FAMVIR 750 mg Tablets (Novartis Pharmaceuticals UK Ltd)

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1. Name Of The Medicinal Product

FAMVIR® 750 mg Tablets

2. Qualitative And Quantitative Composition

Famciclovir 750 mg

3. Pharmaceutical Form

White, oval, film-coated 'Tiltab' tablets containing 750 mg famciclovir for oral administration.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of herpes zoster (shingles) infections.

4.2 Posology And Method Of Administration

Dosage:

Adults:

Herpes Zoster Infections

One 750 mg tablet once daily for seven days. The tablet should be taken at approximately the same time each day. Treatment should be initiated as early as possible in the course of the disease, promptly after diagnosis.

Elderly:

Dosage modification is not required unless renal function is impaired.

Renally Impaired:

As reduced clearance of penciclovir is related to reduced renal function, special attention should be given to dosage in patients with impaired renal function. The following modifications are recommended:

For the treatment of herpes zoster infections:

Creatinine clearance (ml/min/1.73m2 )

Dosage

30-59

250 mg twice daily

10-29

250 mg once daily

When only serum creatinine is available a nomogram or the following formula (Cockcroft and Gault) should be used to estimate creatinine clearance.

Creatinine clearance (ml/min/1.73m2) =

Renally impaired patients on haemodialysis:

For a patient on haemodialysis, a dosage interval of 48 hours is recommended for periods between dialysis. Since four hours' haemodialysis results in approximately 75% reduction in plasma concentrations of penciclovir, the full dose of famciclovir should be administered immediately following dialysis.

Hepatically Impaired:

Dosage modification is not required for patients with well compensated chronic liver disease. There is no information on patients with overtly decompensated chronic liver disease; accordingly no precise dose recommendations can be made for this group of patients.

Children:

There are currently insufficient data on the safety and efficacy of FAMVIR in children and therefore its use in children is not recommended.

Administration:

Oral.

4.3 Contraindications

FAMVIR is contraindicated in patients with known hypersensitivity to famciclovir or other constituents of FAMVIR . It is also contraindicated in those patients who have shown hypersensitivity to penciclovir.

4.4 Special Warnings And Precautions For Use

Special attention should be paid to patients with impaired renal function as dosage adjustment may be necessary. (see sections 4.2 and 4.9) No special precautions are required for hepatically impaired or elderly patients.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant pharmacokinetic interactions have been identified. Probenecid and other drugs that affect renal physiology could affect plasma levels of penciclovir.

4.6 Pregnancy And Lactation

Although animal studies have not shown any embryotoxic or teratogenic effects with famciclovir or penciclovir, the safety of FAMVIR in human pregnancy has not been established. FAMVIR should, therefore , not be used during pregnancy or in nursing mothers unless the potential benefits of treatment outweigh any possible risk.

Studies in rats show that penciclovir is excreted in the breast milk of lactating females given oral famciclovir. There is no information on excretion in human milk.

4.7 Effects On Ability To Drive And Use Machines

There is no evidence that famciclovir (FAMVIR) will affect the ability of a patient to drive or to use machines.

4.8 Undesirable Effects

Famciclovir has been well tolerated in human studies. Headache and nausea have been reported in clinical trials. These were generally mild or moderate in nature and occurred at a similar incidence in patients receiving placebo treatment.

In post-marketing experience, in addition to the above, vomiting, dizziness and skin rash, and confusion which was predominantly in the elderly, have been reported rarely. Hallucinations have been reported very rarely.

4.9 Overdose

Overdose experience with famciclovir is limited. A report of accidental acute overdosage (10.5g) was asymptomatic. In a report of chronic use (10g/day for two years), famciclovir was well tolerated . In the event of an overdose supportive and symptomatic therapy should be given as appropriate.

Acute renal failure has been reported rarely in patients with underlying renal disease where the FAMVIR dosage has not been appropriately reduced for the level of renal function.

Penciclovir is dialysable and plasma concentrations are reduced by approximately 75% following four hours' haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Famciclovir is the oral form of penciclovir. Famciclovir is rapidly converted in vivo into penciclovir, which has in vivo and in vitro activity against human herpes viruses including Varicella zoster virus and Herpes simplex types 1 and 2.

The antiviral effect of orally administered famciclovir has been demonstrated in several animal models, this effect is due to in vivo conversion to penciclovir. In virus-infected cells penciclovir is rapidly and efficiently converted into the triphosphate (mediated via virus-induced thymidine kinase).

Penciclovir triphosphate persists in infected cells for more than 12 hours where it inhibits replication of viral DNA and has a half-life of nine, 10 and 20 hours in cells infected with Varicella zoster, Herpes simplex virus type 1 and herpes simplex virus type 2 respectively. In uninfected cells treated with penciclovir, concentrations of penciclovir-triphosphate are only barely detectable. Accordingly, uninfected cells are unlikely to be affected by therapeutic concentrations of penciclovir.

Penciclovir has been shown to be active against a recently isolated acyclovir-resistant Herpes simplex virus strain which has an altered DNA polymerase.

5.2 Pharmacokinetic Properties

General characteristics

Following oral administration, famciclovir is rapidly and extensively absorbed and rapidly converted to the active compound, penciclovir. Bioavailability of penciclovir after oral FAMVIR is 77%. Mean peak plasma concentration of penciclovir, following 750 mg oral dose of famciclovir, was 4.9 micrograms/ml and occurred at a median time of 50 minutes post-dose. Plasma concentration-time curves of penciclovir are similar following single and repeat (t.i.d.) dosing. The terminal plasma half-life of penciclovir after both single and repeat dosing with famciclovir is approximately 2.0 hours. There is no accumulation of penciclovir on repeated dosing with famciclovir. Penciclovir and its 6-deoxy precursor are poorly (<20%) bound to plasma proteins.

Famciclovir is eliminated principally as penciclovir and its 6-deoxy precursor which are excreted in urine unchanged. FAMVIR has not been detected in urine. Tubular secretion contributes to the renal elimination of the compound.

Characteristics in patients

Uncomplicated herpes zoster infection does not significantly alter the pharmacokinetics of penciclovir measured after oral administration of FAMVIR.

5.3 Preclinical Safety Data

Famciclovir has no significant effects on spermatogenesis or sperm morphology and motility in man. At doses greatly in excess of those used therapeutically impaired fertility was observed in male rats - no such effects being observed in female rats.

At a dose level approximately 50 times the normal therapeutic dose there was an increased incidence of mammary adenocarcinoma in female rats. No such effect was seen in male rats or mice of either sex.

Additionally famciclovir was not found to be genotoxic in a comprehensive battery of in vivo and in vitro tests designed to detect gene mutation, chromosomal damage and repairable damage to DNA. Penciclovir, in common with other drugs of this class, has been shown to cause chromosomal damage, but did not induce gene mutation in bacterial or mammalian cell systems, nor was there evidence of increased DNA repair in vitro.

The findings are not considered to have any clinical significance.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Hydroxypropyl Cellulose EP

Sodium Starch Glycollate BP

Magnesium Stearate EP

Hydroxypropyl Methyl Cellulose EP

Titanium Dioxide EP

Polyethelene Glycol NF

6.2 Incompatibilities

No specific incompatibilities.

6.3 Shelf Life

Famciclovir tablets have a shelf-life of three years.

6.4 Special Precautions For Storage

Store at or below 30°C in a dry place.

6.5 Nature And Contents Of Container

FAMVIR is supplied as a starter pack containing one tablet and as a shingles patient pack in original blister packs containing seven tablets and a patient information leaflet.

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

7. Marketing Authorisation Holder

SmithKline Beecham plc

SB House

Great West Road

Brentford

Middlesex TW8 9BD

Trading as:

SmithKline Beecham Pharmaceuticals

Mundells

Welwyn Garden City

Hertfordshire AL7 1EY

8. Marketing Authorisation Number(S)

PL 10592/0084

9. Date Of First Authorisation/Renewal Of The Authorisation

August 1996.

10. Date Of Revision Of The Text

March 2000

Legal Category:

POM

FAMVIR 750 mg Tablets Novartis Pharmaceuticals UK Ltd

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