Supralip 160mg

1. Name Of The Medicinal Product

Supralip® 160 mg, film-coated tablet.

2. Qualitative And Quantitative Composition

Each tablet contains 160.0 mg fenofibrate.

For excipients, see 6.1.

3. Pharmaceutical Form

Film coated tablet.

White, oblong, film-coated tablets engraved “160” on one side and “Fournier logo” on the other side.

4. Clinical Particulars 4.1 Therapeutic Indications

Supralip® 160mg is indicated as an adjunct to diet and other non-pharmacological treatment (e.g. exercise, weight reduction) for the following:

- Treatment of severe hypertriglyceridaemia with or without low HDL cholesterol.

- Mixed hyperlipidaemia when a statin is contraindicated or not tolerated.

- Mixed hyperlipidaemia in patients at high cardiovascular risk in addition to a statin when triglycerides and HDL cholesterol are not adequately controlled.

4.2 Posology And Method Of Administration

Posology:

Adults: The recommended dose is one tablet containing 160 mg fenofibrate taken once daily. Patients currently taking one Lipantil Micro 200mg capsule can be changed to one Supralip 160 mg tablet without further dose adjustment.

Elderly patients: The usual adult dose is recommended.

Patients with renal impairment: Dosage reduction is required in patients with renal impairment. The use of dosage forms containing a lower dose of active ingredient (67 mg micronised fenofibrate capsules or 100 mg standard fenofibrate capsules) is recommended in these patients.

Children: The use of the 160 mg dosage form is contraindicated in children.

Hepatic disease: Patients with hepatic disease have not been studied.

Dietary measures initiated before therapy should be continued.

If after several months of fenofibrate administration (e.g. 3 months) serum lipid levels have not been reduced satisfactorily, complementary or different therapeutic measures should be considered.

Method of administration: Tablet should be swallowed whole during a meal.

4.3 Contraindications

• hepatic insufficiency (including biliary cirrhosis and unexplained persistent liver function abnormality e.g. persistent elevations in serum transaminases)

• renal insufficiency

• children (age below 18 years)

• hypersensitivity to the active substance or to any of the excipients

• known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen

• gallbladder disease

• chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridemia

• Supralip 160mg should not be taken in patients allergic to peanut or arachis oil or soya lecithin or related products due to the risk of hypersensitivity reactions.

4.4 Special Warnings And Precautions For Use

Liver function: As with other lipid lowering agents, increases have been reported in transaminase levels in some patients. In the majority of cases these elevations were transient, minor and asymptomatic. It is recommended that transaminase levels are monitored every 3 months during the first 12 months of treatment and thereafter periodically. Attention should be paid to patients who develop increase in transaminase levels and therapy should be discontinued if ASAT (SGOT) and ALAT (SGPT) levels increase to more than 3 times the upper limit of the normal range. When symptoms indicative of hepatitis occur (e.g. jaundice, pruritus), laboratory tests are to be conducted for verification and discontinuation of fenofibrate therapy may be considered.

Pancreas: Pancreatitis has been reported in patients taking fenofibrate (see sections 4.3 and 4.8). This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation, resulting in the obstruction of the common bile duct.

Muscle: Muscle toxicity, including very rare cases of rhabdomyolysis, has been reported with administration of fibrates and other lipid-lowering agents. The incidence of this disorder increases in cases of hypoalbuminaemia and previous renal insufficiency. Muscle toxicity should be suspected in patients presenting diffuse myalgia, myositis, muscular cramps and weakness and/or marked increases in CPK (levels exceeding 5 times the normal range). In such cases treatment with fenofibrate should be stopped.

Patients with pre-disposing factors for myopathy and/or rhabdomyolysis, including age above 70 years old, personal or familial history of hereditary muscular disorders, renal impairment, hypothyroidism and high alcohol intake, may be at an increased risk of developing rhabdomyolysis. For these patients, the putative benefits and risks of fenofibrate therapy should be carefully weighed up.

The risk of muscle toxicity may be increased if the drug is administered with another fibrate or an HMG-CoA reductase inhibitor, especially in cases of pre-existing muscular disease. Consequently, the co-prescription of fenofibrate with a statin should be reserved to patients with severe combined dyslipidaemia and high cardiovascular risk without any history of muscular disease. This combination therapy should be used with caution and patients should be monitored closely for signs of muscle toxicity.

For hyperlipidaemic patients taking oestrogens or contraceptives containing oestrogens it should be ascertained whether the hyperlipidaemia is of primary or secondary nature (possible elevation of lipid values caused by oral oestrogen).

This medicinal product contains lactose. Therefore patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Renal function: Treatment should be interrupted in case of an increase in creatinine levels > 50% ULN (upper limit of normal).

It is recommended that creatinine is measured during the first 3 months after initiation of treatment and thereafter periodically (for dose recommendations, see section 4.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Oral anticoagulants: Fenofibrate enhances oral anticoagulant effect and may increase risk of bleeding. It is recommended that the dose of anticoagulants is reduced by about one third at the start of treatment and then gradually adjusted if necessary according to INR (International Normalised Ratio) monitoring. Therefore, this combination is not recommended.

Cyclosporin: Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and cyclosporin. The renal function of these patients must therefore be closely monitored and the treatment with fenofibrate stopped in the case of severe alteration of laboratory parameters.

HMG-CoA reductase inhibitors and other fibrates:

The risk of serious muscle toxicity is increased if fenofibrate is used concomitantly with HMG-CoA reductase inhibitors or other fibrates. Such combination therapy should be used with caution and patients monitored closely for signs of muscle toxicity (See section 4.4).

Cytochrome P450 enzymes: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.

Patients co-administered fenofibrate and CYP2C19, CYP2A6, and especially CYP2C9 metabolised drugs with a narrow therapeutic index should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.

4.6 Pregnancy And Lactation

There are no adequate data from the use of fenofibrate in pregnant women. Animal studies have not demonstrated any teratogenic effects. Embryotoxic effects have been shown at doses in the range of maternal toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, Supralip 160mg film-coated tablet should only be used during pregnancy after a careful benefit/risk assessment.

There are no data on the excretion of fenofibrate and/or its metabolites into breast milk.

Consequently Supralip 160mg film-coated tablet should not be used in nursing mother.

4.7 Effects On Ability To Drive And Use Machines

Supralip 160mg, Film-coated tablet has no influence on the ability to drive and use machines.

4.8 Undesirable Effects

The most commonly reported ADRs during fenofibrate therapy are digestive, gastric or intestinal disorders.

The following undesirable effects have been observed during placebo-controlled clinical trials (n=2344) with the below indicated frequencies:

MedDRA system organ class

Common

>1/100, <1/10

Uncommon

>1/1,000, <1/100

Rare

>1/10,000, <1/1,000

Very rare

<1/10,000 incl. isolated reports

Not knowna

Blood and lymphatic system disorders

   

Haemoglobin decreased

White blood cell count decreased

   

Immune system disorders

   

Hypersensitivity

   

Nervous system disorders

 

Headache

     

Vascular disorders

 

Thromboembolism (pulmonary embolism, deep vein thrombosis)*

     

Respiratory, thoracic and mediastinal disorders

       

Interstitial pneumopathies

Gastrointestinal disorders

Gastrointestinal signs and symptoms (abdominal pain, nausea, vomiting, diarrhoea, flatulence)

Moderate in severity

Pancreatitis*

     

Hepatobiliary disorders

Transaminases increased (see section 4.4)

Cholelithiasis

Hepatitis (see section 4.4)

   

Skin and subcutaneous tissue disorders

 

Cutaneous hypersensitivity (e.g. Rashes, pruritus, urticaria)

Alopecia

Photosensitivity reactions

   

Musculoskeletal, connective tissue and bone disorders

 

Muscle disorder (e.g. myalgia, myositis, muscular spasms and weakness)

   

Rhabdomyolysis

Reproductive system and breast disorders

 

Sexual dysfunction

     

Investigations

 

Blood creatinine increased

Blood urea increased

   

*: In the FIELD-study, a randomized placebo-controlled trial performed in 9,795 patients with type 2 diabetes mellitus, a statistically significant increase in pancreatitis cases was observed in patients receiving fenofibrate versus patients receiving placebo (0.8% versus 0.5%; p = 0.031). In the same study, a statistically significant increase was reported in the incidence of pulmonary embolism (0.7% in the placebo group versus 1.1% in the fenofibrate group; p = 0.022) and a statistically non-significant increase in deep vein thromboses (placebo: 1.0% [48/4,900 patients] versus fenofibrate 1.4% [67/4,895 patients]; p = 0.074).

a: In addition to those events reported during clinical trials, the following side effects have been reported spontaneously during postmarketing use of Supralip 160mg. A precise frequency cannot be estimated from the available data and is therefore classified as “not known”.

- Respiratory, thoracic and mediastinal disorders: Interstitial lung disease.

- Musculoskeletal, connective tissue and bone disorders: Rhabdomyolysis.

4.9 Overdose

Only anecdotal cases of fenofibrate overdosage have been received. In the majority of cases no overdose symptoms were reported.

No specific antidote is known. If an overdose is suspected, treat symptomatically and institute appropriate supportive measures as required. Fenofibrate cannot be eliminated by haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Serum Lipid Reducing Agents / Cholesterol and Triglycerides Reducers / Fibrates.

ATC code: C10 AB 05

Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type alpha (PPAR?).

Through activation of PPAR?, fenofibrate increases the lipolysis and elimination of atherogenic triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein CIII. Activation of PPAR? also induces an increase in the synthesis of apoproteins AI and AII.

The above stated effects of fenofibrate on lipoproteins lead to a reduction in very low- and low density fractions (VLDL and LDL) containing apoprotein B and an increase in the high density lipoprotein fraction (HDL) containing apoprotein AI and AII.

In addition, through modulation of the synthesis and the catabolism of VLDL fractions fenofibrate increases the LDL clearance and reduces small dense LDL, the levels of which are elevated in the atherogenic lipoprotein phenotype, a common disorder in patients at risk for coronary heart disease.

During clinical trials with fenofibrate, total cholesterol was reduced by 20 to 25%, triglycerides by 40 to 55% and HDL cholesterol was increased by 10 to 30%.

In hypercholesterolaemic patients, where LDL cholesterol levels are reduced by 20 to 35%, the overall effect on cholesterol results in a decrease in the ratios of total cholesterol to HDL cholesterol, LDL cholesterol to HDL cholesterol, or Apo B to Apo AI, all of which are markers of atherogenic risk.

Because of its significant effect on LDL cholesterol and triglycerides, treatment with fenofibrate should be beneficial in hypercholesterolaemic patients with or without hypertriglyceridaemia, including secondary hyperlipoproteinaemia such as type 2 diabetes mellitus.

There is evidence that treatment with fibrates may reduce coronary heart disease events but they have not been shown to decrease all cause mortality in the primary or secondary prevention of cardiovascular disease.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus treated with fenofibrate in addition to simvastatin. Fenofibrate plus simvastatin therapy did not show any significant differences compared to simvastatin monotherapy in the composite primary outcome of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08, p = 0.32; absolute risk reduction: 0.74%). In the pre-specified subgroup of dyslipidaemic patients, defined as those in the lowest tertile of HDL-C (

Extravascular deposits of cholesterol (tendinous and tuberous xanthoma) may be markedly reduced or even entirely eliminated during fenofibrate therapy.

Patients with raised levels of fibrinogen treated with fenofibrate have shown significant reductions in this parameter, as have those with raised levels of Lp(a). Other inflammatory markers such as C Reactive Protein are reduced with fenofibrate treatment.

The uricosuric effect of fenofibrate leading to reduction in uric acid levels of approximately 25% should be of additional benefit in those dyslipidaemic patients with hyperuricaemia.

Fenofibrate has been shown to possess an anti-aggregatory effect on platelets in animals and in a clinical study, which showed a reduction in platelet aggregation induced by ADP, arachidonic acid and epinephrine.

5.2 Pharmacokinetic Properties

Supralip 160 mg is a film-coated tablet containing 160 mg of micronised fenofibrate and is suprabioavailable (larger bioavailability) compared to the previous formulations.

Absorption: Maximum plasma concentrations (Cmax) occur within 4 to 5 hours after oral administration. Plasma concentrations are stable during continuous treatment in any given individual.

The absorption of fenofibrate is increased when administered with food.

Distribution: Fenofibric acid is strongly bound to plasma albumin (more than 99%).

Plasma half-life: The plasma elimination half-life of fenofibric acid is approximately 20 hours.

Metabolism and excretion: No unchanged fenofibrate can be detected in the plasma where the principal metabolite is fenofibric acid. The drug is excreted mainly in the urine. Practically all the drug is eliminated within 6 days. Fenofibrate is mainly excreted in the form of fenofibric acid and its glucuronide conjugate. In elderly patients, the fenofibric acid apparent total plasma clearance is not modified.

Kinetic studies following the administration of a single dose and continuous treatment have demonstrated that the drug does not accumulate. Fenofibric acid is not eliminated by haemodialysis.

5.3 Preclinical Safety Data

Chronic toxicity studies have yielded no relevant information about specific toxicity of fenofibrate.

Studies on mutagenicity of fenofibrate have been negative.

In rats and mice, liver tumours have been found at high dosages, which are attributable to peroxisome proliferation. These changes are specific to small rodents and have not been observed in other animal species. This is of no relevance to therapeutic use in man.

Studies in mice, rats and rabbits did not reveal any teratogenic effect. Embryotoxic effects were observed at doses in the range of maternal toxicity. Prolongation of the gestation period and difficulties during delivery were observed at high doses. No sign of any effect on fertility has been detected.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium laurilsulfate

Lactose monohydrate

Povidone

Crospovidone

Microcrystalline cellulose

Silica colloidal anhydrous

Sodium stearyl fumarate

Composition of the coating:

Opadry®:

- polyvinyl alcohol

- titanium dioxide (E171)

- talc

- soybean lecithin

- xanthan gum.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

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

Do not store above 30°C.

6.5 Nature And Contents Of Container

Thermoformed blister strips (PVC/PE/PVDC) of 10 or 14 tablets each.

Boxes of 10, 20, 28, 30, 50, 84, 90, 98 and 100 tablets.

Hospital pack sizes: 280 (10 x 28) and 300 (10 x 30) tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Abbott Healthcare Products Ltd

Mansbridge Road

West End

Southampton

SO18 3JD

United Kingdom

8. Marketing Authorisation Number(S)

PL 00512/0389

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: September 2000

Date of last renewal: 4 November 2004

10. Date Of Revision Of The Text

March 2011

11. Legal category

POM

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Lidocaine Hydrochloride BP Laryngojet 4% (International Medication Systems)

Lidocaine Hydrochloride BP

Laryngojet 4%W/V

Please read this leaflet. It contains important information about your medicine. If you have any questions, please ask your doctor or nurse.

What is this medicine?

This medicine is called Lidocaine Hydrochloride BP Laryngojet 4% w/v. It is a sterile solution which comes in a glass vial and contains 160mg lidocaine hydrochloride in 4ml as the active ingredient. It also contains sodium hydroxide and water.

The active ingredient in this medicine is Lidocaine hydrochloride. This is the new name for Lidocaine (Lignocaine) hydrochloride. The ingredient itself has not changed.

There is one 4ml vial in each carton.

It is a local anaesthetic. It numbs the area it is applied to.

Who makes it? Marketing Authorisation Holder: International Medication Systems (UK) Limited 208 Bath Road Slough Berkshire SL1 3WE UK Manufacturer: International Medication Systems (UK) Ltd. Unit 14 Foster Avenue Woodside Park Dunstable Beds LU5 5TA UK What is it used for?

It is used to numb parts of the body, such as the mouth, throat and lungs, before some medical procedures which would otherwise be uncomfortable or painful. Examples of the kind of procedures lidocaine is used for are putting a breathing tube in during an operation, putting a tube into the lungs to examine them (bronchoscopy), or taking a specimen from the mouth, throat or lungs.

Before you are given lidocaine You should not be given lidocaine and should tell your doctor immediately if: You suffer from porphyria You are allergic to any of the ingredients or to other local anaesthetics You should tell your doctor if: You have epilepsy, any heart problems including heart failure, slow heart beat or delayed heart signals (heart block), very poor breathing, myasthenia gravis, shock, low oxygen levels or low blood volume The area to be anaesthetised is infected or cut You are pregnant, likely to become pregnant, or breast feeding You are taking any other medicines at all, especially ones for your heart (eg. propranolol, and medicines to treat an irregular heartbeat) or ulcers (eg. cimetidine) You are going to have a general anaesthetic where suxamethonium will be used. How much is given?

The lowest dose possible will be given. The usual adult dose is 4ml (160mg). The elderly may need a lower dose. Children can be given up to 3mg for every kg they weigh (so if they weigh 10kg, they could have 3 x 10 = 30mg).

The solution can be sprayed, instilled or applied with a swab to the area to be numbed. It usually works within 5 minutes.

Since this medicine will usually be given to you by a doctor it is unlikely that you will be given too much.

However, if you are worried that you have been given too much, please tell the doctor.

Are there any side effects?

Very rarely, a patient may have an allergic reaction including rashes, swelling (particularly of the lips, face, eyelids, tongue and throat), breathlessness and collapse.

If applied in the mouth it may be difficult to swallow properly until the effect has worn off.

Other side effects may include light headedness, drowsiness, dizziness, mood changes, ringing in your ears, fear, vision difficulties such as blurred or double vision or quivering eyeballs, sickness, sensations of heat, cold or numbness, twitching, fits, shaking, unconsciousness, shallow breathing, stopping breathing, low blood pressure (feeling faint), slow heart beat, collapse including the heart stopping.

If you feel drowsy, dizzy or suffer from blurred or double vision after having lidocaine, do not drive or operate machinery.

The doctor treating you will be watching to see if these effects occur and will have the equipment to treat them.

If you think this medicine has upset you in ANY way, please tell your doctor.

How to store this medicine

Do not use this medicine after the expiry date shown on the carton and vial label.

Do not store above 25°C.

KEEP THIS AND ALL MEDICINES OUT OF THE REACH AND SIGHT OF CHILDREN

Date of preparation: January 2004

Further Information

This leaflet does not contain all the information about your medicine. If you have any questions or are not sure about anything, ask your doctor (or pharmacist), who will have access to further information.

YOU MAY WANT TO READ THIS LEAFLET AGAIN. PLEASE DO NOT THROW IT AWAY IMMEDIATELY.

This leaflet only applies to Lidocaine Hydrochloride BP Laryngojet 4%w/v

6963001C

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Gynoxin 200 mg vaginal capsules

1. Name Of The Medicinal Product

Gynoxin 200 mg Vaginal Capsules

2. Qualitative And Quantitative Composition

Each vaginal capsule contains 200 mg of the active ingredient fenticonazole nitrate.

For excipients, see 6.1

3. Pharmaceutical Form

Vaginal capsule, soft

Ivory white, opaque, soft gelatin capsules

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of vulvovaginal candidiasis.

4.2 Posology And Method Of Administration

Route of Administration:

Intravaginal

Adults:

One 200 mg vaginal capsule at bedtime for 3 days

The capsule must be introduced deeply into the vagina.

Gynoxin is not greasy, does not soil and can easily be removed with water.

Children:

The use of Gynoxin in children is not recommended.

4.3 Contraindications

Ascertained hypersensitive to the product and to other imidazole derivatives.

4.4 Special Warnings And Precautions For Use

The product should not be used in conjunction with barrier contraceptives.

In the event of a hypersensitivity reaction or development of resistant organisms, treatment should be discontinued and the physician consulted.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not investigated. Since systemic absorption of fenticonazole after application is low, interactions with other drugs are unlikely.

4.6 Pregnancy And Lactation

Oral administration of fenticonazole in rats has been reported to produce prolonged gestation and embryotoxic effects after doses above 40mg/kg/day. Fenticonazole does not interfere with the function of male and female gonads and does not modify the first phases of reproduction.

Fenticonazole has shown no teratogenic effects in rats and rabbits. Fenticonazole or its metabolites cross the placental barrier in pregnant rats and rabbits after vaginal application and are excreted in milk of lactating rats.

Since there is no experience of use during pregnancy or lactation, Gynoxin should not be used unless the physician considers it essential to the welfare of the patient.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

After intravaginal administration slight transient burning, which usually disappears rapidly, may occasionally occur.

Prolonged topical application may cause sensitisation reactions.

4.9 Overdose

Because of the low systemic absorption after vaginal application, overdosage is unlikely. In case of a suspected accidental oral ingestion emesis should be induced or gastric lavage may be attempted. Irrespective of success in inducing emesis the patient should be made to drink water or lemonade with active charcoal and a laxative. Symptomatic therapy may be administered if indicated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC code: G01A F12

Fenticonazole is a broad-spectrum antimycotic agent.

• In vitro: high fungistatic and fungicidal activity against Candida albicans

• In vivo: healing of vaginal mycoses due to Candida within 5 days in mice.

5.2 Pharmacokinetic Properties

Pharmacokinetic studies in humans have shown that systemic absorption of fenticonazole nitrate after vaginal administration is minimal.

5.3 Preclinical Safety Data

LD50 mice: oral>3000mg/kg; i.p 1276mg/kg (M), 1265mg/kg (F)

LD50 rats: oral>3000mg/kg; s.c>750mg/kg; i.p. 440mg/kg (M), 309mg/kg (F)

Chronic toxicity: following oral administration of 40-80-160mg/kg/day for 6 months in rats and dogs, fenticonazole was well tolerated, although some evidence of light and moderate general toxicity occurred (increase in liver weight at 160mg/kg without histopathological alterations in rats, and a transient increase in serum SGPT at 80 and 160mg/kg, together with an increase in liver weight in dogs).

Fenticonazole does not interfere with the function of male and female gonads, and does not modify the first phases of reproduction. Studies in reproductive toxicology revealed, as for other imidazole derivatives, an embryolethal effect at high dosages (>20mg/kg). Fenticonazole has shown no teratogenic effects in rats and rabbits and has revealed no mutagenic potential in six mutagenicity tests.

Satisfactory results were obtained in tolerability tests performed in guinea pigs, rabbits as well as in mini-pigs, the skin of which is similar to that of humans, as far as morphology, functionality and sensitivity to irritating agents are concerned.

Fenticonazole has shown no evidence of sensitisation, phototoxicity and photoallergy.

Pharmacokinetic studies have revealed no transcutaneous absorption either in man or in animals and a very low vaginal absorption.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Medium chain triglycerides

Colloidal anhydrous silica

Shell constituents:

Gelatin

Glycerol

Titanium dioxide

Ethyl parahydroxybenzoate sodium (E215)

Sodium propyl parahydroxybenzoate (E217)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30°C. Do not refrigerate or freeze. Store in the original package.

6.5 Nature And Contents Of Container

Blister pack of PVC/PVdC + aluminium foil, in packs of 3.

6.6 Special Precautions For Disposal And Other Handling

None

Administrative Data 7. Marketing Authorisation Holder

Recordati Industria Chimica e Farmaceutica SpA

Via Matteo Civitali

1-20148 Milano

Italy

8. Marketing Authorisation Number(S)

PL 04595/0007

9. Date Of First Authorisation/Renewal Of The Authorisation

22/09/99

10. Date Of Revision Of The Text

14/12/2009

POM

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Pabrinex Intravenous High Potency Injection

1. Name Of The Medicinal Product

Pabrinex Intravenous High Potency, Solution for injection

2. Qualitative And Quantitative Composition

Each presentation (carton) contains either 5ml or 10ml ampoules. Each pair of ampoules to be used in treatment is labelled Pabrinex No 1 and Pabrinex No 2.

Each No 1 ampoule contains: 5ml ampoule 10ml ampoule Thiamine Hydrochloride BP 250mg 500mg Riboflavin (as Phosphate Sodium BP) 4mg 8mg Pyridoxine Hydrochloride BP 50mg 100mg Each No 2 ampoule contains: 5ml ampoule 10ml ampoule Ascorbic Acid BP 500mg 1000mg Nicotinamide BP 160mg 320mg Anhydrous Glucose BP 1000mg 2000mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection

4. Clinical Particulars 4.1 Therapeutic Indications

Rapid therapy of severe depletion or malabsorption of the water soluble vitamins B and C, particularly in alcoholism, where a severe depletion of thiamine can lead to Wernicke's encephalopathy; after acute infections, post-operatively and in psychiatric states. Also used to maintain levels of vitamin B and C in patients on chronic intermittent haemodialysis.

4.2 Posology And Method Of Administration

Pabrinex is also available as an Intramuscular High Potency Injection. Therefore before administration, ensure that both the Summary of Product Characteristics and ampoule labels refer to the INTRAVENOUS injection.

1) The preferred method of administration of Pabrinex Intravenous High Potency is by drip infusion. Equal volumes of the contents of ampoules number 1 and 2 should be added to 50ml to 100ml physiological saline or glucose 5% and infused over 30 minutes (see “Special Precautions for Storage” section).

2) For a combined injection volume of not more than 10ml (e.g. the contents of one 5ml ampoule number 1 and one 5ml ampoule number 2) the contents of the ampoules are drawn up into a syringe to mix them just before use, then injected slowly, over a period of 10 minutes, into a vein.

Adults:

Rapid therapy of severe depletion or malabsorption of the water soluble vitamins B and C, particularly in alcoholism, where a severe depletion of thiamine can lead to Wernicke's encephalopathy    

10ml solution from Ampoule

Number 1

PLUS

10ml solution from Ampoule

Number 2

OR

   

15ml solution from Ampoule

Number 1

PLUS

15ml solution from Ampoule

Number 2

2 to 3 pairs of 5ml ampoules* (1 pair = ampoule 1 + ampoule 2) diluted with 50ml to 100ml infusion solution (physiological saline or glucose 5%) and administered over 30 minutes every 8 hours, or at the discretion of the physician.

* or equivalent volume of 5ml and/or 10ml ampoules

    Psychosis following narcosis or E.C.T; toxicity from acute infections    

5ml Ampoule Number 1

PLUS

5ml Ampoule Number 2

10ml of the mixed ampoules diluted with 50ml to 100ml infusion solution (physiological saline or glucose 5%) administered over 15 to 30 minutes twice daily for up to 7 days.

    Haemodialysis    

5ml Ampoule Number 1

PLUS

5ml Ampoule Number 2

10ml of the mixed ampoules diluted with 50ml to 100ml infusion solution (physiological saline or glucose 5%) administered over 15 to 30 minutes once every two weeks at the end of dialysis.

   

Elderly: as for adults.

Children: Pabrinex Intravenous High Potency is rarely indicated for administration to children, however suitable doses are as follows:

Under 6 years quarter of the adult dose 6 - 10 years third of the adult dose 10 - 14 years half to two thirds of the adult dose 14 years and over as for the adult dose 4.3 Contraindications

Known hypersensitivity to any of the active constituents or to the excipients.

4.4 Special Warnings And Precautions For Use

Although potentially serious allergic adverse reactions such as anaphylactic shock may occur rarely during, or shortly after, parenteral administration of Pabrinex, such rare occurrence of serious allergic reactions should not preclude the use of Pabrinex in patients who need treatment by this route of administration particularly those at risk of Wernicke's encephalopathy - for whom treatment with parenteral thiamine is essential. Initial warning signs of a reaction to Pabrinex are sneezing or mild asthma and those treating patients need to note that the administration of further injections to such patients may give rise to anaphylactic shock. Facilities for treating anaphylactic reactions should be available whenever Pabrinex Intravenous High Potency is administered. To minimise the risk of such events with Pabrinex Intravenous High Potency, the preferred mode of administration is by infusion over a period of 30 minutes.

This medicine is for injection into a vein only and should not be given by any other route

Care should be taken to ensure that the route of administration used (intramuscular or intravenous) is that intended – reports of unintentional administration by the wrong route have been received; these incidents have not been associated with serious adverse reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The content of pyridoxine may interfere with the effects of concurrent levodopa therapy.

4.6 Pregnancy And Lactation

No adverse effects have been noted at recommended doses when used as clinically indicated.

However animal studies are insufficient with respect to effects on pregnancy/ and-or/ embryonal/foetal development/ and-or/ parturition/ and-or/ postnatal development (see section 5.3). The potential risk for humans is unknown.

Caution should be exercised when prescribing to pregnant women.

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. However given the nature of the product, no effects are anticipated.

4.8 Undesirable Effects

Occasionally, hypotension and mild paraesthesia from continued high doses of thiamine; occasionally mild ache at local site of injection.

4.9 Overdose

In the unlikely event of overdosage, treatment is symptomatic and supportive.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pabrinex Intravenous High Potency contains vitamins B1, B2, B6, nicotinamide, vitamin C and glucose.

ATC code: A11EB

5.2 Pharmacokinetic Properties

Not supplied.

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

Edetic acid

Sodium hydroxide

Water for Injections

6.2 Incompatibilities

If it is necessary to administer Pabrinex Intravenous High Potency in infusion, it is recommended that Pabrinex IV HP is administered in physiological saline or glucose 5%.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25°C. Keep the container in the outer carton. Do not freeze.

Storage of diluted Pabrinex Intravenous High Potency

The stability of Pabrinex Intravenous High Potency in intravenous infusion fluids, at room temperature, is as follows:

Intravenous infusion fluid

In the light

Glucose 5%

7 hours

Physiological saline (sodium chloride 0.9%)

7 hours

Glucose 4.3% with sodium chloride 0.18%

4 hours

Glucose 5% with potassium chloride 0.3%

4 hours

Sodium lactate M/6

7 hours

Although no further specific data are available, the solutions are expected to be stable for longer periods when protected from light. Store diluted solutions at 2°C to 8°C if not used immediately. Do not freeze.

6.5 Nature And Contents Of Container

Pabrinex Intravenous High Potency is supplied in pairs of amber glass ampoules of 5ml or 10ml. Pack sizes contain ten pairs of 5ml or five pairs of 10ml ampoules.

6.6 Special Precautions For Disposal And Other Handling

In common with all parenteral products each ampoule should be visually inspected prior to administration and should not be used if particulates are present.

7. Marketing Authorisation Holder

Archimedes Pharma UK Limited

250 South Oak Way

Green Park

Reading

Berkshire

RG2 6UG

UK

8. Marketing Authorisation Number(S)

PL 12406/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: October 1993

Date of the latest renewal: October 2003

10. Date Of Revision Of The Text

22 July 2010

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Refolinon Injection 2 ml / 10 ml

1. Name Of The Medicinal Product

Refolinon Injection

2. Qualitative And Quantitative Composition

Clear pale yellow liquid for injection containing leucovorin 3 mg/ml in ampoules of 2 ml and 10 ml, as the calcium salt

3. Pharmaceutical Form

Solution for injection

4. Clinical Particulars 4.1 Therapeutic Indications

Leucovorin (folinic acid) is the formyl derivative of tetrahydrofolic acid and is an intermediate product of the metabolism of folic acid. Leucovorin is used in cytotoxic therapy as an antidote to folic acid antagonists such as methotrexate. Leucovorin is effective in the treatment of megaloblastic anaemia due to folate deficiency.

Warning: Leucovorin should not be given simultaneously with a folic acid antagonist, for the purpose of reducing or preventing clinical toxicity, as the therapeutic effect of the antagonist may be nullified.

4.2 Posology And Method Of Administration

For intravenous and intramuscular administration only. In the case of intravenous administration, no more than 160mg of calcium folinate should be injected per minute due to the calcium content of the solution.

For intravenous infusion, calcium folinate may be diluted with 0.9% sodium chloride solution or 5% glucose solution before use. Refer also to sections 6.3 and 6.6.

1) Treatment of adverse drug reactions and intoxication induced by folic acid antagonists (injection only)

Trimetrexate toxicity: Prevention: Calcium folinate should be administered every day during treatment with trimetrexate and for 72 hours after the last dose of trimetrexate. Calcium folinate can be administered either by the intravenous route at a dose of 20 mg/m? for 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m?, or by oral route with four doses of 20 mg/m2 administered at equal time intervals. Daily doses of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.

Overdosage (possibly occurring with trimetrexate doses above 90 mg/m2 without concomitant administration of calcium folinate): after stopping trimetrexate, calcium folinate 40 mg/m2 IV every 6 hours for 3 days.

Trimethoprime toxicity:

After stopping trimethoprime, 3-10 mg/day calcium folinate until recovery of a normal blood count.

Pyrimethamine toxicity:

In case of high dose pyrimethamine or prolonged treatment with low doses, calcium folinate 5 to 50 mg/day should be simultaneously administered, based on the results of the peripheral blood counts.

2) Therapy after high-dose methotrexate

Since the calcium folinate rescue dosage regimen depends heavily on the posology and method of the intermediate- or high-dose methotrexate administration, the methotrexate protocol will dictate the dosage regimen of calcium folinate rescue. Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate.

The following guidelines may serve as an illustration of regimens used in adults, elderly and children: Calcium folinate rescue has to be performed by parenteral administration in patients with malabsorption syndromes or other gastrointestinal disorders where enteral absorption is not assured. Dosages above 25-50 mg should be given parenterally due to saturable enteral absorption of calcium folinate. Calcium folinate rescue is necessary when methotrexate is given at doses exceeding 500 mg/m2 body surface and should be considered with doses of 100 mg – 500 mg/m2 body surface.

Dosage and duration of calcium folinate rescue primarily depend on the type and dosage of methotrexate therapy, the occurrence of toxicity symptoms, and the individual excretion capacity for methotrexate. As a rule, the first dose of calcium folinate is 15 mg (6-12 mg/m?) to be given 12-24 hours (24 hours at the latest) after the beginning of methotrexate infusion. The same dose is given every 6 hours throughout a period of 72 hours. After several parenteral doses treatment can be switched over to the oral form.

In addition to calcium folinate administration, measures to ensure the prompt excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the calcium folinate rescue treatment. Renal function should be monitored through daily measurements of serum creatinine.

Forty-eight hours after the start of the methotrexate infusion, the residual methotrexate-level should be measured. If the residual methotrexate-level is >0.5µmol/l, calcium folinate dosages should be adapted according to the following table:

Residual methotrexate blood level 48 hours after the start of the methotrexate administration:

Additional calcium folinate to be administered every 6 hours for 48 hours or until levels of methotrexate are lower than 0.05 µmol/l:

15 mg/m2

100 mg/m2

200 mg/m2

4.3 Contraindications

Leucovorin calcium should not be used in patients who have a known hypersensitivity to any of the constituents of the product.

Calcium folinate should not be used for the treatment of pernicious anaemia or other megaloblastic anaemia where vitamin B12 is deficient.

Calcium folinate should only be given by intramuscular or intravenous injection and must not be administered intrathecally. When folinic acid has been administered intrathecally following intrathecal overdose of methotrexate, death has been reported.

4.4 Special Warnings And Precautions For Use

Calcium folinate should only be used with methotrexate and 5-fluorouracil by clinicians experienced in the use of cancer chemotherapeutic agents.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Leucovorin should not be given simultaneously with a folic acid antagonist, for the purpose of reducing or preventing clinical toxicity, as the therapeutic effect of the antagonist may be nullified.

Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin, as well as primidone and increase the frequency of seizures.

Concurrent administration of chloramphenicol and folic acid in folate-deficient patients may result in antagonism of the haematopoietic response to folic acid.

Calcium folinate may enhance the toxicity of fluorouracil.

4.6 Pregnancy And Lactation

Pregnancy:

There are no adequate and well-controlled clinical studies conducted in pregnant or breast feeding women. No formal animal reproductive toxicity studies with calcium folinate have been conducted. There are no indications that folic acid induces harmful effects if administered during pregnancy. During pregnancy, methotrexate should only be administered on strict indications, where the benefits of the drug to the mother should be weighed against possible hazards to the foetus. Should treatment with methotrexate or other folate antagonists take place despite pregnancy or lactation, there are no limitations as to the use of calcium folinate to diminish toxicity or counteract the effects.

5-fluorouracil use is generally contraindicated during pregnancy and contraindicated during breastfeeding; this applies also to the combined use of calcium folinate with 5-fluorouracil.

Please refer to the SPC for methotrexate, other folate antagonists (and 5-fluorouracil) containing medicinal products.

Lactation

It is not known whether calcium folinate is excreted into human breast milk. Calcium folinate can be used during breast feeding when considered necessary according to the therapeutic indications.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Adverse reactions to leucovorin calcium are rare, but following intravenous and intramuscular administration occasional pyrexial reactions have been reported.

The most common dose-limiting adverse reaction occurring in patients receiving combination of calcium folinate and 5-fluorouracil are stomatitis and diarrhoea. In addition, haematological adverse reactions, such as leucocytopenia and thrombocytopenia, may occur. These adverse reactions are dose-dependent and their occurrence can usually be decreased by reducing the dosage of cytotoxic drugs. These adverse reactions can be controlled by close monitoring of haematological values, e.g. blood leucocyte and thrombocyte levels, and serum electrolyte (e.g. Na, K, Ca) and creatinine levels.

Anaphylactoid and urticaria allergic reactions have also been reported with the use of leucovorin.

4.9 Overdose

There have been no reported sequelae in patients who have received significantly more calcium folinate then the recommended dosage. However, excessive amounts of calcium folinate may nullify the chemotherapeutic effect of folic acid antagonists.

Should overdosage of the combination of 5-fluorouracil and calcium folinate occur, the overdosage instructions for 5-FU should be followed.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment; ATC Code: V03AF03

Calcium folinate is the calcium salt of 5-formyltetrahydrofolic acid. .) It is an active metabolite of folinic acid and an essential coenzyme for nucleic acid synthesis in cytotoxics therapy.

Calcium folinate is frequently used to diminish the toxicity and counteract the action of folate antagonists, such as methotrexate. Calcium folinate and folate antagonists share the same membrane transport carrier and compete for transport into cells stimulating folate antagonist efflux. It also protects cells from the effects of folate antagonist by repletion of the reduce folate pool. Calcium folinate serves as a pre-reduced source of H4 folate; it can therefore bypass folate antagonist blockage and provide a source for the various coenzymes forms of folic acid.

Finally intravenous calcium folinate can be administered for the prevention and treatment of folate deficiency when it cannot be prevented or corrected by the administration of folic acid by the oral route. This may be the case during total parenteral nutrition and severe malabsorption disorders. It is also indicated for the treatment of megaloblastic anaemia due to folic acid deficiency, when oral administration is not feasible.

5.2 Pharmacokinetic Properties

Absorption

Calcium folinate is rapidly absorbed in the gastrointestinal tract after oral administration. The oral absorption of calcium folinate is saturable at doses above 25mg. The bioavailability of calcium folinate is 97% for 25mg, 75% for 50mg, and 37% for 100mg. Following intramuscular administration of the aqueous solution, systemic availability is comparable to an intravenous administration. However, lower peak serum levels (Cmax) are achieved.

Metabolism

Calcium folinate is a racemate where the L-form (L-5-formyl-tetrahydrofolate, L-5-formyl-THF), is the active enantiomer. The major metabolic product of folinic acid is 5-methyl-tetrahydrofolic acid (5-methyl-THF) which is predominantly produced in the liver and intestinal mucosa.

Distribution

The distribution volume of folinic acid is not known. Peak serum levels of the parent substance (D/L-5-formyl-tetrahydrofolic acid, folinic acid) are reached 10 minutes after i.v. administration. AUC for L-5-formyl-THF and 5-methyl-THF were 28.4±3.5 mg.min/l and 129±112 mg.min/l after a dose of 25 mg. The inactive D-isomer is present in higher concentration than L-5-formyltetrahydrofolate. Folate is concentrated in the cerebrospinal fluid, although distribution occurs to all body tissues.

Elimination

The elimination half-life is 32 - 35 minutes for the active L-form and 352 - 485 minutes for the inactive D-form, respectively. The total terminal half-life of the active metabolites is about 6 hours (after intravenous and intramuscular administration).

Excretion

80-90 % with the urine (5- and 10-formyl-tetrahydrofolates inactive metabolites), 5-8 % with the faeces.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium Chloride

Sodium Hydroxide

Hydrochloric Acid

Water for injections

6.2 Incompatibilities

None stated.

6.3 Shelf Life

24 Months

6.4 Special Precautions For Storage

Store at 2oC – 8oC and protect from light.

6.5 Nature And Contents Of Container

Type 1 colourless glass ampoules containing 2 or 10 ml. Packs of 5 or 10 ampoules.

6.6 Special Precautions For Disposal And Other Handling

Prior to administration, calcium folinate should be inspected visually. The solution for injection or infusion should be clear and yellowish solution. If cloudy in appearance or particles are observed, the solution should be discarded. Calcium folinate solution for injection or infusion is intended only for single use. Any unused potion of the solution should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

PL 00032/0346

9. Date Of First Authorisation/Renewal Of The Authorisation

17th July 2002

10. Date Of Revision Of The Text

November 2009

Ref: REA6.0

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Gentamicin Paediatric 20mg / 2ml Solution for Injection

1. Name Of The Medicinal Product

Cidomycin Paediatric Injectable 20mg/2ml

or

Gentamicin Paediatric 20mg/2ml Solution for Injection.

2. Qualitative And Quantitative Composition

Each vial (2ml) contains Gentamicin Sulphate Ph Eur equivalent to 20mg Gentamicin base.

For excipients, see section 6.1.

3. Pharmaceutical Form

Solution for Injection.

Clear, colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Gentamicin is an aminoglycoside antibiotic with broad-spectrum bactericidal activity. It is usually active against most strains of the following organisms: escherichia coli, klebsiella spp., Proteus spp. (indole positive and indole negative), pseudomonas aeruginosa, staphylococci, enterobacer spp., Citrobacter spp. and providencia spp.

Indications : gentamicin injection and gentamicin paediatric injection are indicated in bacteraemia, septicaemia, urinary tract infections, chest infections, severe neonatal infections and other serious systemic infections due to susceptible organisms.

Consideration should be given to official local guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

Adults:

Serious infections: if renal function is not impaired, 5mg/kg daily in divided doses at six or eight hourly intervals. The total daily dose may be subsequently increased or decreased as clinically indicated.

Systemic infections: if renal function is not impaired, 3-5 mg/kg/day in divided doses according to severity of infection, adjusting according to clinical response and body weight.

Urinary tract infections: as 'systemic infections'. Or, if renal function is not impaired, 160mg once daily may be used.

Paediatric Patients

The daily dose recommended in children (aged 1 year and above) and adolescents with normal renal function, is 3-6 mg/kg body weight per day as 1 (preferred) up to 2 single doses.

The daily dose in infants after the first month of life is 4.5-7.5 mg/kg body weight per day as 1 (preferred) up to 2 single doses.

The daily dose in newborns is 4-7 mg/kg body weight per day. Due to the longer half-life, newborns are given the required daily dose in 1 single dose.

Elderly:

There is some evidence that elderly patients may be more susceptible to aminoglycoside toxicity whether secondary to previous eighth nerve impairment or borderline renal dysfunction.

Accordingly, therapy should be closely monitored by frequent determination of gentamicin serum levels, assessment of renal function and signs of toxicity.

Renal impairment

Gentamicin is excreted by simple glomerular filtration. In impaired renal function, the recommended daily dose has to be decreased and adjusted to the renal function.

Nomograms are available for the calculation of the dose, which depends on the patient's age, weight, and renal function

The following table may be useful when treating adults.

Blood Urea

Creatine clearance

Dose and frequency of administration

 

(mg/100ml)

(mmol/I)

(GFR) (ml/min)

 

<40

6-7

>70

80mg* 8 hourly

40-100

6-17

30-70

80mg* 12 hourly

100-200

17-34

10-30

80mg* daily

>200

>34

5-10

80mg* every 48 hours

Twice weekly intermittent haemodialysis

<5

80mg* after dialysis

 

*60mg if body weight <60kg. Frequency of dosage in hours may also be approximated as serum creatine (mg%) x eight or in SI units, as serum creatine (?mol/l) divided by 11. If these dosage guides are used peak serum levels must be measured. Peak levels of genamicin occur approximately one hour after intramuscular injectable and intravenous injectable. Trough levels are measured just prior to the next injectable. Assay of peak serum levels gives confirmation of adequacy of dosage and also serves to detect levels above 10mg/l, at which the possibility of ototoxicity should be considered. One hour concentrations of gentamicin should not exceed 10mg/l (but should reach 4mg/l), while the pre-dose trough concentration should be less than 2mg/l

The recommended dose and precautions for intramuscular and intravenous administration are identical. Gentamicin when given intravenously should be injected directly into a vein or into the drip set tubing over no less than three minutes. If administered by infusion, this should be over no longer than 20 minutes and in no greater volume of fluid than 100ml.

Monitoring advice:

Serum concentration monitoring of gentamicin is recommended, especially in elderly, in newborns and in patients with impaired renal function. Samples are taken at the end of a dosing interval (trough level). Trough levels should not exceed 2 µg/ml administering gentamicin twice daily and 1 µg/ml for a once daily dose.

4.3 Contraindications

Hypersensitivity; maysthenia gravis.

4.4 Special Warnings And Precautions For Use

To avoid adverse events, continuous monitoring (before, during and after) of renal function (serum creatinin, creatinin clearance), control of function of vestibule and cochlea as well as hepatic and laboratory parameters is recommended.

Ototoxicity has been recorded following the use of gentamicin. Groups at special risk include patients with impaired renal function, infants and possibly the elderly. Consequently, renal, auditory and vestibular functions should be monitored in these patients and serum levels determinedso as to avoid peak concentrations above 10mg/l and troughs above 2mg/l. As there is some evidence that risk of both ototixicity and nephrotoxicity is related to the level of total exposure, duration of therapy should be the shortest possible compatible with clinical recovery. In some patients with impaired renal function there has been a transient rise in blood-urea-nitrogen which has usually reverted to normal during or following cessation of therapy. It is important to adjust the frequency of dosage according to the degree of renal function.

Gentamicin should only be used in pregnancy if considered essential by the physician (see section 4.6 Pregnancy and Lactation.)

Gentamicin should be used with care in conditions characterised by muscular weakness.

In cases of significant obesity gentamicin serum concentrations should be closely monitored and a reduction in dose should be considered.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concurrent administration of gentamicin and other potentially ototoxic or nephrotoxic drugs should be avoided. Potent diuretics such as etacrynic acid and furosemide are believed to enhance the risk of otoxicity whilst amphotericin b, cis-platinum and ciclosporin are potential enhancers of nephrotoxicity.

Any potential nephrotoxicity of cephalosporins , and in particular cephaloridine, may also be increased in the presence of gentamicin. Consequently, if this combination is used monitoring of kidney function is advised.

Neuromuscular blockade and respiratory paralysis have been reported from administration of aminoglycosides to patients who have received curare-type muscle relaxants during anaesthesia.

Indometacin possibly increases plasma concentrations of gentamicin in neonates.

Concurrent use with oral anticoagulants may increase the hypothrombinanaemic effect.

Concurrent use of bisphosphonates may increase the risk of hypocalcaemia.

Concurrent use of the Botulinum Toxin and gentamicin may increase the risk of toxicity due to enhanced neuromuscular block.

Antagonism of effect may occur with concomitant administration of gentamicin with either neostigmine or pyridostigmine.

4.6 Pregnancy And Lactation

There are no proven cases of intrauterine damage caused by gentamicin. However, in common with most drugs known to cross the placenta , usage in pregnancy should only be considered in life-threatening situations where the expected benefits outweigh possible risks. In the absence of gastro-intestinal inflammation, the amount of gentamcin ingested from the milk is unlikely to result in significant blood levels in breast-fed infants

4.7 Effects On Ability To Drive And Use Machines

Not known.

4.8 Undesirable Effects

Side-effects include vestibular damage or hearing loss, particularly after exposure to ototoxic drugs or in the presence of renal dysfunction. Nephrotoxicity (usually reversible) and occasionally acute renal failure, hypersensitivity, anaemia, blood dycrasias, purpura, stomatitis, convulsions and effects on liver function occur occasionally.

Rarely hypomagnesia on prolonged therapy and antibiotic–associated colitis have been reported.

Nausea, vomiting and rash have also been reported.

Central neurotoxicity, including encephalopathy, confusion, lethargy, mental depression and hallucinations, has been reported in association with gentamicin therapy but this is extremely rare.

4.9 Overdose

Haemodialysis and peritoneal dialysis will aid removal from the blood but the former is probably more efficient. Calcium salts given intravenously have been used to counter the neuromuscular blockade caused by gentamicin.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Gentamicin is a mixture of antibiotic substances produced by the growth of micromonospora purpurea. It is bactericidal with greater antibacterial activity than streptomycin, neomycin or kanamycin.

Gentamicin exerts a number of effects on cells of susceptible bacteria. It affects the integrity of the plasma membrane and the metabolism of RNA, but its most important effects is inhibition of protein synthesis at the level of the 30s ribosomal subunit.

5.2 Pharmacokinetic Properties

Gentamicin is not readily absorbed from the gastro-intestinal tract. Gentamicin is 70-85% bound to plasma albumin following administration and is excreted 90% unchanged in urine. The half-life for its elimination in normal patients is 2 to 3 hours.

• Effective plasma concentration is 4-8?g/ml.

• The volume of distribution (VD) is 0.31kg.

• The elimination rate constant is:

1. 0.02hr-1 for anuric patients*

2. 0.30hr-1 normal

* Therefore in those with anuria care must be exercised following the initial dose, any subsequent administration being reduced in-line with plasma concentrations of gentamicin.

Paediatric patients, premature infants and neonates

Distribution

The distribution volume of gentamicin is about equivalent to the volume of extracellular water. In the newborn water makes up 70 to 75% of bodyweight, compared with 50 to 55% in adults. The extracellular water compartment is larger (40% of body weight compared with 25% of body weight in adults). Therefore, the volume of distribution of gentamicin per kg bodyweight is affected and decreases with increasing age from 0.5 to 0.7 L/kg for a premature newborn to 0.25 L/kg for an adolescent. The larger volume of distribution per kg bodyweight means that for adequate peak blood concentration a higher dose per kg bodyweight needs to be administered.

Elimination

Gentamicin is not metabolized in the body but is excreted unchanged in microbiologically active form predominantly via the kidneys. In patients with normal renal function the elimination half life is about 2 to 3 hours. In neonates elimination rate is reduced due to immature renal function.

Elimination half life averages approximately 8 hours in neonates at a gestational age of 26 to 34 weeks compared with about 6.7 hours in neonates at a gestational age of 35 to 37 weeks.

Correspondingly, clearance values increase from about 0.05 L/h in neonates at a gestational age of 27 to 0.2 L/h in neonates at a gestational age of 40 weeks.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars 6.1 List Of Excipients

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Disodium Edetate

2M Sodium Hydroxide

1M Sulphuric Acid

Water for Injections

6.2 Incompatibilities

In general, gentamicin injection should not be mixed. In particular the following are incompatible in mixed solution with gentamicin injection: penicillins, cephalosporins, erythromycin, heparins, sodium bicarbonate. * Dilution in the body will obviate the danger of physical and chemical incompatibility and enable gentamicin to be given concurrently with the drugs listed above either as a bolus injection into the drip tubing, with adequate flushing, or at separate sites. In the case of carbenicillin, administration should only be at a separate site.

* Carbon Dioxide may be liberated on addition of the two solutions. Normally this will dissolve in the solution but under some circumstances small bubbles may form.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not Store above 25°C. Do not refrigerate or freeze.

6.5 Nature And Contents Of Container

Cidomycin Paediatric Injectable is supplied in vials.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS

8. Marketing Authorisation Number(S)

PL 17780/0507

9. Date Of First Authorisation/Renewal Of The Authorisation

10/03/2010

10. Date Of Revision Of The Text

01/09/2010

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Subgam, Human normal immunoglobulin solution

1. Name Of The Medicinal Product

Subgam®, Human normal immunoglobulin solution 160g/L, solution for injection

2. Qualitative And Quantitative Composition

Human normal immunoglobulin Ph.Eur. (SC/IMIg)

Subgam is presented as three vial sizes of 250 mg, 750 mg and 1,500 mg of protein. Each millilitre contains: nominal 160mg human protein of which at least 95% is immunoglobulin G (gammaglobulin). The sub-class distribution of IgG1:IgG2:IgG3:IgG4 is approximately 64:29:6:1, which is similar to plasma. The IgA content is less than 0.02% w/w of the total protein. This product is prepared from plasma from screened donors. Donors are selected from the USA.

For excipients see 6.1.

3. Pharmaceutical Form

Solution for injection.

4. Clinical Particulars 4.1 Therapeutic Indications

Replacement therapy in adults and children in primary immunodeficiency syndromes such as:

a. Congenital agammaglobulinaemia and hypogammaglobulinaemia,

b. Common variable immunodeficiency,

c. Severe combined immunodeficiency,

d. IgG subclass deficiencies with recurrent infections

Replacement therapy in myeloma or chronic lymphatic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.

4.2 Posology And Method Of Administration

Posology

Replacement therapy

The product should be administered via the subcutaneous or intramuscular route.

Treatment should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

The dosage may need to be individualised for each patient dependent on the pharmacokinetic and clinical responses. The following dosage regimens are given as a guideline.

The dosage regimen using the subcutaneous route should achieve a sustained trough level of IgG. A loading dose of at least 0.2 - 0.5 g/kg may be required. After steady state IgG levels have been attained, maintenance doses are administered at repeated intervals to reach a cumulative monthly dose of the order of 0.4 - 0.8 g/kg.

Trough levels should be measured in order to adjust the dose and dosage interval.

Method of administration

Subgam® should be administered via the subcutaneous or intramuscular route.

Subcutaneous infusion for home treatment should be initiated by a physician experienced in the guidance of patients for home treatment. The patient will be instructed in the use of a syringe driver, infusion techniques, the keeping of a treatment diary and measures to be taken in case of severe adverse events. The amount of Subgam® infused subcutaneously per injection site will vary depending on the patient's age and amount of subcutaneous tissue. Initially the infusion rate should be no more than 10 mL/hour for each syringe driver. If well tolerated it can be increased at weekly intervals by 2 mL/hour per syringe driver to a maximum of 20 mL/hour. The administration can be performed at two or more different sites simultaneously to reduce infusion time.

Intramuscular injection must be given by a physician or nurse.

4.3 Contraindications

Hypersensitivity to any of the components.

Subgam® must not be given intravenously.

Subgam® must not be administered intramuscularly in cases of severe thrombocytopenia and in other disorders of haemostasis.

4.4 Special Warnings And Precautions For Use

If Subgam® is accidentally administered into a blood vessel, patients could develop shock.

The recommended infusion rate given under “4.2 Method of administration” should be adhered to. Patients should be closely monitored and carefully observed for any adverse events throughout the infusion period.

Certain adverse reactions may occur more frequently in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when treatment has been stopped for more than eight weeks.

True hypersensitivity reactions are rare. They can particularly occur in the very rare cases of IgA deficiency with anti-IgA antibodies and these patients should be treated with caution.

Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

Potential complications can often be avoided by ensuring that:

• patients are not sensitive to human normal immunoglobulin, by first injecting the product slowly (see 4.2);

• patients are carefully monitored for any symptoms throughout the infusion period. In particular, patients na?ve to human normal immunoglobulin, patients switched from an alternative product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs. All other patients should be observed for at least 20 minutes after administration.

Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment should be administered.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to pathogens of unknown nature.

The measure taken are considered effective for enveloped viruses such as HIV, HBV and HCV. The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19.

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.

It is strongly recommended that every time that Subgam® is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore patients receiving measles vaccine should have their antibody status checked.

Interference with serological testing

After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing. Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some serological tests (reticulocyte count, haptoglobin and Coombs' test).

4.6 Pregnancy And Lactation

The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the fetus and the neonate are to be expected.

4.7 Effects On Ability To Drive And Use Machines

No effects on ability to drive and use machines have been observed.

4.8 Undesirable Effects

Adverse reactions such as chills, headache, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally. Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration. Local reactions at infusion sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash.

With intramuscular administration, local pain and tenderness can be observed at the injection site.

From clinical trials with Subgam® the following side effects have been reported. The frequencies relate to the proportion of patients developing each side effect at some time during the trial, but not with every infusion:

Very common>1/10; Common>1/100 to <1/10

Psychiatric disorders:

Common

Anxiety

Nervous system disorders:

Very common

Headache

 

Common

Dizziness

 

Common

Migraine

 

Common

Paraesthesia

Vascular disorders:

Common

Flushing

Respiratory, thoracic and mediastinal disorders:

 

Common

Wheezing/asthma

Gastrointestinal disorders:

Common

Nausea

 

Common

Vomiting

 

Common

Diarrhoea

 

Common

Mouth ulcer

 

Common

Abdominal pain upper

Skin and subcutaneous tissue disorders:

 

Common

Pruritus

 

Common

Sweating increased

 

Common

Rash

Muscular skeletal, Connective tissue and bone disorders:

 

Common

Arthralgia

 

Common

Musculoskeletal pain/stiffness

General disorders and administration site conditions:

 

Very common

Infusion site reaction

 

Common

Chest pain/tightness

 

Common

Fatigue

 

Common

Pyrexia

 

Common

Shivering/feeling cold

Investigations:

Common

Blood pressure increased

For information on viral safety see 4.4.

4.9 Overdose

Consequences of an overdose are not known.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for extravascular administration, ATC code: J06B A02.

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.

Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1,000 donations. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.

5.2 Pharmacokinetic Properties

With subcutaneous administration of Subgam®, peak levels are achieved in the recipient's circulation after a delay of 3 to 4 days.

Data from clinical trials show that trough levels of Subgam® can be maintained by doses of 100 (90 to 115) mg/kg. usually given once weekly.

With intramuscular administration, human normal immunoglobulin is bioavailable in the recipient's circulation after a delay of 2 to 3 days.

IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.

5.3 Preclinical Safety Data

Human normal immunoglobulin is a preparation of human plasma proteins, so safety testing in animals is not particularly relevant to the safety of use in man. However, acute toxicity studies in rat and mouse showed no minimum lethal dose with the clinical strength product used at approximately 1,250 mg/kg. This is equivalent to approximately 10 times the dose in man. Repeated dose testing is impracticable due to induction of, and interference with antibodies, to human protein. Clinical experience provides no evidence of tumourigenic and mutagenic effects.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium chloride, Glycine, Sodium acetate trihydrate, Sodium hydroxide, Polysorbate 80, Hydrochloric acid (if required)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Stored at 2°C - 8°C (in the dark):

2 years

Stored at 25°C (in the dark):

1 week

6.4 Special Precautions For Storage

Subgam® should be stored in its carton to protect it from light, between 2°C and 8°C. DO NOT FREEZE. Storage for up to one week (within the overall shelf-life) at ambient temperatures (25°C) is not detrimental. Product that has been stored out of a fridge for one period of up to one week at temperatures up to 25°C may be returned to the fridge with no change to the expiry date

6.5 Nature And Contents Of Container

The containers are 26 mL brimful (1,500 mg) moulded vials of soda-lime silica glass with a 20 mm neck, or 12 mL brimful (750 mg) and 8 mL brimful (250 mg) tube drawn vials of neutral borosilicate glass with a 13 mm neck. The closure on the largest vial is a 20 mm halobutyl rubber stopper with a 20 mm overseal consisting of a clear lacquered aluminium skirt and a snap-off polypropylene cap. The two smaller vials use a 13 mm diameter overseal, consisting of a snap-off polypropylene cap, a clear lacquered aluminium skirt and a halobutyl rubber wad.

6.6 Special Precautions For Disposal And Other Handling

Detailed infusion technique:

The syringe driver should be checked and the appropriate rate set for the patient. A suitable size syringe should be selected and the IgG solution drawn up aseptically. Attach the 'butterfly' or other infusion system and prime tubing with the solution. Cleanse the injection site and insert the needle into the subcutaneous tissue. Ensure that the needle tip is not in a blood vessel. Switch on the syringe driver. The usual sites of infusion are the subcutaneous tissues over the anterior abdominal wall or the anterior aspect of the thigh(s). When the end-of-infusion signal sounds, remove the needle.

The dose volume for each size is specified on the label. The product should be brought to room or body temperature before use.

The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Bio Products Laboratory

Dagger Lane

Elstree

Hertfordshire

WD6 3BX

United Kingdom.

Tel: +44 (0)20 8258 2200

Fax: +44 (0)20 8258 2608

Email: info@bpl.co.uk

8. Marketing Authorisation Number(S)

PL 08801/0050

9. Date Of First Authorisation/Renewal Of The Authorisation

9 June 2004

10. Date Of Revision Of The Text November 2008 Version Code: SCS2 POM  

Read More:

Verapamil Tablets BP 80mg

1. Name Of The Medicinal Product

VERAPAMIL TABLETS BP 80mg

2. Qualitative And Quantitative Composition

Each tablet contains 80mg Verapamil Hydrochloride PhEur.

3. Pharmaceutical Form

Yellow film-coated tablets.

Yellow, circular, biconvex film-coated tablets, impressed “C” on one face and the identifying letters “VS” on the reverse.

4. Clinical Particulars 4.1 Therapeutic Indications

1) The management of mild to moderate hypertension and renal hypertension, used alone or in combination with other antihypertensive therapy (see 4.3 for warning regarding concomitant administration with beta-blockers).

2) For the management and prophylaxis of angina pectoris (including variant angina).

3) The treatment and prophylaxis of paroxysmal supraventricular tachycardia and the reduction of the ventricular rate in atrial fibrillation/flutter. Verapamil should not be used for atrial fibrillation/flutter in patients with Wolff-Parkinson-White syndrome (see 4.4).

4.2 Posology And Method Of Administration

Adults:

Hypertension: initially 120mg twice daily increasing to 160mg twice daily where necessary. In some cases doses of up to 480mg daily, in divided doses, have been used. A further reduction in blood pressure may be obtained by combining verapamil with other antihypertensive agents, in particular diuretics. For concomitant administration with beta-blockers, see section 4.4.

Angina: 120mg three times daily is recommended. 80mg three times daily may be completely satisfactory in some patients with angina of effort. Less than 120mg three times daily is unlikely to be effective in variant angina.

Supraventricular tachycardias: 40-120mg three times daily depending on the severity of the condition.

Children:

A paradoxical increase in the rate of arrhythmias in children has been noted. Therefore, verapamil should only be used under expert supervision.

Up to 2 years: 20mg 2-3 times a day.

2 years and above: 40-120mg 2-3 times a day according to age and effectiveness.

Elderly: The adult dose is recommended unless liver or renal function is impaired (see section 4.4).

Method of Administration

For oral administration.

4.3 Contraindications

• Hypersensitivity to verapamil or to any of the excipients.

• Hypotension (of less than 90mmHg systolic)

• Second or third degree atrioventricular block; sick sinus syndrome (except in patients with a functioning artifical pacemaker); uncompensated heart failure; marked bradycardia (less than 50 beats/minute).

• Combination with beta-blockers is contraindicated in patients with poor ventricular function.

• Wolff-Parkinson-White syndrome.

• Concomitant ingestion of grapefruit juice is contraindicated.

• Acute myocardial infarction complicated by bradycardia, marked hypotension or left ventricular failure.

4.4 Special Warnings And Precautions For Use

Verapamil may affect left ventricular contractility as a result of its mode of action. The effect is small and not normally important. However, cardiac failure may be aggravated or precipitated if it exists. In cases with poor ventricular function, verapamil should therefore only be administered after appropriate therapy for cardiac failure such as digitalis, etc.

Verapamil may affect impulse conduction and should be administered with caution in patients with first degree atrioventricular block. The effects of verapamil and beta-blockers or other drugs may be additive both in respect of conduction and contraction, therefore care should be exercised when these are administered concurrently or closely together. This is especially true when either drug is administered intravenously.

Caution should be observed in the acute stage of myocardial infarction.

Patients with atrial fibrillation/flutter and an accessory pathway (eg Wolff-Parkinson-White syndrome) may rarely develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.

Since verapamil is extensively metabolised in the liver, careful dose titration of verapamil is required in patients with liver disease. The disposition of verapamil in patients with renal impairment has not been fully established and therefore careful patient monitoring is recommended. Verapamil is not removed during dialysis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro metabolic studies indicate that verapamil hydrochloride is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused

a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.

H2 Receptor antagonists

Cimetidine increases serum levels of verapamil.

Anticonvulsants:

Increased serum levels of carbamazepine which could lead to increased side-effects.

Reduced serum levels of verapamil when taken with phenytoin.

Barbiturates:

Reduced serum levels of verapamil when taken with Phenobarbital.

Lithium:

Serum levels of lithium may be reduced (pharmacokinetic effect). There may be increased sensitivity to lithium causing enhanced neurotoxicity (pharmacodynamic effect).

Alcohol:

Verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

Antihypertensive drugs:

Verapamil may have an additive effect with other antihypertensive drugs; thus, in many cases with verapamil, a reduction in the dosage of the other antihypertensive drug may be possible:

Beta blockers:

Verapamil may increase the plasma concentrations of metoprolol and propranolol which may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).

Intravenous beta-blockers should not be given to patients under treatment with verapamil.

Alpha blockers:

Verapamil may increase the plasma concentrations of prazosin and terazosin which may have an additive hypotensive effect.

Antiarrhythmics:

Verapamil may increase the plasma concentrations of quinidine. Pulmonary oedema may occur in patients with hypertrophic cardiomyopathy.

The combination of verapamil and antiarrhythmic agents may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).

Benzodiazepines and anxiolytics:

Verapamil may increase the plasma concentrations of midazolam.

Lipid lowering agents:

Verapamil may increase the plasma concentrations atorvastatin, lovastatin and simvastatin.

Treatment with HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin or lovastatin) in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. If verapamil treatment is to be added to patients already taking an HMG CoA reductase inhibitor (e.g., simvastatin, atorvastatin or lovastatin), consider a reduction in the statin dose and retitrate against serum cholesterol concentrations.

Atorvastatin has been shown to increase verapamil levels. Although there is no direct in vivo clinical evidence, there is strong potential for verapamil to significantly affect atorvastatin pharmacokinetics in a similar manner to simvastatin or lovastatin. Consider using caution when atorvastatin and verapamil are concomitantly administered.

Fluvastatin, pravastatin and rosuvastatin are not metabolized by CYP3A4 and are less likely to interact with verapamil.

Acetylsalicylic acid

Concomitant use of verapamil with aspirin may increase the risk of bleeding.

Anti-infectives

Reduced serum levels of verapamil when taken with rifampicin.

Erythromycin, clarithromycin and telithromycin may increase the plasma concentrations of verapamil.

Anaesthesia:

Long-term verapamil therapy may give rise to potentiation of neuromuscular blocking agents during anaesthesia.

Interactions have been reported during the concomitant use of verapamil and the following medications:

Theophylline:

Increased serum levels of theophylline which could lead to increased side-effects.

Immunosuppressants

Verapamil may increase the plasma concentrations of ciclosporin, everolimus, sirolimus and tacrolimus which could lead to increased side-effects.

Digoxin:

Verapamil has been shown to increase the serum concentration of digoxin and caution should therefore be exercised with regard to digitalis toxicity.

Dantrolene

Concomitant use of verapamil with intravenous dantrolene may cause hypotension, myocardial depression, and hyperkalaemia. This combination should be avoided.

Colchicine

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (P-gp). Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. Combined use is not recommended.

Other:

An increase in verapamil serum level has been reported when taken with grapefruit juice.

4.6 Pregnancy And Lactation

Animal studies have shown no teratogenic effect. Verapamil should not be administered during pregnancy unless, in the clinicians judgement, it is essential for the welfare of the patient. The possibility that verapamil can cause relaxation of the uterine muscle should be considered at term.

Verapamil is excreted in breast milk at concentrations approximately equal to 0.5-1.0 times that coexisting in maternal plasma. However, the amount ingested in such circumstances is less than 1% of the recommended therapeutic infant dose, assuming normal suckling rates.

4.7 Effects On Ability To Drive And Use Machines

Depending on individual susceptibility, the patient's ability to drive or operate machines may be impaired due to feelings of drowsiness. This is particularly true in the initial stages of treatment, or when changing over from another drug. Verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

4.8 Undesirable Effects

Immune system disorders: allergic reactions (e.g. erythema, pruritus, urticaria) are very rarely seen.

Nervous system disorders: headaches occur rarely, dizziness, paraesthesia, tremor, extrapyramidal syndrome (e.g. parkinsonism), dystonia.

Ear and labyrinth disorders: vertigo, tinnitus.

Cardiac disorders: bradycardic arrhythmias such as sinus bradycardia, sinus arrest with asystole, 2nd and 3rd degree AV block, bradyarrhythmia in atrial fibrillation, palpitations, tachycardia, development or aggravation of heart failure, hypotension.

Vascular disorders: flushing, peripheral oedema.

Gastrointestinal disorders: nausea, vomiting, constipation is not uncommon, ileus and abdominal pain/discomfort. Gingival hyperplasia may very rarely occur when the drug is administered over prolonged periods. This is fully reversible when the drug is discontinued.

Skin and subcutaneous tissue disorders: alopecia, ankle oedema, Quincke's oedema, Steven-Johnson syndrome, erythema multiforme, erythromelalgia, purpura.

Musculoskeletal and connective tissue disorders: muscular weakness, myalgia and arthralgia.

Reproductive system and breast disorders: impotence (erectile dysfunction) has been rarely reported and isolated cases of galactorrhoea. Gynaecomastia was observed on very rare occasions in elderly male patients under longer term verapamil treatment which was fully reversible in all cases when the drug was discontinued.

General disorders and administration site conditions: fatigue.

Investigations: On very rare occasions, a reversible impairment of liver function characterised by an increase in transaminases and/or alkaline phosphatase, may occur during verapamil treatment and is most probably a hypersensitivity reaction.

4.9 Overdose

The course of symptoms in verapamil intoxication depends on the amount taken, the point in time at which detoxification measures are taken and myocardial contractility (age-related). The main symptoms are as follows: blood pressure fall (at times to values not detectable), shock symptoms, loss of consciousness, 1st and 2nd degree AV block (frequently as Wenckebach's phenomenon with or without escape rhythms), total AV block with total AV dissociation, escape rhythm, asystole, bradycardia up to high degree AV block and, sinus arrest, hyperglycaemia, stupor and metabolic acidosis. Fatalities have occurred as a result of overdose.

The therapeutic measures to be taken depend on the point in time at which verapamil was taken and the type and severity of intoxication symptoms. In intoxications with large amounts of slow-release preparations, it should be noted that the release of the active drug and the absorption in the intestine may take more than 48 hours. Verapamil hydrochloride cannot be removed by haemodialysis. Depending on the time of ingestion, it should be taken into account that there may be some lumps of incompletely dissolved tablets along the entire length of the gastrointestinal tract, which function as active drug depots.

General measures to be taken: Gastric lavage with the usual precautions, even later than 12 hours after ingestion, if no gastrointestinal motility (peristaltic sounds) is detectable. Where intoxication by a modified release preparation is suspected, extensive elimination measures are indicated, such as induced vomiting, removal of the contents of the stomach and the small intestine under endoscopy, intestinal lavage, laxative, high enemas. The usual intensive resuscitation measures apply, such as extrathoracic heart massage, respiration, defibrillation and/or pacemaker therapy.

Specific measures to be taken: Elimination of cardiodepressive effects, hypotension or bradycardia. The specific antidote is calcium, e.g. 10 20ml of a 10% calcium gluconate solution administered intravenously (2.25 - 4.5mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5mmol/hour).

The following measures may also be necessary: In case of 2nd or 3rd degree AV block, sinus bradycardia, asystole - atropine, isoprenaline, orciprenaline or pacemaker therapy. In case of hypotension - dopamine, dobutamine, noradrenaline (norepinephrine). If there are signs of continuing myocardial failure - dopamine, dobutamine, if necessary repeated calcium injections.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Verapamil hydrochloride is a calcium channel blocker and is classified as a class IV anti-arrhythmic agent.

Verapamil inhibits the entry of calcium into smooth muscle cells of the systemic and coronary arteries and in the cells of cardiac muscle and the intracardiac conduction system.

Verapamil lowers peripheral vascular resistance with little or no reflex tachycardia. Its efficacy in reducing both raised systolic and diastolic blood pressure is thought to be primarily due to this mode of action.

The decrease in systemic and coronary vascular resistance and the sparing effect on intracellular oxygen consumption appear to explain the anti-anginal properties of the product.

Due to the effect on the movement of calcium in the intracardiac conduction system, verapamil reduces automaticity, decreases conduction velocity and increases the refractory period.

5.2 Pharmacokinetic Properties

Verapamil is approximately 90% absorbed from the gastrointestinal tract, but is subject to very considerable first-pass metabolism in the liver and the bioavailability is only about 20%.

Verapamil exhibits bi- or tri-phasic elimination kinetics and is reported to have a terminal plasma half-life of 2-8 hours following a single oral dose. After repeated oral doses this increases to 4.5-12 hours. Verapamil acts within 1-2 hours after oral administration with a peak plasma concentration after 1-2 hours. There is considerable interindividual variation in plasma concentrations.

Verapamil is about 90% bound to plasma proteins. It is extensively metabolised in the liver to at least 12 metabolites of which norverapamil has been shown to have some activity. About 70% of a dose is excreted by the kidneys in the form of its metabolites but about 16% is also excreted in the bile into the faeces. Less than 4% is excreted unchanged.

Verapamil crosses the placenta and is excreted in breast milk.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Also contains: croscarmellose sodium, magnesium stearate, maize starch, propylene glycol, sunset yellow aluminium lake (E110), quinoline yellow aluminium lake (E104), titanium dioxide (E171), microcrystalline cellulose (E460), hydroxypropylcellulose (E463), methylhydroxypropylcellulose (E464), purified talc (E553).

6.2 Incompatibilities

None known.

6.3 Shelf Life

Shelf-life

Three years from the date of manufacture.

Shelf Life - After dilution or reconstitution

Not applicable.

Shelf Life - After first opening the container

Not applicable.

6.4 Special Precautions For Storage

Store below 25°C in a dry place.

6.5 Nature And Contents Of Container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps.

The product may also be supplied in blister packs and cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-6g/M? PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack size: 28s, 30s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 250s, 500s, 1000s.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data 7. Marketing Authorisation Holder

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing Authorisation Number(S)

PL 0142/0282

9. Date Of First Authorisation/Renewal Of The Authorisation

18.9.89

Renewed 22.4.97

10. Date Of Revision Of The Text

10.01.2011

Read More:

Verapamil Tablets BP 80mg

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