signs of infection Steps in the manufacture which can kill or remove viruses

However, there is still a small chance of an infection being passed on to the patient. This may include a new virus or infection. Therefore, every time Fibrogammin P is used, it is important to note the name and batch number of the medicine (found on the carton).

How To Use Fibrogammin P

The amount of factor XIII you need will depend on several factors, such as your weight, the severity of your condition, the site and severity of bleeding or the need to prevent bleeding during an operation or investigation.

Fibrogammin P is given by injection or infusion into a vein.

If you have been prescribed Fibrogammin P to use at home, your doctor or haemophilia centre nurse will make sure that you are shown how to inject it and how much to use.

If you are in any doubt about injecting Fibrogammin P, go back to your doctor or haemophilia centre for more advice and training before attempting to treat yourself.

Follow the directions given to you by your doctor or haemophilia nurse. You can also use the directions given below as a guide.

Directions for preparing and administering Fibrogammin P Wash your hands thoroughly using soap and warm water. Warm the Fibrogammin P powder vial and the liquid (Water for Injections) ampoule to room or body temperature without opening either container. You can do this by leaving them to stand at room temperature for about an hour after taking them out of the fridge or, if you need them quickly by holding them in your hands for a few minutes.
DO NOT expose the containers to direct heat or stand them on a radiator. They must not be heated above body temperature (37? C). Hold the water ampoule upright and shake it to move any liquid from the ampoule tip. Break off the ampoule tip with your thumb and index finger. Draw the water up into a sterile syringe with a sterile needle attached. Remove the cap from the powder vial and clean the rubber stopper with antiseptic solution. Allow to dry. Inject the water through the rubber stopper into the powder vial and swirl gently to dissolve. The solution should be clear or slightly cloudy, but should not contain particles. Once you have made up the solution, it should be used immediately. If this is not possible it should be used up within 8 hours. The solution should be put back in the fridge during this time. The solution should be injected at a maximum rate of 4 ml per minute. Any unused solution should be left in the vial or syringe. Dispose of all ampoules, vials, needles, syringes and antiseptic swabs in a ‘Sharps box’ or as you have been told. Do not throw them away with your household rubbish. If you use more Fibrogammin P than you should

No symptoms of overdose with Fibrogammin P have been reported. However, if you accidentally inject a large overdose, then you should tell your doctor or haemophilia centre immediately.

If you forget to use Fibrogammin P

Inject your normal dose as soon as you remember and then continue as instructed by your doctor or haemophilia nurse.

Fibrogammin P Side Effects

Like all medicines, Fibrogammin P can cause side effects, although not everybody gets them.

Rare side effects (affect less than 1 in 1,000 people):

Fever Rash, itchy swellings on the skin (hives) Low blood pressure which could make you feel faint or dizzy Difficulty breathing

Fibrogammin P could increase your risk of a thrombosis.

Symptoms of a thrombosis include:

Unusual pain or swelling in your legs Sudden sharp pain in your chest Sudden difficulty breathing An unusual, severe or long-lasting headache Dizziness or fainting

If you have any of these symptoms, stop your injection immediately and contact your doctor.

If you notice that your Fibrogammin P is less effective than usual, contact your doctor or haemophilia centre immediately.

Storing Fibrogammin P

Store in a fridge at 2 °C to 8 °C, in the original packaging. Do not freeze.

Keep out of the reach and sight of children.

Do not use Fibrogammin P after the expiry date on the carton.

Further Information What Fibrogammin P contains

The active substance is:

250 International Units (IU) human plasma coagulation factor XIII

Other ingredients are:

human albumin glucose sodium chloride traces of sodium hydroxide or hydrochloric acid may also be present, (used for pH adjustment).

Bottles of product and liquid may appear partly empty but this is normal and does not mean that there is the wrong amount of powder or solution.

Marketing Authorisation Holder and Manufacturer CSL Behring GmbH Emil-von-Behring-Strasse 76 35041 Marburg Germany

This leaflet was last approved on: 07/2010

For further information contact

CSL Behring UK Limited Hayworth House Market Place Haywards Heath West Sussex RH16 1DB UK Telephone number:01444 447 405

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Mucositis Medications

Definition of Mucositis: Inflammation of a mucous membrane. Oral mucositis is a common complication of chemotherapy and radiation therapy.

Drugs associated with Mucositis

The following drugs and medications are in some way related to, or used in the treatment of Mucositis. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

Drug List: Betasept-Liquid Biopatch Calgon-Vesta Caphosol-Solution Chlorostat Chlorostat-4 Denti-Care-Denti-Rinse Gelclair-Gel Hibiclens-Liquid Hibistat Kepivance Neutrasal-Powder Peridex-Solution Periochip Periogard-Solution Perisol-Oral-Rinse Salivart-Spray Scrub-Care Spectrum-4

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Follicle Stimulation Medications

Drugs associated with Follicle Stimulation

The following drugs and medications are in some way related to, or used in the treatment of Follicle Stimulation. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

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SonoVue 8 microlitres / ml, powder and solvent for dispersion for injection

1. Name Of The Medicinal Product

SonoVue 8 microlitres / ml powder and solvent for dispersion for injection

2. Qualitative And Quantitative Composition

One ml contains 8µl of sulphur hexafluoride microbubbles

On reconstitution as directed, 1 ml of the resulting dispersion contains 8 µl sulphur hexafluoride in the microbubbles, equivalent to 45 microgrammes.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Powder and solvent for dispersion for injection.

SonoVue is a kit including

1 vial containing 25 mg of lyophilised powder

1 pre-filled syringe containing 5 ml sodium chloride

1 Mini-Spike transfer system

Information on the appearance of the reconstituted solution is given in section 6.6.

4. Clinical Particulars 4.1 Therapeutic Indications

This medicinal product is for diagnostic use only.

SonoVue is for use with ultrasound imaging to enhance the echogenicity of the blood, which results in an improved signal to noise ratio.

SonoVue should only be used in patients where study without contrast enhancement is inconclusive.

Echocardiography

SonoVue is a transpulmonary echocardiographic contrast agent for use in patients with suspected or established cardiovascular disease to provide opacification of cardiac chambers and enhance left ventricular endocardial border delineation.

Doppler of macrovasculature

SonoVue increases the accuracy in detection or exclusion of abnormalities in cerebral arteries and extracranial carotid or peripheral arteriesby improving the Doppler signal to noise ratio.

SonoVue increases the quality of the Doppler flow image and the duration of clinically-useful signal enhancement in portal vein assessment.

Doppler of microvasculature

SonoVue improves display of the vascularity of liver and breast lesions during Doppler sonography, leading to more specific lesion characterisation.

4.2 Posology And Method Of Administration

This product should only be used by physicians experienced in diagnostic ultrasound imaging.

The recommended doses of SonoVue are:

B-mode imaging of cardiac chambers, at rest or with stress: 2 ml.

Vascular Doppler imaging: 2.4 ml.

During a single examination, a second injection of the recommended dose can be made when deemed necessary by the physician.

Elderly Patients

The dosage recommendations also apply to elderly patients.

Paediatric Patients

The safety and effectiveness of SonoVue in patients under 18 years old has not been established and the product should not be used in these patients.

The microbubble dispersion is prepared before use by injecting through the septum 5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection to the contents of the vial. The vial is then shaken vigorously for a few seconds until the lyophilisate is completely dissolved. The desired volume of the dispersion can be drawn into a syringe any time up to six hours after reconstitution. Just before drawing into the syringe, the vial should be agitated to re-suspend the microbubbles. SonoVue should be administered immediately after drawing into the syringe by injection into a peripheral vein. Every injection should be followed by a flush with 5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

For instructions for preparation see section 6.6.

4.3 Contraindications

SonoVue should not be administered to patients with known hypersensitivity to sulphur hexafluoride or to any of the components of SonoVue.

SonoVue is contraindicated for use in patients with recent acute coronary syndrome or clinically unstable ischaemic cardiac disease, including: evolving or ongoing myocardial infarction, typical angina at rest within last 7 days, significant worsening of cardiac symptoms within last 7 days, recent coronary artery intervention or other factors suggesting clinical instability (for example, recent deterioration of ECG, laboratory or clinical findings), acute cardiac failure, Class III/IV cardiac failure, or severe rhythm disorders.

SonoVue is contraindicated in patients known to have right-to-left shunts, severe pulmonary hypertension (pulmonary artery pressure>90 mmHg), uncontrolled systemic hypertension, and in patients with adult respiratory distress syndrome.

The safety and efficacy of SonoVue have not been established in pregnant and lactating women therefore, SonoVue should not be administered during pregnancy and lactation (see Section 4.6).

4.4 Special Warnings And Precautions For Use

ECG monitoring should be performed in high-risk patients as clinically indicated.

It should be emphasised that stress echocardiography, which can mimic an ischaemic episode, could potentially increase the risk of SonoVue utilisation. Therefore, if SonoVue is to be used in conjunction with stress echocardiography patients must have a stable condition verified by absence of chest pain or ECG modification during the two preceding days.

Moreover, ECG and blood pressure monitoring should be performed during SonoVue-enhanced echocardiography with a pharmacological stress (e.g. with dobutamine).

Care should be taken in patients with ischaemic cardiac disease because in these patients allergy-like and/or vasodilatory reactions may lead to life-threatening conditions.

Emergency equipment and personnel trained in its use must be readily available. Caution is advised when SonoVue is administered to patients with clinically significant pulmonary disease, including severe chronic obstructive pulmonary disease.

It is recommended to keep the patient under close medical supervision during and for at least 30 minutes following the administration of SonoVue.

Numbers of patients with the following conditions who were exposed to SonoVue in the clinical trials were limited, and therefore, caution is advisable when administering the product to patients with: acute endocarditis, prosthetic valves, acute systemic inflammation and/or sepsis, hyperactive coagulation states and/or recent thromboembolism, and end-stage renal or hepatic disease.

SonoVue is not suitable for use in ventilated patients, and those with unstable neurological diseases.

In animal studies, the application of echo-contrast agents revealed biological side effects (e.g. endothelial cell injury, capillary rupture) by interaction with the ultrasound beam. Although these biological side effects have not been reported in humans, the use of a low mechanical index is recommended.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No specific interaction studies have been performed. There was no apparent relationship with respect to occurrence of adverse events in the clinical studies for patients receiving various categories of the most common concomitant medications.

4.6 Pregnancy And Lactation

No clinical data on exposed pregnancies are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development

(see section 5.3 Preclinical safety data). Caution should be exercised when prescribing to pregnant women. It is not known if sulphur hexafluoride is excreted in human milk. Therefore, caution should be exercised when SonoVue is administered to breast-feeding women.

4.7 Effects On Ability To Drive And Use Machines

On the basis of the pharmacokinetic and pharmacodynamic profiles, no or negligible influence is expected with the use of SonoVue on the ability to drive or use machines.

4.8 Undesirable Effects

The undesirable effects reported with SonoVue were, in general, non-serious, transient and resolved spontaneously without residual effects.

In clinical trials, the most commonly reported adverse reactions are headache (2.3%), injection site reaction including bruising, burning and paraesthesia at the injection site (1.7%) and injection site pain (1.4%).

There were changes in ECG, blood pressure and in some laboratory parameters measured, but these were not deemed to be of clinical significance.

The adverse reactions reported among 1788 adult patients in clinical studies are:

Body system

Common >1/100, <1/10)

Uncommon >1/1,000 - <1/100)

Metabolism and nutrition disorders

 

Hyperglycaemia

Nervous system disorders

Headache

Paraesthesia, dizziness, insomnia, taste perversion

Eye disorders

 

Vision blurred

Vascular disorder

 

Vasodilatation

Respiratory, thoracic and mediastinal disorders

 

Pharyngitis, sinus pain

Gastrointestinal disorders

Nausea

Abdominal pain

Skin and subcutaneous tissue disorders

 

Pruritus, rash erythematous

Musculoskeletal, connective tissue and bone disorders

 

 

Back pain

General disorders and administration site conditions

Injection site pain, injection site reaction, including bruising, burning and paraesthesia at the injection site

Chest pain, pain no organ system, asthenia

One case of sensory-motor paresis was reported.

Post marketing

Rare cases suggestive of hypersensitivity, which could include skin erythema, bradycardia, hypotension or anaphylactic shock have been reported following the injection of SonoVue. In some of these cases, in patients with underlying coronary artery disease, bradycardia and hypotension were accompanied by myocardial ischemia and/or myocardial infarctions.

In very rare cases, fatal outcomes have been reported in temporal association with the use of SonoVue. In all these patients there was a high underlying risk for major cardiac complications, which could have led to the fatal outcome.

4.9 Overdose

Since there have been no cases of overdose reported to date, neither signs nor symptoms of overdose have been identified. In a Phase I study doses up to 56 ml of SonoVue were administered to normal volunteers without serious adverse events being reported. In the event of overdose occurring, the patient should be observed and treated symptomatically.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Ultrasound contrast media

ATC code: VO8DA.

The addition of sodium chloride 9 mg/ml (0.9%) solution for injection to the lyophilised powder followed by vigorous shaking results in the production of the microbubbles of sulphur hexafluoride. The microbubbles have a mean diameter of about 2.5µm, with 90% having a diameter less than 6µm and 99% having a diameter less than 11µm. Each millilitre of SonoVue contains 8µl of the microbubbles.The interface between the sulphur hexafluoride bubble and the aqueous medium acts as a reflector of the ultrasound beam thus enhancing blood echogenicity and increasing contrast between the blood and the surrounding tissues.

The intensity of the reflected signal is dependent on concentration of the microbubbles and frequency of the ultrasound beam. At the proposed clinical doses, SonoVue has been shown to provide marked increase in signal intensity of more than 2 minutes for B-mode imaging in echocardiography and of 3 to 8 minutes for Doppler imaging of the macrovasculature and microvasculature.

Sulphur hexafluoride is an inert, innocuous gas, poorly soluble in aqueous solutions. There are literature reports of the use of the gas in the study of respiratory physiology and in pneumatic retinopexy.

5.2 Pharmacokinetic Properties

The total amount of sulphur hexafluoride administered in a clinical dose is extremely small, (in a 2 ml dose the microbubbles contain 16 µl of gas). The sulphur hexafluoride dissolves in the blood and is subsequently exhaled.

After a single intravenous injection of 0.03 or 0.3 ml of SonoVue/kg (approximately 1 and 10 times the maximum clinical dose) to human volunteers, the sulphur hexafluoride was cleared rapidly. The mean terminal half-life was 12 minutes (range 2 to 33 minutes). More than 80% of the administered sulphur hexafluoride was recovered in exhaled air within 2 minutes after injection and almost 100% after 15 minutes.

In patients with diffuse interstitial pulmonary fibrosis, the percent of dose recovered in expired air averaged 100% and the terminal half-life was similar to that measured in healthy volunteers.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and toxicity to reproduction. Caecal lesions observed in some repeat- dose studies with rats, but not in monkeys, are not relevant for humans under normal conditions of administration.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Powder:

Macrogol 4000

Distearoylphosphatidylcholine

Dipalmitoylphosphatidylglycerol Sodium

Palmitic acid

Solvent:

Sodium chloride 9 mg/ml (0.9%) solution for injection

6.2 Incompatibilities

In the absence of compatibility studies, SonoVue should not be admixed with any other medicinal product except the solvent provided.

6.3 Shelf Life

2 years.

Once reconstituted, chemical and physical stability has been demonstrated for 6 hours. From a microbiological point of view, the product should be used immediately. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user.

6.4 Special Precautions For Storage

The medicinal product does not require any special storage conditions.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Presentation 02 (with separate MiniSpike transfer system):-

25 mg of dry, lyophilised powder in an atmosphere of sulphur hexafluoride in a colourless

Type I glass vial, with elastomeric closure.

Separate transfer system.

Type I glass pre-filled syringe containing 5 ml sodium chloride 9 mg/ml (0.9%) solution for injection.

6.6 Special Precautions For Disposal And Other Handling

Before use examine the product to ensure that the container and closure have not been damaged.

SonoVue must be prepared before use by injecting through the septum 5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection to the contents of the vial. The vial is then shaken vigorously for twenty seconds after which the desired volume of the dispersion can be drawn into a syringe as follows, depending on the presentation:

)

Presentation 02 ( with separate MiniSpike transfer system )

1. Connect the plunger rod by screwing it clockwise into the syringe.

2. Open the MiniSpike transfer system blister and remove syringe tip cap.

3. Open the transfer system cap and connect the syringe to the transfer system by screwing it in clockwise.

4. Remove Flipcap glass protective disk from the vial. Slide the vial into the transparent sleeve of the transfer system and press firmly to lock the vial in place.

5. Empty the contents of the syringe into the vial by pushing on the plunger rod.

6. Shake vigorously for 20 seconds to mix all the contents in the vial (white milky liquid).

7. Invert the system and carefully withdraw SonoVue into the syringe.

8. Unscrew the syringe from the transfer system.

SonoVue should be administered immediately by injection into a peripheral vein.

After reconstitution, a homogeneous white milky liquid is obtained. If solid parts of the lyophilisate are seen or the suspension is not homogeneous, the product should be discarded. If SonoVue is not used immediately after reconstitution the microbubble dispersion should be shaken again before being drawn up into a syringe. Chemical and physical stability of the microbubble dispersion has been demonstrated for 6 hours.

The vial is for a single examination only. Any unused dispersion remaining at the end of an examination or waste material must be discarded in accordance with local requirements.

7. Marketing Authorisation Holder

Bracco International B.V.

Strawinskylaan 3051

NL - 1077 ZX Amsterdam

The Netherlands

8. Marketing Authorisation Number(S)

EU/1/01/177/002

9. Date Of First Authorisation/Renewal Of The Authorisation

26 March 2001/ 24 April 2006

10. Date Of Revision Of The Text

24 April 2006

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SonoVue 8 microlitres / ml, powder and solvent for dispersion for injection

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