Motens Tablets 4mg

1. Name Of The Medicinal Product

Motens^® 4 mg Tablets.

2. Qualitative And Quantitative Composition

Tablets containing lacidipine 4 mg.

Excipient: Lactose 255.25 mg per tablet.

For full list of excipients, see 6.1.

3. Pharmaceutical Form

Film coated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

MOTENS is indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents, including ß-adrenoceptor antagonists, diuretics, and ACE-inhibitors.

4.2 Posology And Method Of Administration

Adults:

The treatment of hypertension should be adapted to the severity of the condition, and according to the individual response.

The recommended initial dose is 2 mg once daily. The dose may be increased to 4 mg (and then, if necessary, to 6 mg) after adequate time has been allowed for the full pharmacological effect to occur. In practice, this should not be less than 3 to 4 weeks. Daily doses above 6 mg have not been shown to be significantly more effective.

MOTENS should be taken at the same time each day, preferably in the morning.

Treatment with MOTENS may be continued indefinitely.

Patients with hepatic impairment:

Lacidipine is metabolised primarily by the liver and therefore in patients with hepatic impairment, the bioavailability of MOTENS may be increased and the hypotensive effect enhanced. These patients should be carefully monitored, and in severe cases, a dose reduction may be necessary.

Patients with kidney disease:

As MOTENS is not cleared by the kidneys, the dose does not require modification in patients with kidney disease.

Use in children:

No experience has been gained with MOTENS in children.

4.3 Contraindications

MOTENS tablets are contraindicated in patients with known hypersensitivity to any ingredient of the preparation. MOTENS should only be used with great care in patients with a previous allergic reaction to another dihydropyridine because there is a theoretical risk of cross-reactivity.

As with other calcium antagonists, MOTENS should be discontinued in patients who develop cardiogenic shock and unstable angina. In addition, dihydropyridines have been shown to reduce coronary arterial blood-flow in patients with aortic stenosis and in such patients MOTENS is contraindicated.

MOTENS should not be used during or within one month of a myocardial infarction.

In case of rare hereditary conditions that may be incompatible with an excipient of the product (please refer to section 4.4 Special Warnings and Precautions for Use) the use of the product is contraindicated.

4.4 Special Warnings And Precautions For Use

In specialised studies lacidipine has been shown not to affect the spontaneous function of the SA node or to cause prolonged conduction within the AV node. However, the theoretical potential for a calcium antagonist to affect the activity of the SA and AV nodes should be noted, and therefore lacidipine should be used with caution in patients with pre-existing abnormalities in the activity of the SA and AV nodes.

As has been reported with other dihydropyridine calcium channel antagonists, lacidipine should be used with caution in patients with congenital or documented acquired QT prolongation. Lacidipine should also be used with caution in patients treated concomitantly with medications known to prolong the QT interval such as class I and III antiarrhythmics, tricyclic antidepressants, some antipsychotics, antibiotics (e.g. erythromycin) and some antihistamines (e.g. terfenadine).

As with other calcium antagonists, lacidipine should be used with caution in patients with poor cardiac reserve.

There is no evidence that lacidipine is useful for secondary prevention of myocardial infarction.

The efficacy and safety of MOTENS in the treatment of malignant hypertension has not been established.

Lacidipine should be used with caution in patients with impaired liver function because antihypertensive effect may be increased.

There is no evidence that lacidipine impairs glucose tolerance or alters diabetic control.

This product contains 255.2 mg lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Co-administration of lacidipine with other agents recognised to have a hypotensive effect, including anti-hypertensive agents, (e.g. diuretics, beta-blockers or ACE-inhibitors), may have an additive hypotensive effect. However, no specific interaction problems have been identified in studies with common antihypertensive agents (e.g. beta-blockers and diuretics) or with digoxin, tolbutamide or warfarin.

The plasma level of lacidipine may be increased by simultaneous administration of cimetidine.

Lacidipine is highly protein-bound (more than 95%) to albumin and alpha-1-glycoprotein.

As with other dihydropyridines, lacidipine should not be taken with grapefruit juice as bioavailability may be altered.

In clinical studies in patients with a renal transplant treated with cyclosporin, lacidipine reversed the decrease in renal plasma flow and glomerular filtration rate induced by cyclosporin.

Lacidipine is known to be metabolised by cytochrome CYP3A4 and, therefore, significant inhibitors and inducers of CYP3A4 (e.g. rifampicin, itraconazole) administered concurrently may interact with the metabolism and elimination of lacidipine.

Concomitant use of lacidipine and corticoids or tetracosactide might decrease antihypertensive effect.

4.6 Pregnancy And Lactation

Pregnancy:

Although some dihydropyridine compounds have been found to be teratogenic in animals, data in the rat and rabbit for lacidipine provide no evidence of a teratogenic effect. Using doses far above the therapeutic range, in animals lacidipine shows evidence of maternal toxicity resulting in increased pre- and post-implantation losses and possibly delayed ossification. Evidence from experimental animals has indicated that administration of lacidipine results in prolongation of gestational period and prolonged and difficult labour as a consequence of relaxation of uterine muscle.

There are no data on the safety of lacidipine in human pregnancy.

Lacidipine should only be used in pregnancy when the potential benefits for the mother outweigh the possibility of adverse effects in the foetus or neonate.

The possibility that lacidipine can cause relaxation of the uterine muscle at term should be considered.

Lactation:

Milk transfer studies in animals have shown that lacidipine (or its metabolites) are likely to be excreted into breast milk.

Lacidipine should only be used during lactation when the potential benefits for the mother outweigh the possibility of adverse effects in the foetus or neonate.

4.7 Effects On Ability To Drive And Use Machines

MOTENS may cause dizziness. Patients should be warned not to drive or operate machinery if they experience dizziness or related symptoms.

4.8 Undesirable Effects

MOTENS is generally well tolerated. Some individuals may experience minor side effects which are related to its known pharmacological action of peripheral vasodilation. Such effects, indicated by a hash (#), are usually transient and usually disappear with continued administration of MOTENS at the same dosage.

Adverse events have been ranked under headings of frequency using the following convention:

Very common
Common
Uncommon
Rare
Very rare	<1/10000
Not known	Cannot be estimated from the available data

Psychiatric disorders:
Depression	rare
Nervous system disorders:
Dizziness#	common
Headache#	common
Tremor	very rare
Cardiac disorders:
Palpitations#	common
Tachycardia	common
Syncope	uncommon
Angina pectoris	uncommon
As with other dihydropyridines aggravation of underlying angina pectoris has been reported in a small number of individuals, especially at the start of treatment. This is more likely to happen in patients with symptomatic ischaemic heart disease. MOTENS should be discontinued under medical supervision in patients who develop unstable angina.
Vascular disorders:
Flushing#	common
Hypotension	uncommon
Gastrointestinal disorders:
Abdominal discomfort	common
Nausea	common
Gingival hyperplasia	uncommon
Skin and subcutaneous tissue disorders:
Rash	common
Erythema	common
Pruritus	common
Angioedema	rare
Urticaria	rare
Musculoskeletal and connective tissue disorders:
Muscle cramps	rare
Renal and urinary disorders:
Polyuria	common
General disorders and administration site conditions:
Asthenia	common
Oedema#	common
Investigations:
Blood alkaline phosphatase increased	common

4.9 Overdose

Symptoms:

There have been no recorded cases of MOTENS overdosage. The expected symptoms could comprise prolonged peripheral vasodilation associated with hypotension and tachycardia. Bradycardia or prolonged AV conduction could occur.

Therapy:

There is no specific antidote. Standard general measures for monitoring cardiac function and appropriate supportive and therapeutic measures should be used.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

MOTENS is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in the vascular smooth muscle. Its main action is to dilate peripheral arterioles, reducing peripheral vascular resistance and lowering blood pressure.

In a study of ten patients with a renal transplant, MOTENS has been shown to prevent an acute decrease in renal plasma flow and glomerular filtration rate about six hours after administering oral cyclosporin. During the trough phase of cyclosporin treatment, there was no difference in renal plasma flow and glomerular filtration rate between patients with or without MOTENS.

Following the oral administration of 4 mg lacidipine to volunteer subjects, a minimal prolongation of QTc interval has been observed (mean QTcF increase between 3.44 and 9.60 ms in young and elderly volunteers). This was not associated with any adverse clinical effects or cardiac arrhythmias on monitoring.

5.2 Pharmacokinetic Properties

MOTENS is a highly lipophilic compound; it is rapidly absorbed from the gastrointestinal tract following oral dosing. Absolute bioavailability averages about 10% due to extensive first-pass metabolism in the liver.

Peak plasma concentrations are reached between 30 and 150 minutes. The drug is eliminated primarily by hepatic metabolism (involving cytochrome P450 CYP3A4). There is no evidence that MOTENS causes either induction or inhibition of hepatic enzymes.

The principal metabolites possess little, if any, pharmacodynamic activity.

Approximately 70% of the administered dose is eliminated as metabolites in the faeces and the remainder as metabolites in the urine.

The average terminal half-life of MOTENS ranges from between 13 and 19 hours at steady state.

5.3 Preclinical Safety Data

In acute toxicity studies, MOTENS has shown a wide safety margin.

In repeated dose toxicological studies, findings in animals, related to the safety profile of MOTENS in man, were reversible and reflected the pharmacodynamic effect of MOTENS.

No data of clinical relevance have been gained from in vivo and in vitro studies on reproduction toxicity, genetic toxicity or oncogenicity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Lactose (monohydrate)

Lactose (spray-dried)

Povidone K30

Magnesium stearate

Film coating:

Titanium Dioxide (E 171)

Methylhydroxypropylcellulose

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Do not store above 30 °C.

MOTENS is light sensitive. MOTENS tablets should, therefore, be stored in the original container and should not be removed from their foil pack until required for administration.

Keep out of the reach of children.

6.5 Nature And Contents Of Container

Cartons containing 7, 14 and 28 tablets packed in blister strips.

[The 7 tablet pack is not currently marketed.]

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom

8. Marketing Authorisation Number(S)

PL 00015/0189

9. Date Of First Authorisation/Renewal Of The Authorisation

29 April 1993

10. Date Of Revision Of The Text

May 2010

Legal category

POM

Neo-Fradin

neomycin sulfate

Dosage Form: oral solution

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Neomycin Sulfate Oral Solution and other antibacterial drugs, Neomycin Sulfate Oral Solution should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

BOXED WARNING

SYSTEMIC ABSORPTION OF NEOMYCIN OCCURS FOLLOWING ORAL ADMINISTRATION AND TOXIC REACTIONS MAY OCCUR. Patients treated with neomycin should be under close clinical observation because of the potential toxicity associated with their use

NEUROTOXICITY (INCLUDING OTOTOXICITY) AND NEPHROTOXICITY FOLLOWING THE ORAL USE OF NEOMYCIN SULFATE HAVE BEEN REPORTED, EVEN WHEN USED IN RECOMMENDED DOSES. THE POTENTIAL FOR NEPHROTOXICITY, PERMANENT BILATERAL AUDITORY OTOTOXICITY AND SOMETIMES VESTIBULAR TOXICITY IS PRESENT IN PATIENTS WITH NORMAL RENAL FUNCTION WHEN TREATED WITH HIGHER DOSES OF NEOMYCIN AND/OR FOR LONGER PERIODS THAN RECOMMENDED. Serial, vestibular, and audiometric tests, as well as tests of renal function, should be performed (especially in high risk patients).

THE RISK OF NEPHROTOXICITY AND OTOTOXICITY IS GREATER IN PATIENTS WITH IMPAIRED RENAL FUNCTION.  Ototoxicity is often delayed in onset and patients developing cochlear damage will not have symptoms during therapy to warn them of developing eighth nerve destruction and total or partial deafness may occur long after neomycin has been discontinued.

Neuromuscular blockage and respiratory paralysis have been reported following the oral use of neomycin. The possibility of the occurrence of neuro-muscular blockage and respiratory paralysis should be considered if neomycin is administered, especially to patients receiving anesthetics, neuro-muscular blocking agents such as tubocurarine, succinylcholine, decamethonium, or in patients receiving massive transfusions of citrate anticoagulated blood. If blockage occurs, calcium salts may reverse these phenomena but mechanical respiratory assistance may be necessary.

Concurrent and/or sequential systemic, oral, or topical use of other aminoglycosides including paromomycin and other potentially nephrotoxic and/or neurotoxic drugs such as bacitracin, cisplatin, vancomycin, amphotericin B, polymyxin B, colistin, and viomycin should be avoided because the toxicity may be additive.

Other factors which increase the risk of toxicity are advanced age and dehydration.

The concurrent use of neomycin with potent diuretics such as ethacrynic acid or furosemide should be avoided since certain diuretics by themselves may cause ototoxicity. In addition, when administered intravenously, diuretics may enhance neomycin toxicity by altering the antibiotic concentration in serum and tissue.

Neo-Fradin Description

Neo-Fradin Oral Solution for oral administration contains neomycin which is an antibiotic obtained from the metabolic products of the actinomycete Streptomyces fradiae. The pH range is 5.0 to 7.5. Neo-Fradin Oral Solution is a clear orange solution with a cherry flavor. Each 5 mL of Neo-Fradin Oral Solution contains 125 mg of neomycin sulfate (equivalent to 87.5 mg of neomycin).

Inactive ingredients: benzoic acid, FD&C yellow no. 6, cherry flavor, glycerin, methylparaben, proplyparaben, sodium phosphate dibasic heptahydrate, sulfuric acid, diatomaceous earth, and purified water.

Sodium phosphate dibasic heptahydrate and sulfuric acid are used as pH adjusters.

The chemical name for Neomycin is: 0-2, 6-diamino-2, 6-dideoxy-α-D-lucopyranosyl-(1→3)- 0β-D-ribofuranosyl-(1→5)0-[2, 6-diamino-2, 6-dideoxy-α-D-glucopyranosyl-(1→4)]-2-deoxy-D-streptamine.

Neomycin B is identical except that the -α-D-glucopyranosyl residue in the neobiosamine moiety is β-L-idopyranosly.

The molecular weight of Neomycin is 614.67. The structural formula is represented below:

Neo-Fradin - Clinical Pharmacology

Neomycin sulfate is poorly absorbed from the gastrointestinal tract. The small absorbed fraction is rapidly distributed in the tissues and is excreted by the kidney in keeping with the degree of kidney function. The unabsorbed portion of the drug (approximately 97 percent) is eliminated unchanged in the feces.

Growth of most intestinal bacteria is rapidly suppressed following oral administration of neomycin sulfate, with the suppression persisting for 48-72 hours. Nonpathogenic yeasts and occasionally resistant strains of Enterobacter aerogenes (formerly Aerobacter aerogenes) replace the intestinal bacteria.

As with other aminoglycosides, the amount of systemically absorbed neomycin transferred to the tissues increases cumulatively with each repeated dose administered until a steady state is achieved. The kidney functions as the primary excretory path as well as the tissue binding site with the highest concentration found in renal cortex. With repeated dosings, progressive accumulation also occurs in the inner ear. Release of tissue bound neomycin occurs slowly over a period of several weeks after dosing has been discontinued.

Protein binding studies have shown that the degree of aminoglycoside protein binding is low and, depending upon the methods used for testing, this may be between 0 and 30 percent.

Microbiology

In vitro tests have demonstrated that neomycin is bactericidal and acts by inhibiting the synthesis of protein in susceptible bacterial cells. It is effective primarily against gram-negative bacilli but does have some activity against gram-positive organisms. Neomycin is active in vitro against Escherichia coli and the Klebsiella-Enterobacter group. Neomycin is not active against anaerobic bowel flora.

If susceptibility testing is needed, using a 30 mcg disc, organisms producing zones of 16 mm or greater are considered susceptible. Resistant organisms produce zones of 13 mm or less. Zones greater than 13 mm and less than 16 mm indicate intermediate susceptibility.

Indications and Usage for Neo-Fradin

Hepatic coma (portal-systemic encephalopathy)

Neomycin sulfate has been shown to be effective adjunctive therapy in hepatic coma by reduction of the ammonia forming bacteria in the intestinal tract. The subsequent reduction in blood ammonia has resulted in neurologic improvement.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Neomycin Sulfate Oral Solution and other antibacterial drugs, Neomycin Sulfate Oral Solution should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Contraindications

Neomycin sulfate oral preparations are contraindicated in the presence of intestinal obstruction and in individuals with a history of hypersensitivity to the drug.

Patients with a history of hypersensitivity or serious toxic reaction to other aminoglycosides may have a cross-sensativity to neomycin.

Neomycin sulfate oral solution is contraindicated in patients with inflammatory or ulcerative gastrointestinal disease because of the potential for enhanced gastrointestinal absorption of neomycin.

Warnings

(see boxed WARNINGS)

Additional manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and convulsions.

The risk of hearing loss continues after drug withdrawal.

Aminoglycosides can cause fetal harm when administered to a pregnant woman.

Aminoglycoside antibiotics cross the placenta and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although serious side effects to fetus or newborn have not been reported in the treatment of pregnant women with other aminoglycosides, the potential for harm exists. Animal reproduction studies of neomycin have not been conducted. If neomycin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Precautions

General

Prescribing Neomycin Sulfate Oral Solution in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

As with other antibiotics, use of oral neomycin may result in overgrowth of non-susceptible organisms, particularly fungi. If this occurs, appropriate therapy should be instituted.

Neomycin is quickly and almost totally absorbed from body surfaces (except the urinary bladder) after local irrigation and when applied topically in association with surgical procedures. Delayed-onset, irreversible deafness, renal failure, and death due to neuromuscular blockade (regardless of the status of renal function) have been reported following irrigation of both small and large surgical fields with minute quantities of neomycin.

Cross-allergenicity among aminoglycosides has been demonstrated.

Aminoglycosides should be used with caution in patients with muscular disorders such as myasthenia gravis or parkinsonism since these drugs may aggravate muscle weakness because of their potential curare-like effect on the neuromuscular junction.

Small amounts of orally administered neomycin are absorbed through intact intestinal mucosa.

There have been many reports in the literature of nephrotoxicity and/or ototoxicity with the oral use of neomycin. If renal insufficiency develops during oral therapy, consideration should be given to reducing the drug dosage or discontinuing therapy.

An oral neomycin dose of 12 grams per day produces a malabsorption syndrome for a variety of substances including fat, nitrogen, cholesterol, carotene, glucose, xylose, lactose, sodium, calcium, cyanocobalamin and iron.

Oral administered neomycin increases fecal bile acid excretion and reduces intestinal lactase activity.

Laboratory Tests

Patients with renal insufficiency may develop toxic neomycin blood levels unless doses are properly regulated. If renal insufficiency develops during treatment, the dosage should be reduced or the antibiotic discontinued. To avoid nephrotoxicity and eighth nerve damage associated with high doses and prolonged treatment, the following should be performed prior to and periodically during therapy: urinalysis for increased excretion of protein, decreased specific gravity, casts and cells; renal function tests such as serum creatinine, BUN or creatinine clearance; tests of the vestibulocochlearis nerve (eighth cranial nerve) function.

Serial, vestibular and audiometric tests should be performed (especially in high risk patients). Since elderly patients may have reduced renal function which may not be evident in the results of routine screening tests such as BUN or serum creatinine, a creatinine clearance determination may be more useful.

Drug Interactions

Caution should be taken in concurrent or serial use of other neurotoxic and/or nephrotoxic drugs because of possible enhancement of the nephrotoxicity and/or ototoxicity of neomycin (see boxed WARNINGS).

Caution should also be taken in concurrent or serial use of other aminoglycosides and polymyxins because they may enhance neomycin's nephrotoxicity and/or ototoxicity and potentiate neomycin's neuromuscular blocking effects.

Oral neomycin inhibits the gastrointestinal absorption of penicillin V, oral vitamin B-12, methotrexate and 5-fluorourcil. The gastrointestinal absorption of digoxin also appears to be inhibited. Therefore, digoxin serum levels should be monitored.

Oral neomycin may enhance the effect of coumarin in anticoagulants by decreasing vitamin K availability.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed with neomycin to evaluate carcinogenic or mutagenic potential or impairment of fertility.

Pregnancy

Category D (see WARNINGS section)

Nursing Mothers

It is not known whether neomycin is excreted in human milk but it has been shown to be excreted in cow milk following a single intramuscular injection. Other aminoglycosides have been shown to be excreted in human milk. Because of the potential for serious adverse reactions from the aminoglycosides in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of oral neomycin in patients less than eighteen years of age have not been established. If treatment of a patient less than eighteen years of age is necessary, neomycin should be used with caution and the period of treatment should not exceed three weeks because of the absorption from the gastrointestinal tract.

Information for Patients

Patients should be counseled that antibacterial drugs including Neomycin Sulfate Oral Solution should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Neomycin Sulfate Oral Solution is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Neomycin Sulfate Oral Solution or other antibacterial drugs in the future.

Before administering the drug, patients or members of their families should be informed of possible toxic effects of the eighth nerve. The possibility of acute toxicity increases in premature infants and neonates.

Adverse Reactions

The most common adverse reactions to oral neomycin are nausea, vomiting, and diarrhea. The "Malabsorption Syndrome" characterized by increased fecal fat, decreased serum carotene and fall in xylose absorption has been reported with prolonged therapy. Nephrotoxicity, ototoxicity, and neuromuscular blockage have been reported (see boxed WARNINGS and PRECAUTIONS section).

Overdosage

Because of low absorption, it is unlikely that acute overdosage would occur with oral neomycin. However, prolonged administration could result in sufficient systemic drug levels to produce neurotoxicity, ototoxicity, and/or nephrotoxicity.

Hemodialysis will remove neomycin from the blood.

Neo-Fradin Dosage and Administration

To minimize the risk of toxicity use the lowest possible dose and the shortest possible treatment period to control the condition. Treatment for periods longer than two weeks is not recommended.

Hepatic coma

For use as an adjunct in the management of hepatic coma, the recommended dose is 4-12 grams per day given in the following regimen:

1. 
   

   Withdraw protein from diet. Avoid use of diuretic agents.

   
   


2. 
   

   Give supportive therapy including blood products, as indicated.

   
   


3. 
   

   Give Neo-Fradin Oral Solution in doses of four to twelve grams of neomycin sulfate per day in divided doses.

   
   

   Treatment should be continued over a period of five to six days during which time protein should be returned incrementally to the diet.

   
   


4. 
   

   If less potentially toxic drugs cannot be used for chronic hepatic insufficiency, neomycin sulfate in doses of up to four grams daily may be necessary. The risks for the development of neomycin induced toxicity progressively increase when the treatment must be extended to preserve the life of a patient with hepatic encephalopathy who has failed to fully respond. Frequent periodic monitoring of these patients to ascertain the presence of drug toxicity is mandatory (see PRECAUTIONS). Also, neomycin serum concentrations should be monitored to avoid potentially toxic levels. The benefits to the patient should be weighed against the risks of nephrotoxicity, permanent ototoxicity and neuromuscular blockade following the accumulation of neomycin in the tissues.

   
   

How is Neo-Fradin Supplied

Neo-Fradin Oral Solution is available as a clear orange solution with a cherry flavor in 16 fl. oz and 2 fl. oz bottles containing 125 mg of neomycin sulfate (equivalent to 87.5 mg of neomycin) per five mL.

NDC 39822-0330-5 for 16 fl. oz.

NDC 39822-0330-2 for 2 fl. oz.

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

Manufactured for:

X-Gen Pharmaceuticals, Inc.

July 2005

Neo-Fradin  neomycin sulfate  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 39822-0330 Route of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength neomycin sulfate (neomycin) Active 125 MILLIGRAM  In 5 MILLILITER benzoic acid Inactive 5 MILLIGRAM  In 5 MILLILITER FD&C yellow no. 6 Inactive 0.75 MILLIGRAM  In 5 MILLILITER Cherry flavor Inactive 4.645 MILLIGRAM  In 5 MILLILITER glycerin Inactive 1.878 GRAM  In 5 MILLILITER methylparaben Inactive 5 MILLIGRAM  In 5 MILLILITER proplyparaben Inactive 1.25 MILLIGRAM  In 5 MILLILITER sodium phosphate dibasic heptahydrate Inactive 15 MILLIGRAM  In 5 MILLILITER sulfuric acid Inactive   standard super cel Inactive   water Inactive   diatomaceous earth Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 39822-0330-5 473 mL (MILLILITER) In 1 BOTTLE None 2 39822-0330-2 59 mL (MILLILITER) In 1 BOTTLE None

Revised: 07/2008X-Gen Pharmaceuticals Inc.

More Neo-Fradin resources

• Neo-Fradin Side Effects (in more detail)
• Neo-Fradin Dosage
• Neo-Fradin Use in Pregnancy & Breastfeeding
• Neo-Fradin Drug Interactions
• Neo-Fradin Support Group
• 0 Reviews for Neo-Fradin - Add your own review/rating

• Neo-Fradin Concise Consumer Information (Cerner Multum)


• Neo-Fradin Solution MedFacts Consumer Leaflet (Wolters Kluwer)


• Neo-Fradin Advanced Consumer (Micromedex) - Includes Dosage Information


• Neomycin MedFacts Consumer Leaflet (Wolters Kluwer)


• Neomycin Sulfate Monograph (AHFS DI)

Compare Neo-Fradin with other medications

• Bowel Preparation
• Diarrhea
• Hepatic Coma
• Hepatic Encephalopathy

Fortral Injection 30mg / 1ml

FORTRAL INJECTION 30MG/ML

(Pentazocine, as lactate)

Read all of this leaflet carefully before you are given this medicine.

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


• If you have further questions, please ask your doctor, nurse or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


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

In this leaflet:

• 1. What Fortral is and what it is used for


• 2. Before you are given Fortral


• 3. How Fortral is given


• 4. Possible side effects


• 5. How Fortral is stored


• 6. Further information

What Fortral Is And What It Is Used For

The name of your medicine is Fortral Injection 30mg/ml (called Fortral throughout this leaflet). Fortral contains a medicine called pentazocine (as lactate). Pentazocine belongs to a group of medicines called analgesics (painkillers).

Fortral is used to treat moderate to severe pain.

Before You Are Given Fortral

Do not have Fortral and tell your doctor if:

• You are allergic (hypersensitive) to pentazocine or any of the other ingredients in your medicine (listed in Section 6: Further information). Signs of an allergic reaction include a rash and breathing problems. There can also be swelling of the legs, arms, face, throat or tongue


• You have asthma or other breathing problems


• You are dependent on alcohol


• You have recently suffered a head injury


• You have raised pressure in the brain (raised intracranial pressure)


• You have heart failure due to lung problems

Do not have Fortral if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before this medicine is given to you.

Take special care and check with your doctor before having Fortral if:

• You have a tumour near your kidney (phaeochromocytoma)


• You have recently had a heart attack


• You have liver, kidney, pancreas or gall bladder problems


• You have epilepsy or have ever had fits or seizures


• You have porphyria. This medicine may cause an attack


• You have bowel problems such as inflammation or blockages


• You have prostate problems


• You have an under-active thyroid or adrenal gland


• You have stomach pains that are unexplained


• You are or have ever been dependent on a drug


• You smoke tobacco. This may make Fortral work less well

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before this medicine is given to you.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines obtained without a prescription, including herbal medicines. This is because Fortral can affect the way some other medicines work. Also, some other medicines can affect the way Fortral works.

Tell your doctor if you are taking any of the following medicines:

• Medicines to treat depression called MAOIs (monoamine oxidase inhibitors). Also tell your doctor if you have taken them in the last 2 weeks. MAOIs are medicines such as moclobemide, phenelzine and tranylcypramine


• Medicines which make you drowsy or sleepy (CNS depressants), including alcohol and other strong pain killers


• Tricyclic antidepressants – used to treat depression


• Morphine or diamorphine (opioids) – used to treat pain


• Doxapram – used to help breathing


• Naloxone – used to treat a drug overdose


• Chlorpromazine or trifluoperazine (phenothiazines) – used to treat mental illness

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before this medicine is given to you.

Having Fortral with food and drink

Do not drink alcohol while you are being treated with this medicine.

This is because alcohol can change the way Fortral works and can make some side effects of Fortral worse.

Pregnancy and breast-feeding

Talk to your doctor before having this medicine if:

• You are pregnant, think you may be pregnant or plan to get pregnant. This is because taking Fortral during pregnancy may cause your baby to have breathing problems or be dependent on Fortral when it is first born. If you take Fortral while you are in the late stages of pregnancy your baby will need special monitoring when born


• You are breast-feeding or planning to breast-feed

Driving and using machines

You may feel dizzy, sleepy or have a change in behaviour (euphoria) after having this medicine. If this happens, do not drive or use any tools or machines.

Important information about some of the ingredients of Fortral

• 
  Sodium: Fortral contains 1.1mg of sodium in each 30mg dose. This is a very small amount so this medicine is classed as ‘sodium free’

How Fortral Is Given

Fortral will be given to you by a doctor or nurse. The injection will be given either under the skin (subcutaneous), into a muscle (intramuscular) or into the blood (intravenous).

How much Fortral is given

Adults and children aged 12 years and over

• The usual starting dose of Fortral is 30mg to 60mg


• Injections may be repeated every 3 to 4 hours


• You should not be given more than 360mg in 24 hours

Children over 1 year and under 12 years of age

• Your child’s doctor will work out the dose for your child. The dose will depend on their weight and how the injection is given

Children under 1 year of age

• Fortral should not be given to children under 1 year of age

Elderly and people with liver or kidney problems

• Your doctor may give you a lower dose

If you have more Fortral than you should

• It is unlikely that your doctor or nurse will give you too much medicine. Your doctor or nurse will monitor your progress and check how much medicine you are given. Always ask if you are not sure why you are being given a medicine


• Having too much Fortral may make you feel drowsy or dizzy with an increased or rapid heartbeat. You may also feel very cold and restless, with writhing movements, stiffness or shaking


• If you think you have had too much Fortral, or you start getting any of
  these symptoms tell your doctor or nurse straight away.
  
  If you are away from the hospital, speak to your doctor or nurse straight away or go to the nearest casualty department
  

Changing or stopping treatment

Chronic usage of Fortral may lead to tolerance and dependence.

If you have had regular daily doses of Fortral for a long time, your doctor will not suddenly increase your dose or stop your treatment.

Possible Side Effects

As with all medicines, Fortral can cause side effects, although not everybody gets them.

The following side effects can happen with this medicine:

Stop taking Fortral and see a doctor or go to a hospital straight away if:

• You get swelling of the hands, feet, ankles, face, lips or throat which may cause difficulty in swallowing or breathing. You could also notice an itchy, lumpy rash (hives) or nettle rash (urticaria).
  
  This may mean you are having an allergic reaction to Fortral
  

• You have a severe rash, with blistering of the skin. Layers of the skin may peel off. You may also feel generally unwell, have a fever, chills and aching muscles. This may mean you are suffering from toxic epidermal necrolysis

Tell your doctor or pharmacist if any of the following side effects gets serious or lasts longer than a few days:

• Feeling tired, drowsy, dizzy or light-headed


• Sweating more than usual


• Pain, hardening, thickening or swelling of the skin where the injection was given


• Aching limbs where the injection was given


• Stomach pain, feeling sick (nausea), being sick (vomiting) or dry mouth


• Constipation


• A fast or slow heartbeat


• Headache


• Changes in mood such as feeling unusually happy


• Seeing or hearing things that aren’t there (hallucinations)


• Nightmares, problems sleeping or numbness and tingling (pins and needles)


• Feeling lost or confused


• Fits (seizures), muscle tremors or fainting


• Blurred vision or very small pupils


• Severe headache which could be due to raised pressure in the brain


• Problems passing urine


• Breathing problems such as breathlessness or wheezing


• You get infections more easily than usual. This could be because of a blood problem

If any of the side effects gets serious, lasts longer than a few days or you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Tell your doctor as soon as possible if you think you may have become dependent on Fortral

Having Fortral injections regularly for a long time can make you become dependent on them. This may mean that you feel as if you need to have Fortral more often or at a higher dose to get the same level of pain relief.

Being dependent on Fortral can cause the following effects if treatment is suddenly stopped.:

• Feeling sick (nausea), being sick (vomiting), feeling nervous, restless, dizzy, feverish, having stomach pains, a runny nose, a fever, chills or weeping eyes

If you are pregnant see section 2 ‘Pregnancy and breast-feeding’. This is because taking this medicine while you are pregnant could cause your baby to become dependent on Fortral.

How Fortral Is Stored

The doctor and hospital pharmacist are usually responsible for storing, using and disposing of Fortral correctly.

Keep this medicine in a safe place out of the reach and sight of children.

Do not use this medicine after the expiry date shown on the pack.

Store your medicine in the original packaging in order to protect from moisture.

Store this medicine in a dark place to protect from light.

The doctor, nurse or pharmacist will usually be responsible for disposing of any unwanted Fortral. If you have any unwanted medicine, please return it to a pharmacist. Do not dispose of medicines, which are no longer needed, by flushing down a toilet or sink or by throwing out with your normal household rubbish. This will help protect the environment.

Further Information

What Fortral Injection 30mg/ml contains

• The active substance of Fortral Injection 30mg/ml is pentazocine. Each 1ml ampoule contains 30mg pentazocine as a solution of pentazocine lactate. Each 2ml ampoule contains 60mg pentazocine as a solution of pentazocine lactate


• The other ingredients are sodium chloride, lactic acid and water for injections

What Fortral Injection 30mg/ml looks like and contents of pack

Fortral Injection 30mg/ml is a solution for injection. The solution comes in 1ml or 2ml ampoules. Boxes of Fortal contain 2 or 10 ampoules.

The Marketing Authorisation Holder is

Winthrop Pharmaceuticals

PO Box 611

Guildford

Surrey

GU1 4YS

The Manufacturer is

Sanofi Winthrop Industrie

1, Rue de la Vierge

33440 Ambares

France

This leaflet was last updated in August 2008

Winthrop is a registered trademark.

©2008 Winthrop Pharmaceuticals.

Westcort

Generic Name: hydrocortisone topical (hye droe KOR ti sone)

Brand Names: Ala-Cort, Ala-Scalp HP, Aquanil HC, Beta HC, Caldecort, Cortaid, Cortaid Intensive Therapy, Cortaid Maximum Strength, Cortaid with Aloe, Cortalo with Aloe, Corticaine, Cortizone for Kids, Cortizone-10, Cortizone-10 Intensive Healing Formula, Cortizone-10 Plus, Cortizone-5, Dermarest Dricort, Dermarest Eczema Medicated, Dermarest Plus Anti-Itch, Dermtex HC, Genasone/Aloe, Gly-Cort, Gynecort Maximum Strength, Hycort, Hydrocortisone 1% In Absorbase, Hydrocortisone with Aloe, Hydrocortisone-Aloe, Hytone, Instacort, Itch-X Lotion, Locoid, Locoid Lipocream, Locoid Lotion, Massengill Medicated Soft Cloth, MD Hydrocortisone, Neutrogena T-Scalp, NuCort with Aloe, NuZon, Pandel, Recort Plus, Rederm, Sarnol-HC, Scalacort, Texacort, U-Cort, Westcort

What is Westcort (hydrocortisone topical)?

Hydrocortisone is a topical steroid. It reduces the actions of chemicals in the body that cause inflammation, redness, and swelling.

Hydrocortisone topical is used to treat inflammation of the skin caused by a number of conditions such as allergic reactions, eczema, or psoriasis.

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

What is the most important information I should know about Westcort (hydrocortisone topical)?

There are many brands and forms of hydrocortisone topical available and not all brands are listed on this leaflet.

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

Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to. If you are treating the diaper area of a baby, do not use plastic pants or tight-fitting diapers. Covering the skin that is treated with hydrocortisone topical can increase the amount of the drug your skin absorbs, which may lead to unwanted side effects. Follow your doctor's instructions.

Avoid using this medication on your face, near your eyes, or on body areas where you have skin folds or thin skin.

Do not use this medication on a child without a doctor's advice. Children are more sensitive to the effects of hydrocortisone topical.

Hydrocortisone topical will not treat a bacterial, fungal, or viral skin infection.

Contact your doctor if your condition does not improve or if it gets worse after using this medication for several days.

What should I discuss with my healthcare provider before using Westcort (hydrocortisone topical)?

Do not use this medication if you are allergic to hydrocortisone.

Hydrocortisone topical will not treat a bacterial, fungal, or viral skin infection.

FDA pregnancy category C. It is not known whether hydrocortisone topical is harmful to an unborn baby. Before using this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether hydrocortisone topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Do not use this medication on a child without a doctor's advice. Children are more sensitive to the effects of hydrocortisone topical.

How should I use Westcort (hydrocortisone topical)?

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

Hydrocortisone topical will not treat a bacterial, fungal, or viral skin infection.

Wash your hands before and after each application, unless you are using hydrocortisone topical to treat a hand condition.

Apply a small amount to the affected area and rub it gently into the skin.

Avoid using this medication on your face, near your eyes or mouth, or on body areas where you have skin folds or thin skin.

Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to. If you are treating the diaper area of a baby, do not use plastic pants or tight-fitting diapers. Covering the skin that is treated with hydrocortisone topical can increase the amount of the drug your skin absorbs, which may lead to unwanted side effects. Follow your doctor's instructions. Contact your doctor if your condition does not improve or if it gets worse after using this medication for several days. It is important to use hydrocortisone topical regularly to get the most benefit. Store hydrocortisone topical at room temperature away from moisture and heat.

What happens if I miss a dose?

Use the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine, or if anyone has accidentally swallowed it. An overdose of hydrocortisone topical applied to the skin is not expected to produce life-threatening symptoms.

What should I avoid while using Westcort (hydrocortisone topical)?

Avoid getting this medication in your eyes, mouth, and nose, or on your lips. If it does get into any of these areas, wash with water. Do not use hydrocortisone topical on sunburned, windburned, irritated, or broken skin. Also avoid using this medication in open wounds.

Avoid using skin products that can cause irritation, such as harsh soaps or shampoos or skin cleansers, hair coloring or permanent chemicals, hair removers or waxes, or skin products with alcohol, spices, astringents, or lime. Do not use other medicated skin products unless your doctor has told you to.

Westcort (hydrocortisone 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 hydrocortisone topical and call your doctor at once if you have any of these serious side effects:

• 
  

  blurred vision, or seeing halos around lights;

  
  


• 
  

  uneven heartbeats;

  
  


• 
  

  sleep problems (insomnia);

  
  


• 
  

  weight gain, puffiness in your face; or

  
  


• 
  

  feeling tired.

  
  

Less serious side effects may include:

• 
  

  skin redness, burning, itching, or peeling;

  
  


• 
  

  thinning of your skin;

  
  


• 
  

  blistering skin; or

  
  


• 
  

  stretch marks.

  
  

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 Westcort (hydrocortisone topical)?

It is not likely that other drugs you take orally or inject will have an effect on topically applied hydrocortisone. 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 Westcort resources

• Westcort Side Effects (in more detail)
• Westcort Use in Pregnancy & Breastfeeding
• Westcort Drug Interactions
• Westcort Support Group
• 1 Review for Westcort - Add your own review/rating

• Westcort Prescribing Information (FDA)


• Westcort Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• Westcort Topical application Advanced Consumer (Micromedex) - Includes Dosage Information


• Anusol-HC Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• Carmol HC MedFacts Consumer Leaflet (Wolters Kluwer)


• Carmol HC Prescribing Information (FDA)


• Cortizone-10 Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• Hydrocortisone Acetate Monograph (AHFS DI)


• Hydrocortisone with Aloe Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• Hytone Prescribing Information (FDA)


• Instacort Gel MedFacts Consumer Leaflet (Wolters Kluwer)


• Locoid Lipocream Prescribing Information (FDA)


• Locoid Lotion Prescribing Information (FDA)


• Nutracort Lotion MedFacts Consumer Leaflet (Wolters Kluwer)


• Pandel Prescribing Information (FDA)


• Pediaderm HC Lotion MedFacts Consumer Leaflet (Wolters Kluwer)


• ProctoCream-HC Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• Proctocort Prescribing Information (FDA)


• Texacort Prescribing Information (FDA)


• U-cort Prescribing Information (FDA)

Compare Westcort with other medications

• Anal Itching
• Aphthous Stomatitis, Recurrent
• Atopic Dermatitis
• Dermatitis
• Eczema
• Gingivitis
• Proctitis
• Pruritus
• Psoriasis
• Seborrheic Dermatitis
• Skin Rash
• Ulcerative Colitis, Active

Where can I get more information?

• Your pharmacist can provide more information about hydrocortisone topical.

See also: Westcort side effects (in more detail)

Bonilux XL Prolonged-release capsules

1. Name Of The Medicinal Product

Bonilux XL 75 mg Prolonged-release Capsules

Bonilux XL 150 mg Prolonged-release Capsules

2. Qualitative And Quantitative Composition

Bonilux XL 75 mg Prolonged-release Capsules:

Each prolonged release capsule, hard contains 75 mg venlafaxine (as venlafaxine hydrochloride).

Bonilux XL 150 mg Prolonged-release Capsules:

Each prolonged release capsule, hard contains 150 mg venlafaxine (as venlafaxine hydrochloride).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged release capsule, hard.

Bonilux XL 75 mg Prolonged-release Capsules are light pink coloured hard gelatin capsule containing white to off white pellets.

Bonilux XL 150 mg Prolonged-release Capsules are brown-red coloured hard gelatin capsule containing white to off white pellets.

4. Clinical Particulars

4.1 Therapeutic Indications

- Treatment of major depressive episodes.

- For prevention of recurrence of major depressive episodes.

- Treatment of social anxiety disorder.

4.2 Posology And Method Of Administration

Major depressive episodes

The recommended starting dose for prolonged-release venlafaxine is 75 mg given once daily. Patients not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 375 mg/day. Dosage increases can be made at intervals of 2 weeks or more. If clinically warranted due to symptom severity, dose increases can be made at more frequent intervals, but not less than 4 days.

Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation (see section 4.4). The lowest effective dose should be maintained.

Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly on a case-by-case basis. Longer-term treatment may also be appropriate for prevention of recurrence of major depressive episodes (MDE). In most of the cases, the recommended dose in prevention of recurrence of MDE is the same as the one used during the current episode.

Antidepressive medicinal products should continue for at least six months following remission.

Social anxiety disorder

The recommended dose for prolonged-release venlafaxine is 75 mg given once daily. There is no evidence that higher doses confer any additional benefit.

However, in individual patients not responding to the initial 75 mg/day, increases up to a maximum dose of 225 mg/day may be considered. Dosage increases can be made at intervals of 2 weeks or more.

Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation (see section 4.4). The lowest effective dose should be maintained.

Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly, on a case-by-case basis.

Use in elderly patients

No specific dose adjustments of venlafaxine are considered necessary based on patient age alone. However, caution should be exercised in treating the elderly (e.g., due to the possibility of renal impairment, the potential for changes in neurotransmitter sensitivity and affinity occurring with aging). The lowest effective dose should always be used, and patients should be carefully monitored when an increase in the dose is required.

Use in children and adolescents under the age of 18 years

Venlafaxine is not recommended for use in children and adolescents.

Controlled clinical studies in children and adolescents with major depressive disorder failed to demonstrate efficacy and do not support the use of venlafaxine in these patients (see sections 4.4 and 4.8).

The efficacy and safety of venlafaxine for other indications in children and adolescents under the age of 18 have not been established.

Use in patients with hepatic impairment

In patients with mild and moderate hepatic impairment, in general a 50% dose reduction should be considered. However, due to inter-individual variability in clearance, individualisation of dosage may be desirable.

There are limited data in patients with severe hepatic impairment. Caution is advised, and a dose reduction by more than 50% should be considered. The potential benefit should be weighed against the risk in the treatment of patients with severe hepatic impairment.

Use in patients with renal impairment

Although no change in dosage is necessary for patients with glomerular filtration rate (GFR) between 30-70 ml/minute, caution is advised. For patients that require haemodialysis and in patients with severe renal impairment (GFR < 30 ml/min), the dose should be reduced by 50%. Because of inter-individual variability in clearance in these patients, individualisation of dosage may be desirable.

Withdrawal symptoms seen on discontinuation of venlafaxine

Abrupt discontinuation should be avoided. When stopping treatment with venlafaxine, the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

For oral use.

It is recommended that venlafaxine prolonged-release capsules be taken with food, at approximately the same time each day. Capsules must be swallowed whole with fluid and not divided, crushed, chewed, or dissolved.

Patients treated with venlafaxine immediate-release tablets may be switched to venlafaxine prolonged-release capsules at the nearest equivalent daily dosage. For example, venlafaxine immediate-release tablets 37.5 mg twice daily may be switched to venlafaxine prolonged-release capsules 75 mg once daily. Individual dosage adjustments may be necessary.

Venlafaxine prolonged-release capsules contain spheroids, which release the active substance slowly into the digestive tract. The insoluble portion of these spheroids is eliminated and may be seen in faeces.

4.3 Contraindications

Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms such as agitation, tremor and hyperthermia. Venlafaxine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI.

Venlafaxine must be discontinued for at least 7 days before starting treatment with an irreversible MAOI (see sections 4.4 and 4.5).

4.4 Special Warnings And Precautions For Use

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which venlafaxine is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients, and in particular those at high risk, should accompany drug therapy, especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour, and to seek medical advice immediately if these symptoms present.

Use in children and adolescents under 18 years of age

Venlafaxine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents, such as MAO-inhibitors, that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).

Narrow-angle glaucoma

Mydriasis may occur in association with venlafaxine. It is recommended that patients with raised intraocular pressure or patients at risk for acute narrow-angle glaucoma (angle-closure glaucoma) be closely monitored.

Blood pressure

Dose-related increases in blood pressure have been commonly reported with venlafaxine. In some cases, severely elevated blood pressure requiring immediate treatment has been reported in postmarketing experience. All patients should be carefully screened for high blood pressure and preexisting hypertension should be controlled before initation of treatment. Blood pressure should be reviewed periodically, after initiation of treatment and after dose increases. Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure, e.g., those with impaired cardiac function.

Heart rate

Increases in heart rate can occur, particularly with higher doses. Caution should be exercised in patients whose underlying conditions might be compromised by increases in heart rate.

Cardiac disease and risk of arrhythmia

Venlafaxine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, it should be used with caution in these patients.

In postmarketing experience, fatal cardiac arrhythmias have been reported with the use of venlafaxine, especially in overdose. The balance of risks and benefits should be considered before prescribing venlafaxine to patients at high risk of serious cardiac arrhythmia.

Convulsions

Convulsions may occur with venlafaxine therapy. As with all antidepressants, venlafaxine should be introduced with caution in patients with a history of convulsions, and concerned patients should be closely monitored. Treatment should be discontinued in any patient who develops seizures.

Hyponatraemia

Cases of hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion may occur with venlafaxine. This has most frequently been reported in volume-depleted or dehydrated patients. Elderly patients, patients taking diuretics, and patients who are otherwise volume-depleted may be at greater risk for this event.

Abnormal bleeding

Medicinal products that inhibit serotonin uptake may lead to reduced platelet function. The risk of skin and mucous membrane bleeding, including gastrointestinal haemorrhage, may be increased in patients taking venlafaxine. As with other serotonin-reuptake inhibitors, venlafaxine should be used cautiously in patients predisposed to bleeding, including patients on anticoagulants and platelet inhibitors.

Serum cholesterol

Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled clinical trials. Measurement of serum cholesterol levels should be considered during long-term treatment.

Co-administration with weight loss agents

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated for weight loss alone or in combination with other products.

Mania/hypomania

Mania/hypomania may occur in a small proportion of patients with mood disorders who have received antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be used cautiously in patients with a history or family history of bipolar disorder.

Aggression

Aggression may occur in a small number of patients who have received antidepressants, including venlafaxine. This has been reported under initiation, dose changes and discontinuation of treatment.

As with other antidepressants, venlafaxine should be used cautiously in patients with a history of aggression.

Discontinuation of treatment

Withdrawal symptoms, when treatment is discontinued, are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on treatment discontinuation (tapering and post-tapering) occurred in approximately 31% of patients treated with venlafaxine and 17% of patients taking placebo.

The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity.

They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that venlafaxine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see section 4.2).

Akathisia/psychomotor restlessness

The use of venlafaxine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Dry mouth

Dry mouth is reported in 10% of patients treated with venlafaxine. This may increase the risk of caries, and patients should be advised upon the importance of dental hygiene.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Monoamine Oxidase Inhibitors (MAOI)

Irreversible non-selective MAOIs

Venlafaxine must not be used in combination with irreversible non-selective MAOIs. Venlafaxine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible nonselective MAOI. Venlafaxine must be discontinued for at least 7 days before starting treatment with an irreversible non-selective MAOI (see sections 4.3 and 4.4).

Reversible, selective MAO-A inhibitor (moclobemide)

Due to the risk of serotonin syndrome, the combination of venlafaxine with a reversible and selective MAOI, such as moclobemide, is not recommended. Following treatment with a reversible MAO-inhibitor, a shorter withdrawal period than 14 days may be used before initiation of venlafaxine treatment. It is recommended that venlafaxine should be discontinued for at least 7 days before starting treatment with a reversible MAOI (see section 4.4).

Reversible, non-selective MAOI (linezolid)

The antibiotic linezolid is a weak reversible and non-selective MAOI and should not be given to patients treated with venlafaxine (see section 4.4).

Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI and started on venlafaxine, or have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, lithium, sibutramine, tramadol, or St. John's Wort [Hypericum perforatum]), with medicinal agents which impair metabolism of serotonin (including MAOIs), or with serotonin precursors (such as tryptophan supplements).

If concomitant treatment of venlafaxine with an SSRI, an SNRI or a serotonin receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see section 4.4).

CNS-active substances

The risk of using venlafaxine in combination with other CNS-active substances has not been systematically evaluated. Consequently, caution is advised when venlafaxine is taken in combination with other CNS-active substances.

Ethanol

Venlafaxine has been shown not to increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active substances, patients should be advised to avoid alcohol consumption.

Effect of other medicinal products on venlafaxine

Ketoconazole (CYP3A4 inhibitor)

A pharmacokinetic study with ketoconazole in CYP2D6 extensive (EM) and poor metabolisers (PM) resulted in higher AUC of venlafaxine (70% and 21% in CYP2D6 PM and EM subjects, respectively) and O-desmethylvenlafaxine (33% and 23% in CYP2D6 PM and EM subjects, respectively) following administration of ketoconazole. Concomitant use of CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin) and venlafaxine may increase levels of venlafaxine and O-desmethylvenlafaxine. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.

Effect of venlafaxine on other medicinal products

Lithium

Serotonin syndrome may occur with the concomitant use of venlafaxine and lithium (see Serotonin syndrome).

Diazepam

Venlafaxine has no effects on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam. Diazepam does not appear to affect the pharmacokinetics of either venlafaxine or O-desmethylvenlafaxine. It is unknown whether a pharmacokinetic and/or pharmacodynamic interaction with other benzodiazepines exists.

Imipramine

Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. There was a dose-dependent increase of 2-OH-desipramine AUC by 2.5 to 4.5-fold when venlafaxine 75 mg to 150 mg daily was administered. Imipramine did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown. Caution should be exercised with co-administration of venlafaxine and imipramine.

Haloperidol

A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral clearance, a 70% increase in AUC, an 88% increase in C_max, but no change in half-life for haloperidol. This should be taken into account in patients treated with haloperidol and venlafaxine concomitantly. The clinical significance of this interaction is unknown.

Risperidone

Venlafaxine increased the risperidone AUC by 50%, but did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.

Metoprolol

Concomitant administration of venlafaxine and metoprolol to healthy volunteers in a pharmacokinetic interaction study for both medicinal products resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. The clinical relevance of this finding in hypertensive patients is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Caution should be exercised with co-administration of venlafaxine and metoprolol.

Indinavir

A pharmacokinetic study with indinavir has shown a 28% decrease in AUC and a 36% decrease in C_max for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of venlafaxine in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Venlafaxine must only be administered to pregnant women if the expected benefits outweigh any possible risk.

As with other serotonin reuptake inhibitors (SSRIs/SNRIs), discontinuation symptoms may occur in the newborns if venlafaxine is used until or shortly before birth. Some newborns exposed to venlafaxine late in the third trimester have developed complications requiring tube-feeding, respiratory support or prolonged hospitalisation. Such complications can arise immediately upon delivery.

The following symptoms may be observed in neonates if the mother has used an SSRI/SNRI late in pregnancy: irritability, tremor, hypotonia, persistent crying, and difficulty in sucking or in sleeping.

These symptoms may be due to either serotonergic effects or exposure symptoms. In the majority of cases, these complications are observed immediately or within 24 hours after partus.

Lactation

Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are excreted in breast milk. A risk to the suckling child cannot be excluded. Therefore, a decision to continue/discontinue breast-feeding or to continue/discontinue therapy with venlafaxine should be made, taking into account the benefit of breast-feeding to the child and the benefit of venlafaxine therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

Any psychoactive medicinal product may impair judgment, thinking, and motor skills. Therefore, any patient receiving venlafaxine should be cautioned about their ability to drive or operate hazardous machinery.

4.8 Undesirable Effects

Adverse reactions are listed below by system organ class and frequency.

Frequencies are defined as: very common (

Body System	Very Common	Common	Uncommon	Rare	Not Known
Haematological/ Lymphatic			Ecchymosis, Gastrointestinal haemorrhage		Mucous membrane bleeding, Prolonged bleeding time, Thrombocytopaenia, Blood dyscrasias, (including agranulocytosis, aplastic anaemia, neutropaenia and pancytopaenia)
Metabolic/Nutritional		Serum cholesterol increased, Weight loss	Weight gain		Abnormal liver function tests, Hyponatraemia, Hepatitis, Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), Prolactin increased
Nervous	Dry mouth (10.0%), Headache (30.3%)*	Abnormal dreams, Decreased libido, Dizziness, Increased muscle tonus (hypertonia), Insomnia, Nervousness, Paresthesia, Sedation, Tremor, Confusion, Depersonalisation	Apathy, Hallucinations, Myoclonus, Agitation, Impaired coordination and balance	Akathisia/Psychomotor restlessness, Convulsion, Manic reaction	Neuroleptic Malignant Syndrome (NMS), Serotonergic syndrome, Delirium, Extrapyramidal reactions (including dystonia and dyskinaesia), Tardive dyskinaesia, Suicidal ideation and behaviours**
Special Senses		Abnormality of accommodation, Mydriasis, Visual disturbance	Altered taste sensation, Tinnitus		Angle-closure glaucoma
Cardiovascular		Hypertension, Vasodilatation (mostly hot flashes/flushes), Palpitations	Postural hypotension, Syncope, Tachycardia		Hypotension, QT prolongation, Ventricular fibrillation, Ventricular tachycardia (including torsade de pointes)
Respiratory		Yawning			Pulmonary eosinophilia
Digestive	Nausea (20.0%)	Appetite decreased (anorexia), Constipation, Vomiting	Bruxism, Diarrhoea		Pancreatitis
Skin	Sweating (including night sweats) [12.2%]		Rash, Alopecia		Erythema multiforme, Toxic epidermal necrolysis, Stevens-Johnson syndrome, Pruritus, Urticaria
Musculoskeletal					Rhabdomyolysis
Urogenital		Abnormal ejaculation / orgasm (males), Anorgasmia, Erectile dysfunction (impotence), Urination impaired (mostly hesitancy), Menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g., menorrhagia, metrorrhagia), Pollakiuria	Abnormal orgasm (females), Urinary retention
Body as a Whole		Asthenia (fatigue), Chills	Photosensitivity reaction		Anaphylaxis

* In pooled clinical trials, the incidence of headache was 30.3% with venlafaxine versus 31.3% with placebo.

** Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy or early after treatment discontinuation (see section 4.4).

Discontinuation of venlafaxine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraethesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, headache and flu syndrome are the most commonly reported reactions. Generally, these events are mild to moderate and are self-limiting; however, in some patients, they may be severe and/or prolonged. It is therefore advised that when venlafaxine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

Paediatric patients

In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical trials) in children and adolescents (ages 6 to 17) was similar to that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed (see section 4.4).

In paediatric clinical trials the adverse reaction suicidal ideation was observed. There were also increased reports of hostility and, especially in major depressive disorder, self-harm.

Particularly, the following adverse reactions were observed in paediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

4.9 Overdose

In postmarketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and/or other medicinal products. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Other reported events include electrocardiographic changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, vertigo, and death.

Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxinetreated patients have a higher burden of suicide risk factors than SSRI patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristics of venlafaxine-treated patients, is not clear.

Prescriptions for venlafaxine should be written for the smallest quantity of the medicinal product consistent with good patient management in order to reduce the risk of overdose.

Recommended treatment

General supportive and symptomatic measures are recommended; cardiac rhythm and vital signs must be monitored. When there is a risk of aspiration, induction of emesis is not recommended. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Administration of activated charcoal may also limit absorption of the active substance. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antidepressants.

ATC Code: N06A X16

The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are inhibitors of serotonin and noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine uptake. Venlafaxine and its active metabolite reduce β-adrenergic responsiveness after both acute (single dose) and chronic administration. Venlafaxine and ODV are very similar with respect to their overall action on neurotransmitter reuptake and receptor binding.

Venlafaxine has virtually no affinity for rat brain muscarinic, cholinergic, H1-histaminergic or α1-adrenergic receptors in vitro. Pharmacological activity at these receptors may be related to various side effects seen with other antidepressant medicinal products, such as anticholinergic, sedative and cardiovascular side effects.

Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity.

In vitro studies revealed that venlafaxine has virtually no affinity for opiate or benzodiazepine sensitive receptors.

Major depressive episodes

The efficacy of venlafaxine immediate-release as a treatment for major depressive episodes was demonstrated in five randomised, double-blind, placebo-controlled, short-term trials ranging from 4 to 6 weeks duration, for doses up to 375 mg/day. The efficacy of venlafaxine prolonged-release as a treatment for major depressive episodes was established in two placebo-controlled, short-term studies for 8 and 12 weeks duration, which included a dose range of 75 to 225 mg/day.

In one longer-term study, adult outpatients who had responded during an 8-week open trial on venlafaxine prolonged-release (75, 150, or 225 mg) were randomised to continuation of their same venlafaxine prolonged-release dose or to placebo, for up to 26 weeks of observation for relapse.

In a second longer-term study, the efficacy of venlafaxine in prevention of recurrent depressive episodes for a 12-month period was established in a placebo-controlled double-blind clinical trial in adult outpatients with recurrent major depressive episodes who had responded to venlafaxine treatment (100 to 200 mg/day, on a b.i.d. schedule) on the last episode of depression.

Social anxiety disorder

The efficacy of venlafaxine prolonged-release capsules as a treatment for social anxiety disorder was established in four double-blind, parallel-group, 12-week, multi-center, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study in adult outpatients. Patients received doses in a range of 75 to 225 mg/day. There was no evidence for any greater effectiveness of the 150 to 225 mg/day group compared to the 75 mg/day group in the 6-month study.

5.2 Pharmacokinetic Properties

Venlafaxine is extensively metabolised, primarily to the active metabolite, O-desmethylvenlafaxine (ODV). Mean ± SD plasma half-lives of venlafaxine and ODV are 5±2 hours and 11±2 hours, respectively. Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibit linear kinetics over the dose range of 75 mg to 450 mg/day.

Absorption

At least 92% of venlafaxine is absorbed following single oral doses of immediate-release venlafaxine.

Absolute bioavailability is 40% to 45% due to presystemic metabolism. After immediate-release venlafaxine administration, the peak plasma concentrations of venlafaxine and ODV occur in 2 and 3 hours, respectively. Following the administration of venlafaxine prolonged-release capsules, peak plasma concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours, respectively. When equal daily doses of venlafaxine are administered as either an immediate-release tablet or prolonged-release capsule, the prolonged-release capsule provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Food does not affect the bioavailability of venlafaxine and ODV.

Distribution

Venlafaxine and ODV are minimally bound at therapeutic concentrations to human plasma proteins (27% and 30%, respectively). The volume of distribution for venlafaxine at steady-state is 4.4±1.6 L/kg following intravenous administration.

Metabolism

Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies indicate that venlafaxine is biotransformed to its major active metabolite, ODV, by CYP2D6. In vitro and in vivo studies indicate that venlafaxine is metabolised to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. In vitro and in vivo studies indicate that venlafaxine is a weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9, or CYP3A4.

Elimination

Venlafaxine and its metabolites are excreted primarily through the kidneys. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Mean ± SD plasma steady-state clearances of venlafaxine and ODV are 1.3±0.6 L/h/kg and 0.4±0.2 L/h/kg, respectively.

Special populations

Age and gender

Subject age and gender do not significantly affect the pharmacokinetics of venlafaxine and ODV.

CYP2D6 extensive/poor metabolisers

Plasma concentrations of venlafaxine are higher in CYP2D6 poor metabolisers than extensive metabolisers. Because the total exposure (AUC) of venlafaxine and ODV is similar in poor and extensive metabolisers, there is no need for different venlafaxine dosing regimens for these two groups.

Patients with hepatic impairment

In Child-Pugh A (mildly hepatically impaired) and Child-Pugh B (moderately hepatically impaired) subjects, venlafaxine and ODV half-lives were prolonged compared to normal subjects. The oral clearance of both venlafaxine and ODV was reduced. A large degree of intersubject variability was noted. There are limited data in patients with severe hepatic impairment (see section 4.2).

Patients with renal impairment

In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance reduced by about 57% compared to normal subjects, while ODV elimination half-life was prolonged by about 142% and clearance reduced by about 56%. Dosage adjustment is necessary in patients with severe renal impairment and in patients that require haemodialysis (see section 4.2).

5.3 Preclinical Safety Data

Studies with venlafaxine in rats and mice revealed no evidence of carcinogenesis. Venlafaxine was not mutagenic in a wide range of in vitro and in vivo tests.

Animal studies regarding reproductive toxicity have found in rats a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation. The cause of these deaths is unknown. These effects occurred at 30 mg/kg/day, 4 times the human daily dose of 375 mg of venlafaxine (on an mg/kg basis). The no-effect dose for these findings was 1.3 times the human dose. The potential risk for humans is unknown.

Reduced fertility was observed in a study in which both male and female rats were exposed to ODV. This exposure was approximately 1 to 2 times that of a human venlafaxine dose of 375 mg/day. The human relevance of this finding is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule contents:

Pellet cores:

Microcrystalline cellulose,

Hypromellose

Pellet coating:

Cetostearyl alcohol,

Ethyl acrylate - methyl methacrylate copolymer,

Nonoxynol,

Macrogol,

Talc

Capsule shell:

Gelatin,

Red iron oxide (E172),

Yellow iron oxide (E172),

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

30 months.

After opening the bottle: 2 months