1. Name Of The Medicinal Product
Famvir 750 mg Tablets
2. Qualitative And Quantitative Composition
Each tablet contains 750 mg famciclovir.
For excipients, see 6.1
3. Pharmaceutical Form
Film-coated tablet.
White, oval, biconvex tablets debossed with 'FAMVIR 750' or 'FV 750' on one side and plain on the reverse side.
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. Initiation of treatment is recommended as soon as possible after rash onset.
- 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 (see section 4.9). 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.
Formula to estimate creatinine clearance (ml/min/1.73 m2 ):
[140 - age in years] x weight (kg) x either 88.5 (for males) or 75.2 (for females)
72 x serum creatinine (µmol/l)
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, a dose of famciclovir (250 mg for herpes zoster patients and 125 mg for herpes simplex patients) 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 decompensated chronic liver disease; accordingly no precise dose recommendations can be made for this group of patients (see section 5.2 Pharmacokinetic properties).
- 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.
Because the systemic availability (AUC) of penciclovir was not altered when famciclovir was administered with food, it appears that famciclovir can be taken without regard to meals (see section 5.2 Pharmacokinetic properties).
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 is necessary (see sections 4.2 and 4.9). No special precautions are required for elderly patients with normal renal function and patients with well-compensated hepatic impairment.
Famciclovir has not been studied in patients with severe uncompensated hepatic impairment (see section 5.2 Pharmacokinetic properties).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Effects of other medicinal products on famciclovir
Probenecid and other drugs that affect renal physiology could affect plasma levels of penciclovir (active metabolite of famciclovir, see section 5.2 Pharmacokinetic properties).
The conversion of the inactive metabolite 6-deoxy penciclovir (formed by deacetylation of famciclovir) to penciclovir is catalysed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme and / or inhibiting this enzyme could potentially occur. Clinical interaction studies of famciclovir with cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir. However raloxifene, the most potent aldehyde oxidase inhibitor observed in vitro, could affect the formation of penciclovir.
Effects of famciclovir on other medicinal products
Although famciclovir is only a weak inhibitor of aldehyde oxidase in vitro, interactions with drugs metabolized by aldehyde oxidase could potentially occur. Evidence from preclinical studies has shown no potential for induction of cytochrome P450 enzymes and inhibition of CYP3A4.
4.6 Pregnancy And Lactation
Pregnancy
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 unless the potential benefits of treatment outweigh any possible risk.
Lactation
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. Famciclovir should not be used in nursing mothers unless the potential benefits are considered to outweigh the potential risks associated with treatment.
4.7 Effects On Ability To Drive And Use Machines
Patients who experience dizziness, somnolence, confusion or other central nervous system disturbances while taking Famvir should refrain from driving or operating machinery.
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.
The following table specifies the estimated frequency of adverse reactions based on all the spontaneous reports and literature cases that have been reported for Famvir since its introduction to the market.
Adverse reactions (Table 1 ) are ranked under headings of frequency, using the following convention: very common ( including isolated reports
Table 1
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4.9 Overdose
Overdose experience with famciclovir is limited. A report of accidental acute overdosage (10.5 g) was asymptomatic. In a report of chronic use (10 g/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
Pharmacotherapeutic group: Oral antiviral agent (ATC code J05A B09)
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 9, 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.
The most common form of resistance encountered with aciclovir among HSV strains is a deficiency in the production of the thymidine kinase (TK) enzyme. Such TK deficient strains would be expected to be cross-resistant to both penciclovir and aciclovir. However, penciclovir has been shown to be active in vitro against a recently isolated acyclovir-resistant herpes simplex virus strain which has an altered DNA polymerase.
Results from penciclovir and famciclovir patient studies, including studies of up to four months' treatment with famciclovir, have shown a small overall frequency of penciclovir resistant isolates: 0.3% in the 981 total isolates tested to date and 0.19% in the 529 virus isolates from immunocompromised patients. The resistant isolates were found at the start of treatment or in a placebo group, with no resistance occurring on or after treatment with famciclovir or penciclovir.
5.2 Pharmacokinetic Properties
General characteristics
Famciclovir is the oral prodrug of the antivirally active compound penciclovir.
Following oral administration, famciclovir is rapidly and extensively absorbed and rapidly converted to penciclovir. Bioavailability of penciclovir after oral administration of Famvir is 77%. Mean peak plasma concentrations of penciclovir, following 125 mg, 250 mg, 500 mg and 750mg oral doses of famciclovir, were 0.8 micrograms/ml, 1.6 micrograms/ml, 3.3 micrograms/ml and 5.1 micrograms/ml, respectively, and occurred at a median time of 45 minutes post-dose. The extent of systemic availability (AUC) of penciclovir from oral famciclovir is unaffected by food. Plasma concentration-time curves of penciclovir are similar following single and repeat (t.i.d. and b.i.d.) dosing. The terminal plasma half-life of penciclovir after both single and repeat dosing with famciclovir is approximately 2 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. Famciclovir has not been detected in urine. Tubular secretion contributes to the renal elimination of the compound.
Patients with herpes zoster infection
Uncomplicated herpes zoster infection does not significantly alter the pharmacokinetics of penciclovir measured after oral administration of Famvir. The terminal plasma half-life of penciclovir in patients with herpes zoster was 2.8h and 2.7h, respectively, after single and repeated doses of famciclovir.
Characteristics in special populations
Subjects with renal insufficiency
The apparent plasma clearance, renal clearance, and plasma elimination rate constant of penciclovir decreased linearly with reductions in renal function, both after single and repeated dosing. Dose adjustment is necessary in patients with renal insufficiency (see section 4.2 Posology and method of administration).
Subjects with hepatic insufficiency
Well-compensated chronic liver disease had no effect on the extent of systemic availability of penciclovir following oral famciclovir. However, there was a 43% decrease in penciclovir mean peak plasma concentration and the time to peak plasma concentration was increased by 0.75 h in patients with hepatic insufficiency compared to healthy subjects.
No dose adjustment is recommended for patients with well-compensated hepatic impairment (see section 4.2 Posology and method of administration and section 4.4 Special warnings and precautions for use). The pharmacokinetics of penciclovir have not been evaluated in patients with severe uncompensated hepatic impairment.
Elderly subjects
Based on cross-study comparisons the mean penciclovir AUC was about 40% higher and penciclovir renal clearance about 20 % lower after oral administration of famciclovir in elderly volunteers (65-79 years) compared to younger volunteers. Some of this difference may be due to differences in renal function between the two age groups. No dose adjustment based on age is recommended unless renal function is impaired (see section 4.2 Posology and method of administration).
Gender
Small differences in renal clearance of penciclovir between females and males have been reported and were attributed to gender differences in renal function. No dose adjustment based on gender is recommended.
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.
These findings are not considered to have any clinical significance.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet core:
Hydroxypropyl Cellulose
Sodium Starch Glycollate
Magnesium Stearate
Tablet coat:
Hydroxypropyl Methyl Cellulose
Titanium Dioxide
Polyethylene Glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Do not store above 30°C. Store in the original package.
6.5 Nature And Contents Of Container
Famvir is supplied as a starter pack containing one tablet and as a shingles patient pack in PVC/PVdC/Aluminium blister packs containing seven tablets.
6.6 Special Precautions For Disposal And Other Handling
No special instructions.
7. Marketing Authorisation Holder
Novartis Pharmaceuticals UK Ltd
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
United Kingdom
8. Marketing Authorisation Number(S)
PL 00101/0622
9. Date Of First Authorisation/Renewal Of The Authorisation
1 October 2001
10. Date Of Revision Of The Text
12 February 2009
Legal category
POM
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