TF Defense
Generic Name: silybum marianum seed, crotalus horridus horridus venom, artemisia cina flower, aconitum napellus and ferrum phosphoricum granule Dosage Form: FOR ANIMAL USE ONLYTF Defense

Boosts red blood cells and the immune system

Indications: Homeopathic remedy to boost red blood cells and immune function.

Dosage: Initial dose: Administer every hour for up to 10 doses. Thereafter 3 times daily for approximately 7-10 days. Cats and dogs under 20 lbs: Large pinch of granules sprinkled into the mouth. Dogs 20-50 lbs: 2 pinches sprinkled into the mouth. Dogs over 50 lbs:1/4 cap of granules sprinkled into the mouth.

Caution: Recommended for use under veterinary supervision. Consult your vet if symptoms persist or worsen. Keep this and all medicines from the reach of children.

Ingredients: Each dose contains equal parts of Carduus mar (3X) (HPUS), Crotalus hor (200C) (HPUS), Cina (6C) (HPUS), Aconitum nap (6C) (HPUS), Ferrum phos (6C) (HPUS)

Sucrose (inactive ingredient).

Contains no gluten, artificial flavors, colors or preservatives.

Zinc Plus Lozenges
Pronunciation: zink/VYE-ta-minGeneric Name: Zinc/Vitamin B12/Vitamin CBrand Name: Zinc Plus Lozenges

Mag-200

Generic Name: magnesium oxide (mag NEE see um OCK side) Brand Names: Mag-200, Mag-Ox 400, MagGel, Uro-Mag

What is Mag-200 (magnesium oxide)?

Magnesium is a naturally occurring mineral. Magnesium is important for many systems in the body especially the muscles and nerves.

Magnesium oxide is used as a supplement to maintain adequate magnesium in the body.

Magnesium oxide may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Mag-200 (magnesium oxide)?

Before taking magnesium oxide, tell your doctor if you have any other medical conditions, allergies, or if you take other medicines or other herbal/health supplements. Magnesium oxide may not be recommended in some situations.

Who should not take Mag-200 (magnesium oxide)? Do not take magnesium oxide without first talking to your doctor if you have kidney disease.

Before taking magnesium oxide, tell your doctor if you have any other medical conditions, allergies, or if you take other medicines or other herbal/health supplements. Magnesium oxide may not be recommended in some situations.

It is not known whether magnesium oxide will harm an unborn baby. Do not take magnesium oxide without first talking to your doctor if you are pregnant or planning a pregnancy. It is not known whether magnesium oxide will harm an nursing baby. Do not take magnesium oxide without first talking to your doctor if you are breast-feeding a baby. How should I take Mag-200 (magnesium oxide)?

Take magnesium oxide exactly as directed by your doctor or as directed on the package. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take the tablets and capsules with a full glass of water.

To ensure that you get the correct dose, measure the liquid form of magnesium with a dose-measuring spoon or cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.

Do not take more magnesium oxide than is directed. Store magnesium oxide at room temperature away from moisture and heat. What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the dose you missed and take only the next regularly scheduled dose. Do not take a double dose of this medication.

What happens if I overdose? Seek emergency medical attention.

Symptoms of an magnesium oxide overdose include nausea, vomiting, flushing, low blood pressure, a slow heartbeat, drowsiness, coma, and death.

What should I avoid while taking Mag-200 (magnesium oxide)?

There are no restrictions on food, beverages, or activity while taking magnesium oxide unless otherwise directed by your doctor.

Mag-200 (magnesium oxide) side effects Stop taking magnesium oxide and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives).

Other, less serious side effects may be more likely to occur. Continue to take magnesium oxide and talk to your doctor if you experience diarrhea or an upset stomach.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Mag-200 (magnesium oxide)?

Before taking magnesium oxide, talk to your doctor if you are taking

a tetracycline antibiotic such as tetracycline (Sumycin, Achromycin V, and others), demeclocycline (Declomycin), doxycycline (Vibramycin, Monodox, Doxy, and others), minocycline (Minocin, Dynacin, and others), or oxytetracycline (Terramycin, and others);

a fluoroquinolone antibiotic such as ciprofloxacin (Cipro), ofloxacin (Floxin), enoxacin (Penetrex), norfloxacin (Noroxin), sparfloxacin (Zagam), levofloxacin (Levaquin), lomefloxacin (Maxaquin), grepafloxacin (Raxar), and others;

penicillamine (Cuprimine);

digoxin (Lanoxin, Lanoxicaps); or

nitrofurantoin (Macrodantin, Furadantin, others).

You not be able to take magnesium oxide, or you may require a dosage adjustment or special monitoring during your treatment if you are taking any of the medicines listed above.

Drugs other than those listed here can also interact with magnesium oxide. Talk to your doctor and pharmacist before taking any over-the-counter or prescription medicines.

More Mag-200 resources Mag-200 Side Effects (in more detail)Mag-200 Use in Pregnancy & BreastfeedingMag-200 Drug InteractionsMag-200 Support Group0 Reviews for Mag-200 - Add your own review/rating Magnesium Oxide Professional Patient Advice (Wolters Kluwer) Magnesium Oxide MedFacts Consumer Leaflet (Wolters Kluwer) Compare Mag-200 with other medications ConstipationDuodenal UlcerGERDHypomagnesemiaIndigestionPathological Hypersecretory DisorderStomach UlcerUrinary Tract Stones Where can I get more information? Your pharmacist has additional information about magnesium oxide written for health professionals that you may read.

See also: Mag-200 side effects (in more detail)

Becodisks 200mcg
1. Name Of The Medicinal Product

Becodisks 200 Micrograms

2. Qualitative And Quantitative Composition

Beclometasone Dipropionate 200micrograms

3. Pharmaceutical Form

Dry Powder for Inhalation via Diskhaler Device

4. Clinical Particulars 4.1 Therapeutic Indications

Clinical Indications

Beclometasone dipropionate provides effective anti-inflammatory action in the lungs, with a lower incidence and severity of adverse effects than those observed when corticosteroids are administered systemically. It also offers preventive treatment of asthma.

Becodisks are indicated for the following:

Adults

Prophylactic management in:

Mild asthma (PEF values greater than 80% predicted at baseline with less than 20% variability):

Patients requiring intermittent symptomatic bronchodilator asthma medication on more than an occasional basis.

Moderate asthma (PEF values 60-80% predicted at baseline with 20-30% variability):

Patients requiring regular asthma medication and patients with unstable or worsening asthma on other prophylactic therapy or bronchodilator alone.

Severe asthma (PEF values less than 60% predicted at baseline with greater than 30% variability):

Patients with severe chronic asthma. On transfer to high dose inhaled beclometasone dipropionate, many patients who are dependent on systemic corticosteroids for adequate control of symptoms may be able to reduce significantly or eliminate their requirement for oral corticosteroids.

4.2 Posology And Method Of Administration

Becodisks are for administration by the inhalation route only using a Diskhaler device.

Patients should be made aware of the prophylactic nature of therapy with inhaled beclometasone dipropionate and that it should be taken regularly everyday even when they are asymptomatic.

Patients should be given a starting dose of inhaled beclometasone dipropionate which is appropriate for severity of their disease. The dose may then be adjusted until control is achieved and should be titrated to the lowest dose at which effective control of asthma is maintained.

Adults

400 microgram twice daily is the usual starting dose. One 400 microgram blister or two 200 micrograms blisters twice daily is the usual maintenance dose. Alternatively, 200 micrograms may be administered three or four times daily.

Children

100 micrograms two, three or four times a day, according to the response. Alternatively, the usual starting dose of 200 micrograms twice daily may be administered.

Special Patient Groups

There is no need to adjust the dose in elderly patients or in those with hepatic or renal impairment.

4.3 Contraindications

Hypersensitivity to Becodisks or any of its compnents is a contraindication. (See Pharmaceutical Particulars – List of Excipients).

Special care is necessary in patients with active or quiescent pulmonary tuberculosis.

4.4 Special Warnings And Precautions For Use

Patients should be instructed in the proper use of the Diskhaler to ensure that the drug reaches the target areas within the lungs. They should be made aware that Becodisks have to be used regularly everyday for optimum benefit. Patients should be made aware of the prophylactic nature of therapy with Becodisks and that they should be used regularly, even when they are asymptomatic.

Becodisks are not designed to relieve acute asthmatic symptoms for which an inhaled short-acting bronchodilator is required. Patients should be advised to have such rescue medication available.

Severe asthma requires regular medical assessment including lung function testing as patients are at risk of severe attacks and even death.

Increasing use of bronchodilators, in particular short-acting inhaled beta2 agonists to relieve symptoms indicates deterioration of asthma control. If patients find that short acting relief bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought.

In this situation patients should be reassessed and consideration given to the need for increased anti-inflammatory therapy (e.g. Higher doses of inhaled corticosteroids or a course of oral corticosteroids). Severe exacerbations of asthma must be treated in the normal way.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important therefore that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than recommended doses, may result in clinically significant adrenal suppression. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Lack of response or severe exacerbations of asthma should be treated by increasing the dose of inhaled beclometasone dipropionate and, if necessary, by giving a systemic steroid and/or antibiotic if there is an infection, and by use of beta-agonist therapy.

For the transfer of patients being treated with oral corticosteroids:

The transfer of oral steroid-dependent patients to Becodisks and their subsequent management needs special care as recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy, may take a considerable time.

Patients who have been treated with systemic steroids for long periods of time or at a high dose may have adrenocortical suppression. With these patients adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously.

After approximately a week, gradual withdrawal of the systemic steroid is commenced. Decrements in dosages should be appropriate to the level of maintenance systemic steroid, and introduced at not less than weekly intervals. For maintenance doses of prednisolone (or equivalent) of 10mg daily or less, the decrements in dose should not be greater than 1mg per day, at not less than weekly intervals. For maintenance doses of prednisolone in excess of 10mg daily, it may be appropriate to employ cautiously, larger decrements in dose at weekly intervals.

Some patients feel unwell in a non-specific way during the withdrawal phase despite maintenance or even improvement of the respiratory function. They should be encouraged to persevere with the Diskhaler and withdrawal of systemic steroid continued, unless there are objective signs of adrenal insufficiency.

Patients weaned off oral steroids whose adrenocortical function is impaired should carry a steroid warning card indicating that they may need supplementary systemic steroid during periods of stress, e.g. Worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc.

Replacement of systemic steroid treatment with inhaled therapy sometimes unmasks allergies such as allergic rhinitis or eczema previously controlled by the systemic drug. These allergies should be symptomatically treated with antihistamine and/or topical preparations, including topical steroids.

Treatment with Becodisks should not be stopped abruptly.

As with all inhaled corticosteroids, special care is necessary in patients with active or quiescent pulmonary tuberculosis

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions have been reported

4.6 Pregnancy And Lactation

There is inadequate evidence of safety in human pregnancy. Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate and intra-uterine growth retardation. There may therefore be a very small risk of such effects in the human foetus. It should be noted, however, that the foetal changes in animals occur after relatively high systemic exposure. Because beclometasone dipropionate is delivered directly to the lungs by the inhaled route it avoids the high level of exposure that occurs when corticosteroids are given by systemic routes.

The use of beclometasone dipropionate in pregnancy requires that the possible benefits of the drug be weighed against the possible hazards. It should be noted that the drug has been in widespread use for many years without apparent ill consequence.

No specific studies examining the transference of beclometasone dipropionate into the milk of lactating animals have been performed. It is reasonable to assume that beclometasone dipropionate is secreted in milk but at the dosages used for direct inhalation, there is low potential for significant levels in breast milk. The use of beclometasone dipropionate in mothers breast feeding their babies requires that the therapeutic benefits of the drug be weighed against the potential hazards to the mother and baby.

4.7 Effects On Ability To Drive And Use Machines

No adverse effect has been reported.

4.8 Undesirable Effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (

System Organ Class

Adverse Event

Frequency

Infections & Infestations

Candidiasis of the mouth and throat.

Very Common

Immune System Disorders

Hypersensitivity reactions with the following manifestations:

 

Rashes, urticaria, pruritis, erythema.

Uncommon

 

Oedema of the eyes, face, lips and throat

Very Rare

 

Respiratory symptoms (dyspnoea and/or bronchospasm)

Very Rare

 

Anaphylactoid/anaphylactic reactions

Very Rare

 

Endocrine Disorders

Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma

Very Rare

Psychiatric Disorders

Anxiety, sleep disorders, behavioural changes, including hyperactivity and irritability (predominantly in children)

Very Rare

Depression, aggression (predominantly in children)

Not known

 

Respiratory, Thoracic & Mediastinal Disorders

Hoarseness/throat irritation

Common

Paradoxical bronchospasm

Very Rare

 

Candidiasis of the mouth and throat (thrush) occurs in some patients, the incidence of which is increased with doses greater than 400 micrograms beclometasone dipropionate per day. Patients with high blood levels of Candida precipitins, indicating a previous infection, are most likely to develop this complication. Patients may find it helpful to rinse out their mouth with water after using the Diskhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with beclometasone dipropionate treatment.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma (see 4.4 Special Warnings and Precautions for Use).

In some patients inhaled beclometasone dipropionate may cause hoarseness or throat irritation. It may be helpful to rinse out the mouth with water immediately after inhalation.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. The beclometasone dipropionate preparation should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

4.9 Overdose

Acute - inhalation of the drug in doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not necessitate emergency action being taken. In these patients treatment with beclometasone dipropionate by inhalation should be continued at a dose sufficient to control asthma; adrenal function recovers in a few days and can be verified by measuring plasma cortisol.

Chronic - use of inhaled beclometasone dipropionate in daily doses in excess of 1500 micrograms over prolonged periods may lead to adrenal suppression. Monitoring of adrenal reserve may be indicated. Treatment with inhaled beclometasone dipropionate should be continued at a dose sufficient to control asthma.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

BDP is a pro-drug with weak glucocorticoid receptor binding activity. It is hydrolysed via esterase enzymes to the active metabolite beclometasone-17-monopropionate (B-17-MP), which has high topical anti-inflammatory activity.

5.2 Pharmacokinetic Properties

Absorption

When administered via inhalation (via metered dose inhaler) there is extensive conversion of BDP to the active metabolite B-17-MP within the lungs prior to systemic absorption. The systemic absorption of B-17-MP arises from both lung deposition and oral absorption of the swallowed dose. When administered orally, in healthy male volunteers, the bioavailability of BDP is negligible but pre-systemic conversion to B-17-MP results in 41% (95% CI 27- 62 %) of the dose being available as B-17-MP.

Metabolism

BDP is cleared very rapidly from the systemic circulation, owing to extensive first pass metabolism. The main product of metabolism is the active metabolite (B-17-MP). Minor inactive metabolites, beclometasone-21-monopropionate (B-21-MP) and beclometasone (BOH), are also formed but these contribute little to systemic exposure.

Distribution

The tissue distribution at steady state for BDP is moderate (20L) but more extensive for B-17-MP (424L). Plasma protein binding is moderately high (87%).

Elimination

The elimination of BDP and B-17-MP are characterised by high plasma clearance (150 and 120L/h) with corresponding terminal elimination half lives of 0.5h and 2.7h. Following oral administration of tritiated BDP, approximately 60% of the dose was excreted in the faeces within 96 hours mainly as free and conjugated polar metabolites. Approximately 12% of the dose was excreted as free and conjugated polar metabolites in the urine.

5.3 Preclinical Safety Data

No clinically relevant findings were observed in preclinical studies.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lactose(which contains milk protein)

6.2 Incompatibilities

No incompatibilities have been reported.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 30?C.

6.5 Nature And Contents Of Container

Circular double foil blister pack consisting of:

A) Lidding material (i) polyester over-lacquer/hard tempered aluminium foil/heat seal lacquer of total thickness = 39.4 - 48.6microns or (ii) nitrocellulose over-lacquer/hard tempered aluminium foil/heat seal lacquer of total thickness = 37.0 - 42.0microns.

B) Blister material - pvc film/aluminium foil/orientated polyamide.

Becodisks are supplied as 8 blisters per Becodisk as follows:

-Carton containing 14 disks plus a Diskhaler

-Carton containing 15 disks plus a Diskhaler

-Carton containing 5 disks plus a Diskhaler (Hospital pack)

-Refill packs of 14 disks

-Refill packs of 15 disks

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

See Patient Information Leaflet

Administrative Data 7. Marketing Authorisation Holder

Glaxo Wellcome UK Ltd.

Trading as Allen & Hanburys,

Stockley Park West,

Uxbridge

Middlesex,

UB11 1BT

8. Marketing Authorisation Number(S)

PL 10949/0056

9. Date Of First Authorisation/Renewal Of The Authorisation

27 September 1993/11 December 1997

10. Date Of Revision Of The Text

23 August 2011

11. Legal Status

POM

Formula E 400

Generic Name: vitamin e (Oral route)

VYE-ta-min E

Commonly used brand name(s)

In the U.S.

Alpha-E Aqua Gem-E Aquasol E D-Alpha Gems E-400 E-600 E-Gems Formula E 400 Gamma E-Gems Gamma E Plus Key-E Natural Vitamin Blend E-400IU Nutr-E-Sol

Available Dosage Forms:

Liquid Solution Tablet Capsule, Liquid Filled Tablet, Chewable Powder for Solution Capsule

Therapeutic Class: Nutritive Agent

Pharmacologic Class: Vitamin E (class)

Uses For Formula E 400

Vitamins are compounds that you must have for growth and health. They are needed in only small amounts and are available in the foods that you eat. Vitamin E prevents a chemical reaction called oxidation, which can sometimes result in harmful effects in your body. It is also important for the proper function of nerves and muscles.

Some conditions may increase your need for vitamin E. These include:

Intestine disease Liver disease Pancreas disease Surgical removal of stomach

Increased need for vitamin E should be determined by your health care professional.

Infants who are receiving a formula that is not fortified with vitamin E may be likely to have a vitamin E deficiency. Also, diets high in polyunsaturated fatty acids may increase your need for vitamin E.

Claims that vitamin E is effective for treatment of cancer and for prevention or treatment of acne, aging, loss of hair, bee stings, liver spots on the hands, bursitis, diaper rash, frostbite, stomach ulcer, heart attacks, labor pains, certain blood diseases, miscarriage, muscular dystrophy, poor posture, sexual impotence, sterility, infertility, menopause, sunburn, and lung damage from air pollution have not been proven. Although vitamin E is being used to prevent certain types of cancer, there is not enough information to show that this is effective.

Lack of vitamin E is extremely rare, except in people who have a disease in which it is not absorbed into the body.

Vitamin E is available without a prescription.

Importance of Diet

For good health, it is important that you eat a balanced and varied diet. Follow carefully any diet program your health care professional may recommend. For your specific dietary vitamin and/or mineral needs, ask your health care professional for a list of appropriate foods. If you think that you are not getting enough vitamins and/or minerals in your diet, you may choose to take a dietary supplement.

Vitamin E is found in various foods including vegetable oils (corn, cottonseed, soybean, safflower), wheat germ, whole-grain cereals, and green leafy vegetables. Cooking and storage may destroy some of the vitamin E in foods.

Vitamin supplements alone will not take the place of a good diet and will not provide energy. Your body also needs other substances found in food such as protein, minerals, carbohydrates, and fat. Vitamins themselves often cannot work without the presence of other foods. For example, small amounts of fat are needed so that vitamin E can be absorbed into the body.

The daily amount of vitamin E needed is defined in several different ways.

For U.S.— Recommended Dietary Allowances (RDAs) are the amount of vitamins and minerals needed to provide for adequate nutrition in most healthy persons. RDAs for a given nutrient may vary depending on a person's age, sex, and physical condition (e.g., pregnancy). Daily Values (DVs) are used on food and dietary supplement labels to indicate the percent of the recommended daily amount of each nutrient that a serving provides. DV replaces the previous designation of United States Recommended Daily Allowances (USRDAs). For Canada— Recommended Nutrient Intakes (RNIs) are used to determine the amounts of vitamins, minerals, and protein needed to provide adequate nutrition and lessen the risk of chronic disease.

Vitamin E is available in various forms, including d- or dl-alpha tocopheryl acetate, d- or dl-alpha tocopherol, and d- or dl-alpha tocopheryl acid succinate. In the past, the RDA for vitamin E have been expressed in Units. This term has been replaced by alpha tocopherol equivalents (alpha-TE) or milligrams (mg) of d-alpha tocopherol. One Unit is equivalent to 1 mg of dl-alpha tocopherol acetate or 0.6 mg d-alpha tocopherol. Most products available in stores continue to be labeled in Units.

Normal daily recommended intakes in milligrams (mg) of alpha tocopherol equivalents (mg alpha-TE) and Units for vitamin E are generally defined as follows:

                                                  Persons U.S. Canada mg alpha-TE Units mg alpha-TE Units   Infants and children

Ketoprofen Extended-Release Capsules
Pronunciation: KEE-toe-PROE-fenGeneric Name: KetoprofenBrand Name: Oruvail

Pavagen

Generic Name: papaverine (pa PAV uh reen) Brand Names: Papacon, Para-Time S. R., Pavabid Plateau, Pavacot, Pavagen

What is Pavagen (papaverine)?

Papaverine is in a class of drugs called vasodilators. Papaverine relaxes veins and arteries, which makes them wider and allows blood to pass through them more easily. These actions may help to increase the amount of oxygen-rich blood in your brain, heart, and muscles.

Papaverine may also be useful in treating conditions involving spasms of the intestines and urinary tract.

Papaverine may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Pavagen (papaverine)? Use caution when driving, operating machinery, or performing other hazardous activities. Papaverine may cause dizziness. If you experience dizziness, avoid these activities. If you experience dizziness, rise slowly from a sitting or lying position to avoid falling. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while you are taking papaverine.

Notify your doctor if you experience especially bothersome sweating, rash, flushing, headache, tiredness, yellowing of your skin, nausea, decreased appetite, diarrhea, or constipation.

Who should not take Pavagen (papaverine)?

Before taking this medication, tell your doctor if you have

heart disease or irregular heartbeats,

liver disease,

glaucoma, or

Parkinson's disease.

You may not be able to take papaverine, or you may require a lower dose or special monitoring during treatment if you have any of the conditions listed above.

Papaverine is in the FDA pregnancy category C. This means that it is not known whether papaverine will harm an unborn baby. Do not take papaverine without first talking to your doctor if you are pregnant. It is not known whether papaverine passes into breast milk. Do not take this medication without first talking to your doctor if you are breast-feeding a baby. How should I take Pavagen (papaverine)?

Take papaverine exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water.

The regular-release form of papaverine is usually taken three to five times a day. The timed-release tablets and capsules are usually taken two or three times a day (every 8 to 12 hours). Follow your doctor's instructions.

Do not crush, chew, break, or open the timed-release tablets or capsules. Swallow them whole. They are specially formulated to release slowly in your body. Store papaverine at room temperature away from moisture and heat. What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and take only your next regularly scheduled dose. Do not take a double dose of this medication.

What happens if I overdose? Seek emergency medical attention.

Symptoms of a papaverine overdose include drowsiness, weakness, double vision, poor coordination, headache, blue-colored lips or skin, and coma.

What should I avoid while taking Pavagen (papaverine)? Use caution when driving, operating machinery, or performing other hazardous activities. Papaverine may cause dizziness. If you experience dizziness, avoid these activities. If you experience dizziness, rise slowly from a sitting or lying position to avoid falling. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while you are taking papaverine. Do not crush, chew, break, or open the timed-release tablets or capsules. Swallow them whole. These are specially formulated to release slowly in your body. Pavagen (papaverine) side effects Stop taking papaverine and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives).

Stop taking papaverine and contact your doctor if your skin or eyes develop a yellow tint.

Other, less serious side effects may be more likely to occur. Continue to take papaverine and talk to your doctor if you experience

nausea, decreased appetite, diarrhea, or constipation;

dizziness or drowsiness;

headache;

sweating and flushing;

a rash; or

irregular heartbeats.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Pavagen (papaverine)?

Papaverine may decrease the effects of levodopa (Dopar, Larodopa) which is used to treat Parkinson's disease. You may need a change in your levodopa dosage if you are taking levodopa.

Drugs other than those listed here may also interact with papaverine or affect your condition. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

More Pavagen resources Pavagen Use in Pregnancy & BreastfeedingPavagen Drug InteractionsPavagen Support Group0 Reviews · Be the first to review/rate this drug Papaverine MedFacts Consumer Leaflet (Wolters Kluwer) Papacon Advanced Consumer (Micromedex) - Includes Dosage Information Papaverine Hydrochloride Monograph (AHFS DI) Where can I get more information? Your pharmacist has additional information about papaverine written for health professionals that you may read.

Cerovite Jr Chewables
Pronunciation: MUL-ti-VYE-ta-min/MIN-er-alsGeneric Name: Pediatric Multivitamin/MineralsBrand Name: Examples include Cerovite Jr and Flintstones Gummies

Esoterica Sunscreen Formula Cream
Pronunciation: HYE-droe-KWIN-aneGeneric Name: Hydroquinone with SunscreenBrand Name: Examples include Esoterica Sunscreen Formula and Solaquin Forte

Urethral Stricture with Infection Medications

There are currently no drugs listed for "Urethral Stricture with Infection".

Learn more about Urethral Stricture with Infection

Medical Encyclopedia:

Urethral stricture Drug List:

Monistat 3 Cream
Pronunciation: mi-KON-a-zoleGeneric Name: MiconazoleBrand Name: Monistat 3

Vibra-Tabs

Generic Name: doxycycline (DOX i SYE kleen) Brand Names: Adoxa, Adoxa CK, Adoxa TT, Alodox, Avidoxy, Doryx, Monodox, Oracea, Oraxyl, Periostat, Vibramycin, Vibramycin Calcium, Vibramycin Monohydrate

What is Vibra-Tabs (doxycycline)?

Doxycycline is a tetracycline antibiotic. It fights bacteria in the body.

Doxycycline is used to treat many different bacterial infections, such as urinary tract infections, acne, gonorrhea, and chlamydia, periodontitis (gum disease), and others.

Doxycycline is also used to treat blemishes, bumps, and acne-like lesions caused by rosacea. Doxycycline will not treat facial redness caused by rosacea.

Doxycycline may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Vibra-Tabs (doxycycline)? Do not use this medicine if you are pregnant. It could harm the unborn baby or cause permanent tooth discoloration later in life.

Doxycycline can make birth control pills less effective. Ask your doctor about using a non hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while using doxycycline.

You should not take this medicine if you are allergic to doxycycline or to other tetracycline antibiotics such as demeclocycline (Declomycin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap).

Before taking doxycycline, tell your doctor if you have liver disease, kidney disease, asthma, or if you are allergic to sulfites.

Drink plenty of liquids while you are taking doxycycline. Children should not use doxycycline. Doxycycline can cause permanent yellowing or graying of the teeth in children younger than 8 years old. Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. What should I discuss with my healthcare provider before taking Vibra-Tabs (doxycycline)? You should not take this medicine if you are allergic to doxycycline or to other tetracycline antibiotics such as demeclocycline (Declomycin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap).

To make sure you can safely take doxycycline, tell your doctor if you have any of these other conditions:

liver disease;

kidney disease; or

asthma or sulfite allergy.

If you are using doxycycline to treat gonorrhea, your doctor may test you to make sure you do not also have syphilis, another sexually transmitted disease.

FDA pregnancy category D. Do not use doxycycline if you are pregnant. It could harm the unborn baby or cause permanent tooth discoloration later in life. Tell your doctor right away if you become pregnant during treatment.

Doxycycline can make birth control pills less effective. Ask your doctor about using a non hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while using doxycycline.

Doxycycline passes into breast milk and may affect bone and tooth development in a nursing baby. You should not breast-feed while you are taking doxycycline. Children should not use doxycycline. Doxycycline can cause permanent yellowing or graying of the teeth in children younger than 8 years old. How should I take Vibra-Tabs (doxycycline)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take doxycycline with a full glass of water. Drink plenty of liquids while you are taking doxycycline.

Different brands of doxycycline may have different instructions about taking them with or without food.

Most brands of doxycyline may be taken with food or milk if the medicine upsets your stomach. Take Oracea or Periostat on an empty stomach, at least 1 hour before or 2 hours after a meal.

You may open a Doryx capsule or break up a Doryx tablet and sprinkle the medicine into a spoonful of applesauce to make swallowing easier. Swallow right away without chewing. Do not save the mixture for later use. Drink a full glass (8 ounces) of cool water right away.

Do not crush, break, or open a delayed-release capsule. Swallow the pill whole. Breaking or opening the pill may cause too much of the drug to be released at one time. The enteric coated pill has a special coating to protect your stomach. Breaking the pill will damage this coating.

Measure liquid medicine with a special dose measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose measuring device, ask your pharmacist for one.

Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Doxycycline will not treat a viral infection such as the common cold or flu.

If you need surgery, tell the surgeon ahead of time that you are using doxycycline. You may need to stop using the medicine for a short time.

Store at room temperature away from moisture and heat. Throw away any unused medicine after the expiration date on the label has passed. Using expired doxycycline can cause damage to your kidneys. What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, vomiting, and diarrhea.

What should I avoid while taking Vibra-Tabs (doxycycline)?

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, stop taking doxycycline and call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.

Avoid exposure to sunlight or tanning beds. Doxycycline can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors. Do not take iron supplements, multivitamins, calcium supplements, antacids, or laxatives within 2 hours before or after taking doxycycline. Vibra-Tabs (doxycycline) side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

severe headache, dizziness, blurred vision;

fever, chills, body aches, flu symptoms, swollen glands, rash or itching, joint pain, or general ill feeling;

urinating less than usual or not at all;

diarrhea that is watery or bloody

pale or yellowed skin, dark colored urine, fever, confusion or weakness;

severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;

loss of appetite, jaundice (yellowing of the skin or eyes); or

severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Less serious side effects may include:

mild nausea, mild diarrhea;

upset stomach;

mild skin rash or itching; or

vaginal itching or discharge.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Vibra-Tabs (doxycycline)?

Tell your doctor about all other medicines you use, especially:

cholesterol-lowering medications such as cholestyramine (Prevalite, Questran) or colestipol (Colestid);

isotretinoin (Accutane);

tretinoin (Renova, Retin-A, Vesanoid);

an antacid such as Tums, Rolaids, Milk of Magnesia, Maalox, and others;

a product that contains bismuth subsalicylate such as Pepto-Bismol;

minerals such as iron, zinc, calcium, magnesium, and over-the-counter vitamin and mineral supplements;

a blood thinner such as warfarin (Coumadin, Jantoven); or

a penicillin antibiotic such as amoxicillin (Amoxil, Augmentin, Dispermox, Moxatag), ampicillin (Principen, Unasyn), dicloxacillin (Dycill, Dynapen), oxacillin (Bactocill), or penicillin (Bicillin L-A, PC Pen VK, Pfizerpen).

This list is not complete and other drugs may interact with doxycycline. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Vibra-Tabs resources Vibra-Tabs Side Effects (in more detail)Vibra-Tabs Use in Pregnancy & BreastfeedingDrug ImagesVibra-Tabs Drug InteractionsVibra-Tabs Support Group0 Reviews for Vibra-Tabs - Add your own review/rating Vibra-Tabs MedFacts Consumer Leaflet (Wolters Kluwer) Vibra-Tabs Advanced Consumer (Micromedex) - Includes Dosage Information Doxycycline Prescribing Information (FDA) Doxycycline Professional Patient Advice (Wolters Kluwer) Doxycycline Monograph (AHFS DI) Doxycycline MedFacts Consumer Leaflet (Wolters Kluwer) Adoxa MedFacts Consumer Leaflet (Wolters Kluwer) Alodox Prescribing Information (FDA) Doryx Delayed-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer) Doryx Prescribing Information (FDA) Doxycycline Calcium Monograph (AHFS DI) Monodox Prescribing Information (FDA) Ocudox Convenience Kit MedFacts Consumer Leaflet (Wolters Kluwer) Oracea Consumer Overview Oracea Prescribing Information (FDA) Periostat MedFacts Consumer Leaflet (Wolters Kluwer) Periostat Prescribing Information (FDA) Vibramycin Prescribing Information (FDA) Compare Vibra-Tabs with other medications AcneActinomycosisAmebiasisAnthraxAnthrax ProphylaxisBacterial InfectionBartonellosisBronchitisBrucellosisBullous PemphigoidChlamydia InfectionCholeraCutaneous Bacillus anthracisEhrlichiosisEnterocolitisEpididymitis, Sexually TransmittedGastroenteritisGranuloma InguinaleInclusion ConjunctivitisLyme DiseaseLyme Disease, ArthritisLyme Disease, CarditisLyme Disease, Erythema Chronicum MigransLyme Disease, NeurologicLymphogranuloma VenereumMalariaMalaria PreventionMelioidosisMycoplasma PneumoniaNongonococcal UrethritisOcular RosaceaOrnithosisPelvic Inflammatory DiseasePemphigoidPemphigusPeriodontitisPlaguePleural EffusionPneumoniaProctitisProstatitisPsittacosisRabbit FeverRickettsial InfectionRosaceaSkin InfectionSTD ProphylaxisSyphilis, EarlySyphilis, LatentTertiary SyphilisTrachomaUpper Respiratory Tract InfectionUrinary Tract Infection Where can I get more information? Your pharmacist can provide more information about doxycycline.

See also: Vibra-Tabs side effects (in more detail)

Summers Eve Anti-Itch

Generic Name: pramoxine topical (pra MOX een TOP i kal) Brand Names: Anest Hemor, Blistex Pro Relief, Calaclear, Caladryl Clear, Callergy Clear, Curasore, Fleet Pain Relief Pad, Gold Bond Anti-Itch, Itch-X, PrameGel, Pramox, Prax, Proctofoam, Proctozone-P, Sarna Sensitive, Sarna Sensitive Eczema Itch Relief, Sarna Ultra, Soothe-It Plus Hemmorhoidal Pad, Summers Eve Anti-Itch, Tronolane

What is Summers Eve Anti-Itch (pramoxine topical)?

Pramoxine is an anesthetic, or "numbing medicine." It works by interfering with pain signals sent from the nerves to the brain.

Pramoxine topical (for the skin) is used to treat pain or itching caused by insect bites, minor burns or scrapes, hemorrhoids, and minor skin rash, dryness, or itching. Pramoxine topical is also used to treat chapped lips, and pain or skin irritation caused by coming into contact with poison ivy, poison oak, or poison sumac.

Pramoxine topical may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Summers Eve Anti-Itch (pramoxine topical)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Less serious side effects are more likely, and you may have none at all.

What should I discuss with my health care provider before using Summers Eve Anti-Itch (pramoxine topical)? You should not use this medication if you are allergic to pramoxine.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you are allergic to any drugs or any other numbing medicines.

FDA pregnancy category C. It is not known whether pramoxine topical will harm an unborn baby. Do not use this medication without medical advice if you are pregnant. It is not known whether pramoxine topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without medical advice if you are breast-feeding a baby. How should I use Summers Eve Anti-Itch (pramoxine topical)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Pramoxine is usually applied to the affected area 3 to 5 times daily, depending on which form of this medication you use. Follow the label directions or your doctor's instructions about how much medication to use and how often.

Pramoxine hemorrhoid cream, lotion, foam, or medicated wipe may be used on the rectum after each bowel movement to treat hemorrhoid pain and itching.

Wash your hands before and after applying pramoxine topical. Wash the affected skin area with warm water and a mild soap. Rinse and dry the area thoroughly.

To use pramoxine on the skin, (spray, lotion, gel, or stick), apply just enough of the medication to cover the area to be treated.

To use the pramoxine medicated wipe to treat the hemorrhoid area, apply the medication by patting the wipe onto the rectal area. Avoid harsh rubbing. You may fold the wipe and leave it in place for up to 15 minutes. Each pramoxine medicated wipe is for one use only. Throw the wipe away after using.

Shake the pramoxine rectal foam before each use. Squirt only a small amount of the medicine onto a clean tissue and apply it to your rectum. Do not insert this medication or the medicated wipe into your rectum. Use pramoxine topical only on the outside of the area.

Stop using pramoxine and call your doctor if your symptoms do not improve after 7 days of treatment, or if your condition clears up and then comes back.

Store at room temperature away from moisture and heat. What happens if I miss a dose?

Since pramoxine topical is used on an as needed basis, you are not likely to miss a dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. What should I avoid while using Summers Eve Anti-Itch (pramoxine topical)? Avoid getting this medication in your eyes or nose. If this does happen, rinse with water. Do not use pramoxine topical on deep skin wounds, blistered skin, severe burns, or large skin areas. Seek medical attention for more severe skin irritation or injury.

Avoid using other medications on the areas you treat with pramoxine topical unless you doctor tells you to.

Summers Eve Anti-Itch (pramoxine topical) side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using pramoxine topical and call your doctor at once if you have a serious side effect such as:

any new redness or swelling where the medicine was applied; or

severe pain, burning, or stinging where the medicine is applied.

Less serious side effects are more likely, and you may have none at all.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Summers Eve Anti-Itch (pramoxine topical)?

It is not likely that other drugs you take orally or inject will have an effect on topically applied pramoxine. But many drugs can interact with each other. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Summers Eve Anti-Itch resources Summers Eve Anti-Itch Side Effects (in more detail)Summers Eve Anti-Itch Use in Pregnancy & BreastfeedingSummers Eve Anti-Itch Support Group0 Reviews for Summers Eve Anti-Itch - Add your own review/rating Caladryl Clear MedFacts Consumer Leaflet (Wolters Kluwer) Itch-X Foam MedFacts Consumer Leaflet (Wolters Kluwer) PrameGel Gel MedFacts Consumer Leaflet (Wolters Kluwer) Pramoxine Hydrochloride Monograph (AHFS DI) Prax Lotion MedFacts Consumer Leaflet (Wolters Kluwer) Proctofoam Foam MedFacts Consumer Leaflet (Wolters Kluwer) Sarna Sensitive Lotion MedFacts Consumer Leaflet (Wolters Kluwer) Tronolane Cream MedFacts Consumer Leaflet (Wolters Kluwer) Compare Summers Eve Anti-Itch with other medications Anal ItchingPruritus Where can I get more information? Your pharmacist can provide more information about pramoxine topical.

See also: Summers Eve Anti-Itch side effects (in more detail)

Ceplene 0.5 mg / 0.5 ml solution for injection
1. Name Of The Medicinal Product

Ceplene 0.5 mg/0.5 ml solution for injection

2. Qualitative And Quantitative Composition

One vial of 0.5 ml of solution contains 0.5 mg of histamine dihydrochloride.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection.

Clear, colourless aqueous solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Ceplene maintenance therapy is indicated for adult patients with acute myeloid leukaemia in first remission concomitantly treated with interleukin-2 (IL-2). The efficacy of Ceplene has not been fully demonstrated in patients older than age 60.

4.2 Posology And Method Of Administration

Ceplene maintenance therapy should be administered following completion of consolidation therapy in patients concomitantly treated with IL-2 under the supervision of a physician experienced in the management of acute myeloid leukaemia.

For dosing instructions for Ceplene in combination with IL-2, see posology below.

Interleukin-2 (IL-2)

IL-2 is administered twice daily as a subcutaneous injection 1 to 3 minutes prior to the administration of Ceplene; each dose of IL-2 is 16 400 IU/kg (1µg/kg).

Interleukin-2 (IL-2) is commercially available as a recombinant IL-2; aldesleukin. The reconstitution, dilution, dispensing and storage directions below are specific to aldesleukin.

Dispensing Instructions for IL-2 (aldesleukin)

IL-2 (aldesleukin) should be aseptically reconstituted, diluted and dispensed in capped polypropylene tuberculin syringes by the pharmacy based on the individual patient's weight (see administration chart for aldesleukin below) at the recommended dose of 16 400 IU/kg (1 µ?g/kg). Up to two weeks supply of pre-filled capped tuberculin syringes may be provided to patients for home administration, with instructions that the syringes be stored under refrigeration at 2°– 8°C prior to administration.

Studies have shown chemical stability and sterility of diluted aldesleukin (dispensed in capped polypropylene tuberculin syringes) for up to three weeks when prepared in a controlled aseptic environment and stored under refrigeration at 2°– 8°C.

NOTE: Dispensing of aldesleukin must be carried out under controlled aseptic conditions.

Initial Reconstitution: Each vial of aldesleukin (1.3 mg / vial) is reconstituted aseptically with 1.2 mL Water for Injections (see commercially available aldesleukin Summary of Product Characteristics). Direct the diluent against the side of the vial to avoid excessive foaming. Gently swirl to facilitate complete dissolution of the powder. Do NOT shake the vial during the entire reconstitution process. The resulting solution contains 22 x 10 6 IU (1,300µg) of aldesleukin per 1.2 ml.

Subsequent Dilution to 200 µg/ml: The entire contents of the reconstituted vial (1.2ml) is then further diluted aseptically with 5.3ml Dextrose 5% w/v Solution for Injection to a total volume of 6.5 ml providing a final concentration of 200µg/ml (3.3 x 106 IU/ml) of IL-2 (aldesleukin).

Dispensing of dilute IL-2 (Aldesleukin) for each patient: The diluted IL-2 (aldesleukin) is aseptically drawn up into sterile polypropylene tuberculin syringes and capped for each patient at 1 µg/kg dose, with a minimum standard dosage volume of 0.25 ml (50 µg) and a maximum dose of 0.5 ml (100 µg). Dosing volumes based on patient weight are provided in Table 1 below. This table also provides the volume required if a 20 % dose reduction is prescribed.

Table 1: Administration Chart for IL-2 (aldesleukin)

Patient Weight

(kg)

Standard Dosage

(µg)

Injection Volume*

(ml)

20% Dose Reduction Injection Volume

(ml)**

50

0.25

0.20

>50 to

60

0.30

0.25

>60 to

70

0.35

0.30

>70 to

80

0.40

0.30

>80 to

90

0.45

0.35

>90 to

100

0.50

0.40

>100

100

0.50

0.40

*Injection volume rounded up to the nearest 0.05ml

** Injection volumes based on 20 % reductions are rounded thus actual dose reductions vary from 15%-25%

Ceplene

0.5 ml solution is sufficient for a single dose (see section 6.6).

Ceplene is administered 1 to 3 minutes after each injection of IL-2. Each 0.5 ml Ceplene dose is injected slowly, over 5-15 minutes.

Treatment cycles

Ceplene and IL-2 are administered for 10 treatment cycles: each cycle consists of a treatment period of 21 days (3 weeks) followed by a three-week or six-week treatment-free period.

For cycles 1-3, each cycle consists of 3 weeks of treatment, followed by a 3-week treatment free period. For cycles 4-10, each cycle consists of 3 weeks of treatment, followed by a 6-week treatment-free period.

The recommended dosing regimen is presented in Tables 2 and 3.

Table 2: For treatment cycles 1-3 with Ceplene and IL-2

Week number (w)*

Treatment*

   

Cycle 1

Cycle 2

Cycle 3

 

w.1 to w.3

(Days 1-21)

w.7 to w.9

(Days 1-21)

w.13 to w.15

(Days 1-21)

IL-2 16 400 IU/kg followed by 0.5 ml Ceplene. Twice daily.

w.4 to w.6

w.10 to w.12

w.16 to w.18

Treatment-free (3 weeks)

*see dose modification for provisions for the modification to dose and dosage schedule

Table 3: For treatment cycles 4-10 with Ceplene and IL-2, same as for Table 2 above, with the exception of number of cycles and duration of rest periods

Week number (w)*

Treatment*

           

Cycles

             

4

5

6

7

8

9

10

 

w.19 to w.21

w.28 to w.30

w.37 to w.39

w.46 to w.48

w.55- to w.57

w.64 to w.66

w.73 to w.75

IL-2 16 400 IU/kg followed by 0.5 ml Ceplene. Twice daily

w.22 to w.27

w.31 to w.36

w.40 to w.45

w.49 to w.54

w.58 to w.63

w.67 to w.72

w.76 to w.81

Treatment-free (6 weeks)

*see dose modification for provisions for the modification to dose and dosage schedule

Dose modification

Patients should be monitored for the expected symptomatic adverse reactions and laboratory changes associated with this treatment. Doses of Ceplene and IL-2 should be modified as necessary based on individual patient tolerance to treatment. It is recommended that dose modifications be addressed early in treatment. The dose reductions can be temporary or permanent.

Should Ceplene related toxicities occur (such as hypotension, headache), the injection time can be increased from 5 minutes to a maximum of duration of 15 minutes.

For patients experiencing grade 1 toxicity events:

No altered dose recommendations with the exception of grade 1 neurologic toxicity and grade 1 generalised toxic dermatitis. For the dose recommendations for these grade 1 toxicity events refer to the relevant sections below:

For patients experiencing grade 1-4 neurologic toxicity

-for grade 1 to 3 toxicity, treatment should be discontinued until grade 0 toxicity event has been achieved. Treatment should then be resumed at a 20% dose reduction for both Ceplene and IL-2.

-for grade 4 toxicity, discontinuation of treatment should be considered.

For patients experiencing grade 1-4 generalised toxic dermatitis

-for grade 1 toxicity, the treatment should be delayed for 48 hours or until all symptoms have been resolved. Treatment should then be resumed using the full dose of Ceplene, but reducing the IL-2 dose by 20%.

-for grade 2 toxicity, the IL-2 dose should be reduced 50% and only increased to full dose if the symptoms do not reappear. Ceplene and IL-2 doses should be separated by 60 minutes, which should be maintained throughout treatment.

-for grade 3 and 4 toxicity, treatment should be discontinued and not resumed until events have been resolved. Treatment should only be resumed after consideration of risk – benefit to the patient.

For patients experiencing grade 2 (including cardiac function, renal, hepatic) toxicity:

- treatment should be discontinued until the event has returned to grade 1

- the time of injection of the dose of Ceplene should be extended to a maximum of 15 minutes.

- for cardiac, hepatic or renal toxicities the dose should be reduced by 20% for both Ceplene and IL-2.

For patients experiencing grade 3 and 4 (including hypotension, arrhythmia) toxicities:

- treatment should be discontinued until the event is resolved. A maximum delay of one treatment cycle can be considered for the resolution of grade 3 and 4 events.

For persistent hypotension, headache, arrhythmia, cardiac, hepatic and renal toxicities:

- the time of injection of the dose of Ceplene should be extended to a maximum of 15 minutes.

- the dose amount of both Ceplene and IL-2 should be reduced by 20%.

Fever

- IL-2 can be discontinued for 24 hours and then restarted at a 20% dose reduction level.

Abnormal WBC counts

- the dose of IL-2 can be reduced by 20% for the remaining duration of the treatment course and if abnormal WBC counts re-occur during the following cycle a permanent IL-2 reduction is recommended.

Localised toxic dermatitis

- treatment should be discontinued until symptoms resolved. Treatment can be resumed by administering Ceplene at the full dose and IL-2 at 50%.

Special populations

Renal impairment:

Patients with renal impairment may be more sensitive to the blood pressure lowering effects of Ceplene. Although the degree of renal impairment has no demonstrable effect on the pharmacokinetic disposition of Ceplene, caution is warranted when Ceplene is administered to patients with severe renal impairment. However, no Ceplene dose reduction is normally required in renally impaired patients.

Hepatic impairment:

Ceplene should be used with caution in patients with moderate to severe hepatic impairment (see section 5.2). Plasma Ceplene levels are higher in patients with moderate and severe liver impairment, and these patient groups tend to experience more tachycardia and lower blood pressure after Ceplene dosing than do patients with normal or mildly affected liver function. Plasma drug levels were not predictive of adverse effects, however, and effects did not correlate closely with drug exposure. Dose reduction of Ceplene is normally not required in hepatically impaired patients, but caution should be used in these patients.

Paediatric Population:

Ceplene is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy in this age group (see section 5.1 and 5.2).

Method of administration

For subcutaneous use only.

One to 3 minutes after the subcutaneous administration of IL-2 has been completed, Ceplene should be administered by slow subcutaneous injection at a rate not to exceed 0.1 ml (0.1 mg histamine dihydrochloride) per minute. The usual time for administering a 0.5 ml Ceplene dose is 5 minutes. To reduce potential adverse reactions, the administration time may be lengthened to a maximum of 15 minutes, see below. Ceplene can be administered via an ambulatory infusion syringe pump or by controlled manual subcutaneous injection by syringe with a timer.

The first dose of Ceplene and IL-2 on day 1 of the initiation of the first cycle of treatment should be administered in the clinic under direct supervision by a physician. Patient monitoring on day 1 should include vital signs, including pulse, blood pressure and respiratory rate. If the patient experiences a significant change in vital signs, the physician should evaluate the status of the patient and continue to monitor vital signs; these patients should be monitored during subsequent treatments.

Subsequent injections of Ceplene may be self-administered at home by a patient who demonstrates a good understanding of necessary precautions and who has demonstrated adequate injection skills.

Injections should be preferably administered in a supervised setting in the presence of an adult family member, friend, or other care provider who is capable of responding appropriately should signs or symptoms of hypotension occur.

The preferred injection areas are the thighs and the abdomen. Ceplene should not be injected into the same anatomic region as IL-2.

The twice daily dosing of IL-2 and Ceplene should be separated by a minimum of 6 hours. Patients should remain at rest for 20 minutes after injection of Ceplene.

4.3 Contraindications

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

• Patients with significantly compromised cardiac function, e.g., NYHA Class III/IV.

• Patients receiving systemic steroid therapy, clonidine and H2 blocking agents.

• Patients who have received an allogenic stem cell transplant.

• During pregnancy.

• During breast feeding.

4.4 Special Warnings And Precautions For Use

Ceplene should be administered 1 to 3 minutes after IL-2 administration, and not concomitantly.

• Rapid subcutaneous injection or injection into a vascular space may result in severe hypotension, tachycardia, or syncope.

Treatment with Ceplene in conjunction with IL-2 should be used with caution in patients with poorly compensated cardiac function. Patients with cardiac disease should be evaluated for ventricular ejection fraction and wall function by echocardiography or nuclear medicine stress test and then treated with caution.

• Patients should be monitored during treatment for possible clinical complications due to hypotension or hypovolaemia. Ceplene should be administered in the clinic under supervision of the physician on day 1 of the initial treatment cycle. Patient monitoring on day 1 should include vital signs, including pulse, blood pressure and respiratory rate.

• Patient monitoring during subsequent treatment days or cycles should be performed as long as the patient continues to experience significant changes in vital signs during administration of Ceplene. If significant hypotension or related symptoms are observed in subsequent treatment cycles, dose reduction should be initiated and if required, administered in hospital until responses to treatment allow for home administration.

• Caution should be used for patients with any of the following: symptomatic peripheral arterial disease, past or present peptic or oesophageal ulcer disease with a history of bleeding, clinically significant renal disease and stroke within the last 12 months. Where appropriate, consideration should be made to providing concomitant treatment with a proton pump inhibitor.

• Patients with clinically significant infection requiring the use of antibiotics, antifungals, or antivirals, or who have completed prior anti-infectious therapy within 14 days of starting treatment should be treated with caution unless the use of antibiotics and antivirals were for prophylaxis purposes.

• Patients with a prior history of autoimmune disease (including systemic lupus, inflammatory bowel disease, psoriasis and rheumatoid arthritis) should be treated with caution.

• Monitoring of laboratory test results is recommended including standard haematological and blood chemistry tests.

• Patients receiving the following medicinal products should be treated with caution (see section 4.5)

-Beta-blockers or other anti

-H1 blocking agents and neuroleptics (anti-psychotics) with H1 receptor blocking properties.

-Tricyclic anti-depressants that may have H1 and H2 receptor blocking properties.

-Monoamine oxidase inhibitors and anti-malarial and anti-trypanosomal agents.

-Neuromuscular blocking agents, narcotic analgesics, and various contrast media.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

While posology differs, when Ceplene is used in conjunction with IL-2, physicians should also refer to the SmPC for IL-2 and observe the respective medical product interactions.

H2 receptor antagonists with imidazole structures similar to histamine, e.g., cimetidine, systemic steroids and clonidine, must not be used during treatment with Ceplene (see section 4.3).

Beta-blockers and other anti-hypertensive agents should be used with caution during treatment with Ceplene. Concurrent administration of medicinal products with cardiotoxicity or blood pressure lowering effects may increase the toxicity of Ceplene.

H1 receptor blocking antihistamines or neuroleptics (anti-psychotics) with H1 receptor blocking properties that might decrease efficacy of Ceplene should be avoided.

Tricyclic anti-depressants may have H1 and H2 receptor blocking properties and should be avoided.

Monoamine oxidase inhibitors, anti-malarial, and anti-trypanosomal active substances may alter the metabolism of Ceplene and should be avoided (see section 4.4).

It has been noted that neuromuscular blocking agents, narcotic analgesics, and various contrast media can induce the release of endogenous histamine; therefore in patients undergoing diagnostic or surgical procedures, the additive effect of Ceplene treatment should be considered prior to the procedure (see section 4.4).

4.6 Pregnancy And Lactation

For Ceplene, no clinical data on exposed pregnancies are available. Animal studies showed reproductive toxicity but only at maternotoxic doses, and did not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Section 5.3). Ceplene in conjunction with IL-2 must not be used during pregnancy.

It is unknown whether histamine is excreted in human breast milk. The excretion of histamine in milk has not been studied in animals, but at maternotoxic doses in rats, offspring showed slight toxicity during early lactation (see Section 5.3). Ceplene in conjunction with IL-2 must not be used during breast-feeding.

No clinical data are available on the effects of Ceplene on fertility. Animal studies revealed no adverse effects on fertility apart from a slight reduction in implantations and viable foetuses (see section 5.3). Women of childbearing potential and sexually active men must use effective methods of contraception during treatment with Ceplene and IL-2.

Refer to the IL-2 SmPC for information on pregnancy and lactation with IL-2.

4.7 Effects On Ability To Drive And Use Machines

Ceplene has minor or moderate influence on the ability to drive and use machines. Administration of Ceplene can cause hypotension and may result in dizziness, light-headedness and blurred vision. Patients should not drive or operate machines for at least 1 hour after receiving Ceplene.

4.8 Undesirable Effects

Acute Myeloid Leukaemia

Adverse reactions were reported to be at least possibly related to IL-2 and Ceplene treatment in almost all patients in studies in acute myeloid leukaemia (AML).

The most common adverse reactions experienced by 30% or more of patients receiving IL-2 and Ceplene (listed in descending order of frequency) were: flushing, headache, fatigue, injection site granuloma, pyrexia and injection site erythema.

The adverse reactions occurring in at least 5% of patients considered at least possibly related to the treatment of low-dose IL-2 with Ceplene in AML studies (n=196 for the IL-2 and Ceplene treatment arm) are listed below by body system organ, class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (

Blood and lymphatic system disorders

Very common: eosinophilia, thrombocytopenia

Metabolism and nutrition disorders

Common: anorexia

Psychiatric disorders

Common: insomnia

Nervous system disorders

Very common: headache, dizziness, dysgeusia

Cardiac disorders

Very common: tachycardia

Common: palpitations

Vascular disorders

Very common: flushing, hypotension

Respiratory, thoracic, and mediastinal disorders

Very common: cough, dyspnoea

Common: nasal congestion

Gastrointestinal disorders

Very common: nausea, dyspepsia, diarrhoea.

Common: vomiting, upper abdominal pain, dry mouth

Skin and subcutaneous tissue disorders

Very common: rash

Common: erythema, increased sweating, night sweats, pruritus

Musculoskeletal and connective tissue disorders

Very common: arthralgia, myalgia

Common: limb pain, back pain

General disorders and administration site conditions

Very common: injection site granuloma, fatigue, pyrexia, injection site erythema, feeling hot, injection site reaction, injection site pruritus, influenza like illness, rigors, injection site inflammation, injection site pain

Common: injection site urticaria, injection site bruising, injection site rash, injection site swelling, weakness, chest pain

Other oncology (advanced tumour) studies

Ceplene and low dose IL-2 have been investigated in other clinical studies at different doses (1.0 mg histamine dihydrochloride twice a day) and with different dose regimens of low-dose IL-2 and interferon-alfa. The following adverse events, not listed above, were reported in at least 5% of patients and as at least possibly related to the study medicine:

Blood and lymphatic system disorders

Common: anaemia

Skin and subcutaneous tissue disorders

Very common: dry skin

Ear and labyrinth disorders

Common: vertigo

Endocrine disorders

Common: acquired hypothyroidism

Metabolism and nutrition disorders

Very common: decreased appetite

Common: dehydration

Psychiatric disorders

Very common: anxiety

Common: depression

Nervous system disorders

Common: paraesthesia

Vascular disorders

Common: hot flushes

Respiratory, thoracic, and mediastinal disorders

Common: wheezing

Gastrointestinal disorders

Common: constipation, abdominal distention, stomatitis

General disorders and administration site conditions

Very common: malaise, oedema peripheral, weight decreased

Common: injection site fibrosis, pain

4.9 Overdose

Administration of Ceplene or IL-2 by rapid infusion or into vascular spaces, at higher doses than the approved ones, may exaggerate the adverse reactions associated with Ceplene.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other cytokines and immunomodulators; ATC code: L03AX14.

Ceplene/IL-2 is an immunotherapy which aims to induce immune-mediated destruction of residual myeloid leukaemic cells and thereby to prevent relapse of leukaemia. The role of Ceplene is to protect lymphocytes, in particular NK cells and T cells, which are responsible for the immune-mediated destruction of residual leukaemic cells. The role of IL-2 is to promote the functions of NK cells and T cells by activating the anti-leukaemic properties of these cells and by expanding these cell populations by inducing cell cycle proliferation. The mechanism by which Ceplene improves the anti-leukaemic function of lymphocytes in AML is not completely established; it is considered to be by inhibition of reactive oxygen species (ROS or “oxygen free radicals”), which are synthesised by monocytes/macrophages and granulocytes. ROS are known to limit the anti-leukaemic effects of lymphocyte activators such as IL-2, by triggering dysfunction and death by apoptosis in NK cells and T cells. Ceplene inhibits NAPDH oxidase which initiates the formation and release of ROS from phagocytes. By inhibiting oxidase function and reducing ROS production, Ceplene protects IL-2-activated NK cells and T cells from oxygen free radical-induced inhibition and apoptosis. The concomitant administration of Ceplene and IL-2 therefore aims to optimise the anti-leukaemic functions of NK cells and T cells.

There have been 2 clinical studies to evaluate the use of Ceplene in the maintenance of remission in adult AML patients. Study AML-1 was exploratory, enrolling 39 AML patients in remission to determine the dose and feasibility of Ceplene administered together with IL-2. Results of this pilot study were used to design and implement a multi-national phase 3 trial. The randomised phase 3 trial (0201) compared Ceplene+IL-2 treatment to no treatment in 261 patients in first remission (CR1) and in another 59 patients in subsequent remission after relapse (CR>1). For CR1 patients, the median duration of leukaemia-free survival increased from 291 days (9.7 months) to 450 days (15 months) after Ceplene/IL-2 versus no maintenance treatment (ITT, p=0.01. n=261). The number of CR1 patients remaining leukaemia-free for 3 years was 40% after Ceplene+IL-2 versus 26% in patients not receiving this treatment (p=0.01).

This medicinal product has been authorised under “Exceptional circumstances”. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SPC will be updated as necessary.

5.2 Pharmacokinetic Properties

Histamine is rapidly absorbed after subcutaneous injection. Maximum plasma concentration is reached approximately 10 minutes after end of subcutaneous infusion. Histamine concentrations and PK were highly variable across studies, as well as within the normal volunteer and patient groups. Patients showed a higher degree of variability with respect to systemic exposure as compared to healthy subjects.

Histamine is eliminated by metabolism in kidney, liver and other tissues. The main enzymes involved in the metabolism of histamine are HNMT (histamine-N-methyltransferase) and DAO (diamine oxidase). The metabolites are mainly excreted in urine. The mean half-life was 0.75 to 1.5 hours in patients.

There are no significant effects of age or weight on the pharmacokinetic properties of histamine. Clearance of Ceplene is almost twice as high in females resulting in considerably lower systemic exposure than in males.

It is not known whether histamine crosses the placenta.

Renal impairment

The pharmacokinetics of histamine are similar in healthy volunteers with normal renal function compared to volunteers with mild, moderate, or severe renal impairment. In subjects with severe renal impairment, there were decreases in systolic and diastolic blood pressure at plasma histamine concentrations which caused no appreciable decrease in blood pressure in other subjects. Thus, subjects with severe renal impairment may be more sensitive to the blood pressure lowering effects of exogenously administered histamine than subjects with normal renal function or subjects with mild or moderate renal impairment. Although the degree of renal impairment has little effect on the PK disposition of histamine, caution should be used in the administration of histamine to patients with severe renal impairment.

Hepatic impairment

A study was performed to measure the PK of histamine in normal volunteers compared to patients with mild, moderate, and severe hepatic impairment. There were no clinically significant differences in safety parameters or in pharmacodynamics. Plasma histamine concentrations were highly variable and were considerably higher in the groups of patients with moderate or severe hepatic impairment (medians 10 and 5 times the normal volunteers respectively). Patients with all degrees of hepatic impairment may have tachycardia or hypotension for 30-60 minutes after Ceplene+IL-2 administration.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated-dose toxicity, local tolerance and genotoxicity. Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use. No carcinogenicity studies have been performed on Ceplene.

Histamine dihydrochloride was not teratogenic in rats or rabbits at doses resulting in several hundred-fold greater systemic exposures than the clinical exposure. In female rats dosed before mating to gestation day 7, slightly reduced numbers of implantations and viable foetuses were found, but without any dose-response and within the range of historical control data. In the peri-post natal development study, high doses of histamine dihydrochloride caused maternal toxicity, and the offspring showed toxicity during lactation (fewer live pups at day 21 compared to lactation at day 4) but not after weaning.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium chloride

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies this medicinal product should not be mixed with other medicinal products, diluents or infusion solutions.

6.3 Shelf Life

Unopened vials: 3 years

6.4 Special Precautions For Storage

Ceplene

Do not freeze.

Interleukin-2 (IL-2; aldesleukin)

Diluted IL-2 (aldesleukin) dispensed in capped polypropylene tuberculin syringes is to be stored in the refrigerator at 2– 8°C.

6.5 Nature And Contents Of Container

2 ml type I glass vial, with bromobutyl rubber stopper and flip-off aluminium over seal, containing 0.5 ml of solution (0.70 ml including overfill).

Each carton contains 14 vials.

6.6 Special Precautions For Disposal And Other Handling

Ceplene

The vials contain 0.5 ml of solution (0.70 ml including overfill) to facilitate the dose extraction of a single 0.5 ml dose.

Patients are provided with capped polypropylene syringes and instructed to extract 0.5 ml of solution into the syringe.

The solution should be visually inspected for particulate matter and discolouration prior to administration. The solution must be clear and colourless.

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

Interleukin-2 ( IL-2; aldesleukin)

Dilute IL-2 dispensed in capped polypropylene tuberculin syringes is to be prepared by the Pharmacy in a controlled aseptic environment and stored in a refrigerator at 2°– 8° C.

When reconstituted and diluted according to the directions in Section 4.2, stability of dilute IL-2 (aldesleukin) in capped polypropylene tuberculin syringes has been demonstrated for up to 21 days when stored at refrigerated temperatures (2°C - 8°C).

Please see Section 4.2 for IL-2 dispensing instructions.

7. Marketing Authorisation Holder

EpiCept GmbH

Goethestrasse 4

D-80336 M?nchen

Germany

8. Marketing Authorisation Number(S)

EU/1/08/477/001

9. Date Of First Authorisation/Renewal Of The Authorisation

07/10/2008

10. Date Of Revision Of The Text

January 2011

Ultravist 300
1. Name Of The Medicinal Product

Ultravist® 300

2. Qualitative And Quantitative Composition

1ml contains 623mg of iopromide (equivalent to 300mg iodine).

3. Pharmaceutical Form

Aqueous solution for injection.

4. Clinical Particulars 4.1 Therapeutic Indications

X-ray contrast medium for computerised tomography, digital subtraction angiography, intravenous urography, venography (phlebography), arteriography, arthrography, hysterosalpingography and fistulography.

4.2 Posology And Method Of Administration

• General information

Experience shows that contrast medium is tolerated better if it is warmed to body temperature.

Intravenous urography

Adults: The minimum dose is 0.8ml/kg body weight Ultravist 370, (1ml/kg Ultravist 300 or 1.3ml/kg Ultravist 240). These doses should provide adequate filling of the ureters. It may be necessary to increase the dose in individual cases.

Children: The poor concentrating ability of the immature nephron of infantile kidneys necessitates the use of relatively high doses of contrast medium, i.e. for Ultravist 300:

Neonates: 4.0 ml/kg body weight Babies: 3.0 ml/kg body weight Small children: 1.5 ml/kg body weight

Computerised tomography

Cranial CT: The following dosages are recommended for cranial CT:

Ultravist 240: 1.5-2.5ml/kg body weight Ultravist 300: 1-2ml/kg body weight Ultravist 370: 1-1.5ml/kg body weight

Whole-body CT: For whole-body computerised tomography, the doses of contrast medium and the rates of administration depend on the organs under investigation, the diagnostic problem and, in particular, the different scan and image-reconstruction times of the scanners in use.

Angiography: The dosage depends on the age, weight, cardiac output and general condition of the patient, the clinical problem, examination technique and the nature and volume of the vascular region to be investigated.

The following dosages may serve as a guide:

Cerebral angiography   Aortic arch angiography 50-80 ml Ultravist 300/inj. Selective angiography 6-15 ml Ultravist 300/inj. Retrograde carotid angiography 30-40 ml Ultravist 300/inj.     Thoracic aortography: 50-80 ml Ultravist 300/inj. Abdominal aortography: 40-60 ml Ultravist 300/inj. Bifemoral arteriography: 40-60 ml Ultravist 300/inj.     Peripheral angiography:   Upper extremities:   Arteriography 8-12 ml Ultravist 300/inj. Venography 50-60 ml Ultravist 240/inj.   15-30 ml Ultravist 300/inj. Lower extremities:   Arteriography 20-30 ml Ultravist 300/inj. Venography 50-80 ml Ultravist 240/inj.   30-60 ml Ultravist 300/inj. Angiocardiography:  

Cardiac-ventriculography

40-60 ml Ultravist 370/inj. Coronary angiography: 5-8 ml Ultravist 370/inj.

Digital subtraction angiography (DSA): I.V. injection of 30-60 ml Ultravist 300 or 370 as a bolus (flow-rate: 8-12 ml/second into the cubital vein; 10-20 ml/second into the vena cava) is recommended for high-contrast demonstrations of the great vessels, of the pulmonary arteries and of the arteries of the neck, head, kidneys and extremities.

Intra-arterial digital subtraction angiography requires smaller volumes and lower iodine concentrations than the intravenous technique.

4.3 Contraindications

Uncontrolled thyrotoxicosis (see section 4.4).

4.4 Special Warnings And Precautions For Use

• Hypersensitivity reactions

As Ultravist can be associated with anaphylactoid/hypersensitivity or other idiosyncratic reactions with cardiovascular, respiratory and/or cutaneous effects, appropriate emergency drugs and equipment should be available for immediate use. It is also advisable to use a flexible indwelling cannula for intravenous contrast medium administration.

Due to an increased risk of hypersensitivity reactions, particularly careful risk/benefit judgment is required in patients:

- with known hypersensitivity to Ultravist or any excipient of Ultravist

- with a previous hypersensitivity reaction to any other iodinated contrast medium

- history of bronchial asthma or other allergic disorders.

If pre-medication is given, a corticosteroid regimen is recommended.

Allergy-like reactions range from mild to severe (including shock – see section 4.8). Most reactions occur within one hour of administration. However, as with other contrast agents, delayed reaction (after hours to days) may occur.

In order to minimise risk if a severe reaction should occur, patients

- should lie down during Ultravist administration

- must be kept under close observation for 15 minutes following the last injection as the majority of severe reactions occur at this time

- should remain in the hospital environment (but not necessarily the radiology department) for one hour after the last injection, and should be advised to return to the radiology department immediately if any symptoms develop.

If the administration does not take place on the X-ray table, any patient with a labile circulation should be brought to the X-ray machine sitting or lying down.

If hypersensitivity reactions occur, administration of the contrast medium must be stopped at once and – if necessary – specific therapy instituted intravenously. Patients who experience hypersensitivity reactions while taking beta-blockers may be resistant to treatment effects of beta agonists (see section 4.5). In the event of a severe hypersensitivity reaction, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes.

• Thyroid dysfunction

Particularly careful risk/benefit judgement is required in patients with known or suspected hyperthyroidism or goitre, as iodinated contrast media may induce hyperthyroidism and thyrotoxic crisis in these patients. Testing of thyroid function prior to Ultravist administration and/or preventive thyrostatic medication may be considered in patients with known or suspected hyperthyroidism.

• Cerebral arteriosclerosis, pulmonary emphysema or poor general health

For patients with cerebral arteriosclerosis, pulmonary emphysema or poor general health, the need for examination with X-ray contrast media merits careful consideration.

• Renal impairment

Contrast media-induced nephrotoxicity, presenting as a transient impairment of renal function, may occur after intravascular administration of iodinated contrast media.

Acute renal failure may occur in rare cases.

Risk factors include, for example:

- pre-existing renal insufficiency

- dehydration

- diabetes mellitus

- multiple myeloma / paraproteinaemia

- repetitive and / or large doses of iodinated contrast media.

• Hydration

Adequate hydration should be ensured in all patients who receive Ultravist administration. This applies especially to patients with multiple myeloma, diabetes mellitus, polyuria, oliguria or gout and in babies, small children and patients in a very poor state of health. Existing disturbances of the balance of water and electrolytes must be corrected before the administration of Ultravist.

• Cardiovascular disease

There is an increased risk of clinically relevant haemodynamic changes and arrhythmia in patients with significant cardiac disease or severe coronary artery disease. In the event of a severe hypersensitivity reaction, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes.

• CNS disorders

Patients with seizure history or other CNS disorders may be at increased risk of seizures and neurological complications with administration of iodinated contrast media. Neurological complications are more frequent in cerebral angiography and related procedures.

• Thromboembolic events

Non-ionic contrast media have less anticoagulant activity in-vitro than ionic media. Meticulous attention should therefore be paid to angiographic technique. Non-ionic media should not be allowed to remain in contact with blood in a syringe, and intravascular catheters should be flushed frequently with physiological saline solution (if necessary with heparin added) to minimise the risk of clotting, which has rarely led to serious thromboembolic complications of the procedure.

• Phaeochromocytoma

Premedication with an alpha-blocker is recommended in patients with phaeochromocytoma because of the risk of blood pressure crises.

• Anxiety

Experience shows that pronounced states of excitement, anxiety and pain can be the cause of side effects or intensify contrast medium-related reactions. They can be counteracted by calm management of the patient and the use of suitable drugs.

• Myelography

Ultravist should not be used in myelography.

• Hysterosalpingography

Hysterosalpingography must not be carried out during pregnancy or in patients with acute inflammatory conditions in the pelvic cavity.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Biguanides (metformin): Diabetic nephropathy may predispose to renal impairment following intravascular contrast medium administration. This may precipitate lactic acidosis in patients who are taking biguanides. As a precaution, biguanides should be stopped 48 hours prior to the contrast medium examination and reinstated only after control of renal function has been regained.

Beta-blockers: Patients who experience hypersensitivity reactions while taking beta-blockers may be resistant to treatment effects of beta agonists (see section 4.4).

Interleukin: The prevalence of delayed reactions (e.g. fever, rash, flu-like symptoms, joint pain and pruritus) to contrast media is higher in patients who have received interleukin.

Radioisotopes: If iodine isotopes are to be administered for the diagnosis of thyroid disease, it should be borne in mind that after the administration of iodinated contrast media which are excreted via the kidneys, the capacity of the thyroid tissue to take up iodine will be reduced for 2 weeks and sometimes up to 6 weeks.

4.6 Pregnancy And Lactation

X-ray examinations should, if possible, be avoided during pregnancy. It has not yet been proved beyond question that Ultravist may be used without hesitation in pregnant patients. Therefore, an examination with a contrast medium during pregnancy should be carried out only if considered absolutely necessary by the physician.

It is not known whether Ultravist enters the breast milk.

4.7 Effects On Ability To Drive And Use Machines

There is no known effect on the ability to drive or operate machines. However, because of the risk of reactions, driving or operating machinery is not advisable for one hour after the last injection (see Section 4.4).

4.8 Undesirable Effects

Undesirable effects in association with the use of iodinated contrast media are usually mild to moderate and transient in nature. However, severe and life-threatening reactions as well as deaths have been reported. Nausea, headache, a sensation of pain and a general feeling of warmth are the most frequently recorded reactions.

System organ class

Common

(

Uncommon

(

Rare

(< 1/1,000)

Immunological

 

 

Anaphylactoid reactions / hypersensitivity

Anaphylactoid shock (including fatal cases)

Endocrine

 

 

 

 

Alteration in thyroid function, thyrotoxic crisis

Nervous, Psychiatric

 

 

Dizziness, restlessness

Paraesthesia / hypoaesthesia, confusion, anxiety, agitation, amnesia, speech disorders, somnolence, unconciousness, coma, tremor, convulsion, paresis / paralysis, cerebral ischaemia / infarction, stroke.

Transient cortical blindnessa

Eye

 

 

Blurred / disturbed vision

Conjunctivitis, lacrimation.

Ear

 

 

 

 

Hearing disorders.

Cardiac

 

 

Arrhythmia

Palpitations, chest pain / tightness, bradycardia, tachycardia, cardiac arrest, heart failure, myocardial ischaemia/infarction, cyanosis.

Vascular

 

 

Vasodilatation

Hypotension, hypertension, shock.

Vasospasm,a thromboembolic eventsa

Respiratory

 

 

Sneezing, coughing

Rhinitis, dyspnoea, mucosal swelling, asthma, hoarseness, laryngeal / pharyngeal / tongue / face oedema, bronchospasm, laryngeal/pharyngeal spasm, pulmonary oedema, respiratory insufficiency, respiratory arrest.

Gastrointestinal

Nausea

Vomiting, taste disturbance

Throat irritation , dysphagia, swelling of salivary glands, abdominal pain, diarrhoea

Skin and subcutaneous tissue

 

 

Urticaria, pruritus, rash, erythema

Angioedema, mucocutaneous syndrome (e.g. Stevens-Johnson's or Lyell's syndrome)

Renal and urinary

 

 

Renal impairmenta

Acute renal failurea

General disorders and administration site conditions

Heat or pain sensations, headache

Malaise, chills, sweating, vasovagal reactions

Pallor, body temperature alterations, oedema

Local pain, mild warmth and oedema, inflammation and tissue injury in case of extravasation

a intravascular use only

     

Frequency estimates are based on data obtained in pre-marketing studies in more than 3900 patients and post-marketing studies in more than 74000 patients, as well as data from spontaneous reporting and literature. (Frequency estimations are based predominantly on intravascular use.).

4.9 Overdose

Symptoms may include fluid and electrolyte imbalance, renal failure, cardiovascular and pulmonary complications.

Monitor fluids, electrolytes and renal function. Treatment of overdose should be directed towards the support of vital functions.

Ultravist is dialysable.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Ultravist (iopromide) is a non-ionic contrast medium for intravascular radiological examinations and has only minimal pharmacological activity within the body.

The rate of protein binding is low and iopromide is a weak liberator of histamine. Cardiovascular and renal tolerance are good.

Ultravist has low osmolality.

The physico-chemical characteristics of the Ultravist range are listed below:

Iodine concentration (mg/ml)

150

240

300

370

Osmolality (osm/kg H2 O)

at 37 °C

 

0.33

 

0.48

 

0.59

 

0.77

Viscosity (mPa·s)

at 20 °C

at 37 °C

 

2.3

1.5

 

4.9

2.8

 

8.9

4.7

 

22.0

10.0

Density (g/ml)

at 20 °C

at 37 °C

 

1.164

1.158

 

1.263

1.255

 

1.328

1.322

 

1.409

1.399

5.2 Pharmacokinetic Properties

Following intravascular administration, iopromide is very rapidly distributed in the extracellular space. Plasma protein binding with a concentration of 1.2mg I/ml plasma is 0.9±0.2%. 5 minutes after intravenous bolus injection (within 1-5 min) of Ultravist 300, 28±6% of the dose was found in the total plasma volume, irrespective of the size of the dose. The contrast medium is first of all rapidly distributed, the half-life being 3 minutes, while the elimination half-life in patients with normal kidney function is approximately 2 hours, irrespective of the size of the dose. Under the doses recommended for diagnostic purposes, filtration of iopromide is exclusively glomerular. Renal excretion is approximately 18% of the dose within 30 minutes, approximately 60% within 3 hours and 92% within 24 hours. No metabolites were demonstrable in man following administration of the clinically relevant doses of iopromide.

5.3 Preclinical Safety Data

There are no pre-clinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium calcium edetate, trometamol, hydrochloric acid (diluted 10%), water for injection.

6.2 Incompatibilities

Some radiologists give an antihistamine or a corticosteroid prophylactically to patients with a history of allergy.

Because of possible precipitation, X-ray contrast media and prophylactic agents must not be injected as mixed solutions.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store below 30?C. Protect from light and X-rays.

6.5 Nature And Contents Of Container

Colourless glass infusion bottles of 50, 75, 100 and 200ml. Colourless glass ampoules and vials of 20ml. Packs of 10 x 20ml vials, 10 x 50, or 75ml bottles and 1 x 100 or 200ml bottles.

6.6 Special Precautions For Disposal And Other Handling

Contrast media should be visually inspected prior to use and must not be used, if discoloured, nor in the presence of particulate matter (including crystals) or defective containers. As Ultravist is a highly concentrated solution, crystallization (milky-cloudy appearance and/or sediment at the bottom, or floating crystals) may occur very rarely.

The contrast medium solution should not be drawn up into the syringe of the infusion bottle attached to the infusion set until immediately before the examination.

Vials containing contrast medium are not intended for the withdrawal of multiple doses. The rubber stopper should never be pierced more than once.

Contrast medium solution not used in one examination session must be discarded.

7. Marketing Authorisation Holder

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire RG14 1JA

United Kingdom

Trading as Bayer plc, Bayer Schering Pharma

8. Marketing Authorisation Number(S)

PL 00010/0566

9. Date Of First Authorisation/Renewal Of The Authorisation

01 May 2008

10. Date Of Revision Of The Text

22 January 2009

Previfem
norgestimate and ethinyl estradiol Dosage Form: tabletsPrevifem®

Acyclovir Oral Suspension
Acyclovir Oral Suspension, USP Acyclovir Oral Suspension Description

Acyclovir is a synthetic nucleoside analogue active against herpesviruses.

Each teaspoonful (5 mL) of Acyclovir Oral Suspension, USP, for oral administration, contains 200 mg of acyclovir and the inactive ingredients artificial banana flavor, carboxymethylcellulose sodium, glycerin, methylparaben 0.1% (added as a preservative), microcrystalline cellulose, propylparaben 0.02% (added as a preservative), purified water, and sorbitol.

Acyclovir is a white, crystalline powder with the molecular formula C8H11N5O3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5 mg/mL. The pka’s of acyclovir are 2.27 and 9.25.

The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]- 6H-purin-6-one; it has the following structural formula:

VIROLOGY: Mechanism of Antiviral Action:

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV).

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities:

The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL.

Drug Resistance:

Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.

Acyclovir Oral Suspension - Clinical Pharmacology Pharmacokinetics:

The pharmacokinetics of acyclovir after oral administration have been evaluated in healthy volunteers and in immunocompromised patients with herpes simplex or varicella-zoster virus infection. Acyclovir pharmacokinetic parameters are summarized in Table 1.

Table 1: Acyclovir Pharmacokinetic Characteristics (Range) Parameter Range Plasma protein binding 9% to 33% Plasma elimination half-life 2.5 to 3.3 hr Average oral bioavailability 10% to 20%*

*Bioavailability decreases with increasing dose.

In one multiple-dose, cross-over study in healthy subjects (n = 23), it was shown that increases in plasma acyclovir concentrations were less than dose proportional with increasing dose, as shown in Table 2. The decrease in bioavailability is a function of the dose and not the dosage form.

Table 2: Acyclovir Peak and Trough Concentrations at Steady State Parameter 200 mg 400 mg 800 mg Cssmax 0.83 mcg/mL 1.21 mcg/mL 1.61 mcg/mL Csstrough 0.46 mcg/mL 0.63 mcg/mL 0.83 mcg/mL

There was no effect of food on the absorption of acyclovir (n=6); therefore, Acyclovir Oral Suspension, USP may be administered with or without food.

The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine.

Special Populations: Adults with Impaired Renal Function:

The half-life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION).

Geriatrics:

Acyclovir plasma concentrations are higher in geriatric patients compared with younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use).

Pediatrics:

In general, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half-life after oral doses of 300 mg/m2 and 600 mg/m2 in pediatric patients aged 7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours).

Drug Interactions:

Coadministration of probenecid with intravenous acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced.

Clinical Trials: Initial Genital Herpes:

Double-blind, placebo-controlled studies have demonstrated that orally administered acyclovir significantly reduced the duration of acute infection and duration of lesion healing. The duration of pain and new lesion formation was decreased in some patient groups.

Recurrent Genital Herpes:

Double-blind, placebo-controlled studies in patients with frequent recurrences (6 or more episodes per year) have shown that orally administered acyclovir given daily for 4 months to 10 years prevented or reduced the frequency and/or severity of recurrences in greater than 95% of patients.

In a study of patients who received orally administered acyclovir 400 mg twice daily for 3 years, 45%, 52%, and 63% of patients remained free of recurrences in the first, second, and third years, respectively. Serial analyses of the 3-month recurrence rates for the patients showed that 71% to 87% were recurrence free in each quarter.

Herpes Zoster Infections:

In a double-blind, placebo-controlled study of immunocompetent patients with localized cutaneous zoster infection, acyclovir (800 mg 5 times daily for 10 days) shortened the times to lesion scabbing, healing, and complete cessation of pain, and reduced the duration of viral shedding and the duration of new lesion formation.

In a similar double-blind, placebo-controlled study, acyclovir (800 mg 5 times daily for 7 days) shortened the times to complete lesion scabbing, healing, and cessation of pain; reduced the duration of new lesion formation; and reduced the prevalence of localized zoster-associated neurologic symptoms (paresthesia, dysesthesia, or hyperesthesia).

Treatment was begun within 72 hours of rash onset and was most effective if started within the first 48 hours.

Adults greater than 50 years of age showed greater benefit.

Chickenpox:

Three randomized, double-blind, placebo-controlled trials were conducted in 993 pediatric patients aged 2 to 18 years with chickenpox. All patients were treated within 24 hours after the onset of rash. In 2 trials, acyclovir was administrated at 20 mg/kg 4 times daily (up to 3,200 mg per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered 4 times daily for 5 to 7 days. Treatment with acyclovir shortened the time to 50% healing; reduced the maximum number of lesions; reduced the median number of vesicles; decreased the median number of residual lesions on day 28; and decreased the proportion of patients with fever, anorexia, and lethargy by day 2. Treatment with acyclovir did not affect varicella-zoster virus-specific humoral or cellular immune responses at 1 month or 1 year following treatment.

Indications and Usage for Acyclovir Oral Suspension Herpes Zoster Infections:

Acyclovir Oral Suspension, USP is indicated for the acute treatment of herpes zoster (shingles).

Genital Herpes:

Acyclovir Oral Suspension, USP is indicated for the treatment of initial episodes and the management of recurrent episodes of genital herpes.

Chickenpox:

Acyclovir Oral Suspension, USP is indicated for the treatment of chickenpox (varicella).

Contraindications

Acyclovir is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir.

Warnings

Acyclovir is intended for oral ingestion only. Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see ADVERSE REACTIONS: Observed During Clinical Practice and OVERDOSAGE:).

Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy.

Precautions

Dosage adjustment is recommended when administering acyclovir to patients with renal impairment (see DOSAGE AND ADMINISTRATION). Caution should also be exercised when administering acyclovir to patients receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction and/or the risk of reversible central nervous system symptoms such as those that have been reported in patients treated with intravenous acyclovir. Adequate hydration should be maintained.

Information for patients

Patients are instructed to consult with their physician if they experience severe or troublesome adverse reactions, they become pregnant or intend to become pregnant, they intend to breastfeed while taking orally administered acyclovir, or they have any other questions.

Patients should be advised to maintain adequate hydration.

Herpes Zoster:

There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster.

Genital Herpes Infections:

Patients should be informed that acyclovir is not a cure for genital herpes. There are no data evaluating whether acyclovir will prevent transmission of infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding. If medical management of genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.

Chickenpox:

Chickenpox in otherwise healthy children is usually a self-limited disease of mild to moderate severity. Adolescents and adults tend to have more severe disease. Treatment was initiated within 24 hours of the typical chickenpox rash in the controlled studies, and there is no information regarding the effects of treatment begun later in the disease course.

Drug Interactions:

See CLINICAL PHARMACOLOGY: Pharmacokinetics.

Carcinogenesis, mutagenesis, impairment of fertility

The data presented below include references to peak steady-state plasma acyclovir concentrations observed in humans treated with 800 mg given orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given orally 5 times a day (dosing appropriate for treatment of genital herpes). Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir at the higher and lower dosing schedules (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of up to 450 mg/kg administered by gavage. There was no statistically significant difference in the incidence of tumors between treated and control animals, nor did acyclovir shorten the latency of tumors. Maximum plasma concentrations were 3 to 6 times human levels in the mouse bioassay and 1 to 2 times human levels in the rat bioassay.

Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was positive in 5 of the assays.

Acyclovir did not impair fertility or reproduction in mice (450 mg/kg per day, PO) or in rats (25 mg/kg per day, SC). In the mouse study, plasma levels were 9 to 18 times human levels, while in the rat study, they were 8 to 15 times human levels. At higher doses (50 mg/kg per day, SC) in rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) implantation efficacy, but not litter size, was decreased. In a rat peri- and post-natal study at 50 mg/kg per day, SC, there was a statistically significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses.

No testicular abnormalities were seen in dogs given 50 mg/kg per day, IV for 1 month (21 to 41 times human levels) or in dogs given 60 mg/kg per day orally for 1 year (6 to 12 times human levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.

Pregnancy Teratogenic effects

Pregnancy Category B. Acyclovir administered during organogenesis was not teratogenic in the mouse (450 mg/kg per day, PO), rabbit (50 mg/kg per day, SC and IV), or rat (50 mg/kg per day, SC). These exposures resulted in plasma levels 9 and 18, 16 and 106, and 11 and 22 times, respectively, human levels.

There are no adequate and well-controlled studies in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers

Acyclovir concentrations have been documented in breast milk in 2 women following oral administration of acyclovir and ranged from 0.6 to 4.1 times corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg per day. Acyclovir should be administered to a nursing mother with caution and only when indicated.

Pediatric use

Safety and effectiveness of oral formulations of acyclovir in pediatric patients younger than 2 years of age have not been established.

Geriatric use

Of 376 subjects who received acyclovir in a clinical study of herpes zoster treatment in immunocompetent subjects greater than or equal to 50 years of age, 244 were 65 and over while 111 were 75 and over. No overall differences in effectiveness for time to cessation of new lesion formation or time to healing were reported between geriatric subjects and younger adult subjects. The duration of pain after healing was longer in patients 65 and over. Nausea, vomiting, and dizziness were reported more frequently in elderly subjects. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to CNS adverse events observed during clinical practice, somnolence, hallucinations, confusion, and coma were reported more frequently in elderly patients (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS: Observed During Clinical Practice, and DOSAGE AND ADMINISTRATION).

Adverse Reactions

To report SUSPECTED ADVERSE REACTIONS, contact Hi-Tech Pharmacal Co., Inc. at 1-800-262-9010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Herpes Simplex: Short-Term Administration:

The most frequent adverse events reported during clinical trials of treatment of genital herpes with acyclovir 200 mg administered orally 5 times daily every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient treatments (2.7%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) patients who received placebo.

Long-Term Administration:

The most frequent adverse events reported in a clinical trial for the prevention of recurrences with continuous administration of 400 mg (two 200-mg capsules) 2 times daily for 1 year in 586 patients treated with acyclovir were nausea (4.8%) and diarrhea (2.4%). The 589 control patients receiving intermittent treatment of recurrences with acyclovir for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%).

Herpes Zoster:

The most frequent adverse event reported during 3 clinical trials of treatment of herpes zoster (shingles) with 800 mg of oral acyclovir 5 times daily for 7 to 10 days in 323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%).

Chickenpox:

The most frequent adverse event reported during 3 clinical trials of treatment of chickenpox with oral acyclovir at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days or 800 mg 4 times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving placebo reported diarrhea (2.2%).

Observed During Clinical Practice:

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of acyclovir. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to acyclovir, or a combination of these factors.

General:

Anaphylaxis, angioedema, fever, headache, pain, peripheral edema.

Nervous:

Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with renal impairment (see PRECAUTIONS).

Digestive:

Diarrhea, gastrointestinal distress, nausea.

Hematologic and Lymphatic:

Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia.

Hepatobiliary Tract and Pancreas:

Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice.

Musculoskeletal:

Myalgia.

Skin:

Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens- Johnson syndrome, toxic epidermal necrolysis, urticaria.

Special Senses:

Visual abnormalities.

Urogenital:

Renal failure, renal pain (may be associated with renal failure), elevated blood urea nitrogen, elevated creatinine, hematuria (see WARNINGS).

OVERDOSAGE:

Overdoses involving ingestion of up to 20 g have been reported. Adverse events that have been reported in association with overdosage include agitation, coma, seizures, and lethargy. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Overdosage has been reported following bolus injections or inappropriately high doses and in patients whose fluid and electrolyte balance were not properly monitored. This has resulted in elevated BUN and serum creatinine and subsequent renal failure. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see DOSAGE AND ADMINISTRATION).

Acyclovir Oral Suspension Dosage and Administration Acute Treatment of Herpes Zoster:

800 mg every 4 hours orally, 5 times daily for 7 to 10 days.

Genital Herpes: Treatment of Initial Genital Herpes:

200 mg every 4 hours, 5 times daily for 10 days.

Chronic Suppressive Therapy for Recurrent Disease:

400 mg 2 times daily for up to 12 months, followed by re-evaluation. Alternative regimens have included doses ranging from 200 mg 3 times daily to 200 mg 5 times daily.

The frequency and severity of episodes of untreated genital herpes may change over time. After 1 year of therapy, the frequency and severity of the patient’s genital herpes infection should be re-evaluated to assess the need for continuation of therapy with Acyclovir Oral Suspension.

Intermittent Therapy:

200 mg every 4 hours, 5 times daily for 5 days. Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence.

Treatment of Chickenpox: Children (2 years of age and older):

20 mg/kg per dose orally 4 times daily (80 mg/kg per day) for 5 days. Children over 40 kg should receive the adult dose for chickenpox.

Adults and Children over 40 kg:

800 mg 4 times daily for 5 days.

Intravenous Acyclovir Oral Suspension is indicated for the treatment of varicellazoster infections in immunocompromised patients.

When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox. There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs and symptoms.

Patients With Acute or Chronic Renal Impairment:

In patients with renal impairment, the dose of Acyclovir Oral Suspension should be modified as shown in Table 3:

Table 3: Dosage Modification for Renal Impairment Normal Dosage Regimen

Creatinine

Clearance (mL/min/1.73 m2)

Adjusted Dosage Regimen

Dose

(mg)

Dosing Interval

    200 mg every 4 hours

> 10

0-10

200

200

every 4 hours, 5x daily

every 12 hours

400 mg every 12 hours

> 10

0-10

400

200

every 12 hours

every 12 hours

800 mg every 4 hours

> 25

10-25

0-10

800

800

800

every 4 hours, 5x daily

every 8 hours

every 12 hours

Hemodialysis:

For patients who require hemodialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations following a 6-hour dialysis period. Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis.

Peritoneal Dialysis:

No supplemental dose appears to be necessary after adjustment of the dosing interval.

How is Acyclovir Oral Suspension Supplied

Acyclovir Oral Suspension, USP (off-white, artificial banana-flavored) containing 200 mg acyclovir in each teaspoonful (5 mL) – Bottle of 1 pint (473 mL).

Store at 20° - 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Manufactured by:

Hi-Tech Pharmacal Co., Inc.

Amityville, NY 11701

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