Famciclovir 500mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Famciclovir 500 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Famciclovir 500 mg tablet contains 500 mg of famciclovir.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
500 mg film-coated tablets: white, oval, film-coated tablets, scored on both sides with dimensions of 18.2 x 8.6 mm approximately.
The tablet can be divided into equal halves.Use lower dosage strength tablets, where these are available.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of genital herpes infections (initial and recurrent epidoses) in immunocompetent patients.
Suppression of recurrent genital herpes infections in immunocompetent patients. Treatment of herpes zoster infections of the skin and mucous membranes in immunocompetent patients in whom a severe course of infection is anticipated,including herpes zoster ophthalmicus.
Treatment of herpes zoster and herpes simplex infections in immunocompromised patients.
4.2 Posology and method of administration
Herpes zoster in immunocompetent adults 500 mg three times daily for seven days.
Treatment should be initiated as soon as possible after a diagnosis of herpes zoster.
Herpes zoster in immunocompromised adults 500 mg three times daily for ten days.
Treatment should be initiated as soon as possible after a diagnosis of herpes zoster. Genital herpes in immunocompetent adults
First episode of genital herpes: 250 mg three times daily for five days. Initiation of treatment is recommended as soon as possible after a diagnosis of first episode of genital herpes.
Episodic treatment of recurrent genital herpes: 125 mg twice daily for five days. Initiation of
treatment is recommended as soon as possible after onset of prodromal symptoms (e.g. tingling, itching, burning, pain) or lesions.
Recurrent genital herpes in immunocompromised adults
Episodic treatment of recurrent genital herpes: 500 mg twice daily for seven days. Initiation of treatment is recommended as soon as possible after onset of prodromal symptoms (e.g. tingling, itching, burning, pain) or lesions.
Suppression of recurrent genital herpes in immunocompetent adults 250 mg twice daily. Suppressive therapy should be discontinued after a maximum of 12 months of continuous antiviral therapy to reassess recurrence frequency and severity. The minimum period of reassessment should include two recurrences. Patients who continue to have significant disease may restart suppressive therapy.
Suppression of recurrent genital herpes in immunocompromised adults 500 mg twice daily.
Patients with renal impairment
Because reduced clearance of penciclovir is related to reduced renal function, as measured by creatinine clearance, special attention should be given to doses in patients with impaired renal function. Dose recommendations for adult patients with renal impairment are provided in Table 1.
|
Indication and nominal dose regimen |
Creatinine clearance [ml/min] |
Adjusted dose regimen |
|
Herpes zoster in immunocompetent adults | ||
|
500 mg three times daily for 7 days |
>60 |
500 mg three times daily for 7 days |
|
40 to 59 |
500 mg twice daily for 7 days | |
|
20 to 39 |
500 mg once daily for 7 days | |
|
< 20 |
250 mg once daily for 7 days | |
|
Haemodialysis patients |
250 mg following each dialysis during 7 days | |
|
Herpes zoster in immunocompromis ed adults | ||
|
500 mg three times daily for 10 days |
>60 |
500 mg three times daily for 10 days |
|
40 to 59 |
500 mg twice daily for 10 days | |
|
20 to 39 |
500 mg once daily for 10 days | |
|
< 20 |
250 mg once daily for 10 days | |
|
Haemodialysis patients |
250 mg following each dialysis during 10 days | |
|
Genital herpes in immunocompetent adults - first episode of genital herpes | ||
|
250 mg three times daily for 5 days |
>40 |
250 mg three times daily for 5 days |
|
20 to 39 |
250 mg twice daily for 5 days | |
|
< 20 |
250 mg once daily for 5 days | |
|
Haemodialysis patients |
250 mg following each dialysis during 5 days | |
|
Genital herpes in immunocompetent adults - episodic treatment of recurrent genital herpes |
|
125 mg twice daily for 5 days |
> 20 |
125 mg twice daily for 5 days |
|
< 20 |
125 mg once daily for 5 days | |
|
Haemodialysis patients |
125 mg following each dialysis during 5 days | |
|
Genital herpes in immunocompromis ed adults - episodic treatment of recurrent genital herpes | ||
|
500 mg twice daily for 7 days |
>40 |
500 mg twice daily for 7 days |
|
20 to 39 |
500 mg once daily for 7 days | |
|
< 20 |
250 mg once daily for 7 days | |
|
Haemodialysis patients |
250 mg following each dialysis during 7 days | |
|
Suppression of recurrent genital herpes in immunocompetent adults | ||
|
250 mg twice daily |
>40 |
250 mg twice daily |
|
20 to 39 |
125 mg twice daily | |
|
< 20 |
125 mg once daily | |
|
Haemodialysis patients |
125 mg following each dialysis | |
|
Suppression of recurrent genital herpes in immunocompromis ed adults | ||
|
500 mg twice daily |
> 40 |
500 mg twice daily |
|
20 to 39 |
500 mg once daily | |
|
< 20 |
250 mg once daily | |
|
Haemodialysis patients |
250 mg following each dialysis |
Patients with renal impairment on haemodialysis
Since 4 h haemodialysis resulted in up to 75% reduction in plasma penciclovir concentrations, famciclovir should be administered immediately following dialysis. The recommended dose regimens for haemodialysis patients are included in Table 1.
Patients with hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment. No data are available for patients with severe hepatic impairment (see sections 4.4).
Elderly patients (>65 years)
Dose modification is not required unless renal function is impaired.
Paediatric population
The safety and efficacy of Famciclovir in children and adolescents aged less than 18 years have not been established.
Black patients
A placebo-controlled study in immunocompetent black patients with recurrent genital herpes showed no difference in efficacy between patients receiving famciclovir 1000 mg twice daily for one day and placebo. There were no unexpected or new safety findings in this trial in Black patients.
This lack of efficacy in the one-day treatment regimen cannot be extrapolated to the five-day treatment regimen for recurrent genital herpes (125 mg twice daily for five days) or other indications in Black patients.
Method of administration
Famciclovir can be taken without regard to meals.
4.3 Contraindications
Hypersensitivity to famciclovir, penciclovir or to any of the excipients.
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 with normal renal function.
Genital herpes is a sexually transmitted disease. Patients should avoid sexual intercourse when symptoms are present even if treatment with an antiviral has been initiated, in order to protect their partners.
During treatment with antiviral agents, the frequency of viral shedding is significantly reduced. However, the risk of transmission is still theoretically possible. Patients should therefore take appropriate steps for protected intercourse (i.e. use condoms).
4.5 Interaction with other medicinal products and other forms of interaction
No clinically significant interactions have been identified. Probenecid and other substances that affect renal physiology could affect the plasma levels of
penciclovir. Account must be taken of the possibility of interactions with substances eliminated by active tubular excretion such as acetylsalicylic acid, ibuprofen.
Evidence from preclinical studies has shown no potential for induction of cytochrome P450. In a Phase I study, no interactions were observed after coadministration of zidovudine and famciclovir.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is a limited amount of data (less than 300 pregnancy outcomes) from the use of famciclovir in pregnant women. Based on these limited amounts of information, the cumulative analysis of both prospective and retrospective pregnancy cases did not provide evidence indicating that the product causes any specific foetal defect or congenital anomaly. Animal studies have not shown any embryotoxic or teratogenic effects with famciclovir or penciclovir (the active metabolite of famciclovir). Famciclovir should only be used during pregnancy when the potential benefits of treatment outweigh the potential risks.
Lactation
It is unknown whether famciclovir is excreted in human breast milk. Animal studies have shown
excretion of penciclovir in breast milk. If the woman’s condition mandates treatment with famciclovir, discontinuation of breast-feeding may be considered.
Fertility
Clinical data do not indicate an impact of famciclovir on male fertility following long-term treatment at an oral dose of 250 mg twice daily.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed..Patients who experience dizziness, somnolence, confusion or other central nervous system disturbances while taking Famciclovir 500 mg film-coated tablets should refrain from driving or operating machinery.
4.8 Undesirable effects
Headache and nausea have been reported in clinical studies. These were generally mild or moderate in nature and occurred at a similar incidence in patients receiving placebo treatment. All other adverse reactions were added during postmarketing.
A total of 1,587 patients have received famciclovir at recommended doses in placebo-(n=657) and active- (n=930) controlled studies. These clinical studies were retrospectively reviewed to obtain a frequency category for all adverse reactions mentioned below. For adverse reactions which have never been observed in these studies, the upper limit of the 95% confidence interval is not expected to be higher than 3/X (based on the “rule of three”), with X representing the total sample size (n=1,587).
Adverse reactions (Table 2) are ranked under headings of frequency, using the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000).
Table 2: Adverse reactions
|
System Organ Class |
Very Common (> 1/10) |
Common (> 1/100 to < 1/10) |
Uncommon (> 1/1,000 to < 1/100) |
Rare (> 1/10,00 to < 1/1,000) |
Very Rare (<10,000) |
|
Blood and Lymphatic system Disorders |
Thrombocytopenia | ||||
|
Psychiatric Disorders |
Confusion |
Hallucinations | |||
|
Nervous System Disorders |
Headache |
Dizziness, somnolence | |||
|
Gastrointestinal Disorders |
Nausea, vomiting | ||||
|
Hepatobiliary Disorders |
Abnormal liver function tests |
Cholestatic j aundice. | |||
|
Skin and Subcutaneous Tissue Disorders |
Rash, pruritus. |
Urticaria, serious skin reactions* (e.g. erythema multiforme, Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis), angioedema, (e.g. face edema, eyelid edema, periorbital edema, pharyngeal edema). |
* Never reported in clinical trials; category is based on the “rule of three”
Overall, adverse reactions reported from clinical studies with immunocompromised patients were similar to those reported in the immunocompetent population. Nausea, vomiting and abnormal liver function tests were reported more frequently, especially at higher doses.
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 famciclovir dosage has not been appropriately reduced for the level of renal function.
Penciclovir is dialysable and plasma concentrations are reduced by approximately 75% following 4 hours of haemodialysis.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05A B09.
Famciclovir is a prodrug. After absorption, famciclovir is rapidly converted to penciclovir, which has demonstrable in vitro activity against herpes simplex (HSV) (types 1 and 2) and varicella zoster (VZV) and Epstein-Barr (EBV) viruses. The drug exhibits only limited activity in vitro against cytomegalovirus.
The antiviral effect of orally administered famciclovir has been demonstrated in several animal models, including various studies in HSV-infected mice. This effect is due to in vivo conversion to penciclovir. Penciclovir targets virus-infected cells, where it is rapidly and efficiently converted into the triphosphate by viral thymidine kinase (TK).
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 TK enzyme. Such TK-deficient strains would be expected to be cross-resistant to both penciclovir and aciclovir.
Results from penciclovir and famciclovir clinical trials, including studies in which patients were treated with famciclovir for up to four months, 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 during or after treatment with famciclovir or penciclovir.
As has been found with all other antiretroviral agents, it can be anticipated that resistance will develop in some patients receiving long-term treatment. However, the frequency at which this occurs has not yet been established.
The effects of famciclovir on directly virus-related parameters such as virus spread and skin lesions have been demonstrated in clinical trials.
A placebo-controlled study in patients with immunodeficiency due to HIV has shown that famciclovir 500 mg twice daily significantly reduced the number of days with both symptomatic and asymptomatic HSV (herpes simplex virus) secretion.
In a large clinical study famciclovir proved to be effective and have good tolerance in the treatment of ophthalmic zoster.
5.2 Pharmacokinetic properties
Following oral administration, famciclovir is rapidly absorbed and extensively converted to penciclovir. The bioavailability of penciclovir after oral administration of famciclovir is 77%.
Mean peak plasma concentrations of penciclovir, following 125 mg, 250 mg and 500 mg oral doses of famciclovir, were 0.8 micrograms/ml, 1.6 micrograms/ml and 3.3 micrograms/ml, respectively, and occurred at a mean time of 45 minutes post-dose. Slight passage of the metabolites across the blood-brain barrier was observed in rats. Penciclovir clearance is reduced in patients with renal impairment. The bioavailability of penciclovir is unaffected by hepatic impairment, but the mean peak plasma level is diminished. Ingestion with food leads to lower mean peak penciclovir concentrations, without effect on its bioavailability.
Plasma concentration-time curves of penciclovir are similar following single and repeat (two or three times daily) 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. No unchanged famciclovir can be detected in urine. Tubular secretion contributes to the renal elimination.
5.3 Preclinical safety data
Carcinogenicity
In 2-year studies in female rats receiving the maximum tolerated dose (600 mg/kg/day), an increased incidence of mammary adenocarcinoma was observed, a common tumour in the strain of rats used in these studies.
No effect on tumour incidence was found with a dose 3 times lower (200 mg/kg/day), which corresponds to 3 times the exposure achieved in humans receiving a therapeutic dose (250 mg twice daily).
There was no effect on the incidence of neoplasia in male rats or in mice of either sex.
Although the relevance of these findings to humans is unknown, the safety margin is very narrow. Furthermore, the long-term use of famciclovir is not recommended.
Genotoxicity
Famciclovir was not found to be genotoxic in a comprehensive battery of in vivo and in vitro tests.
Penciclovir, in common with other substances 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.
Reproductive toxicity
Famciclovir is well tolerated in laboratory animals. In common with other substances of this class, degenerative changes of the testicular epithelium were noted.
In animal studies, impaired fertility was observed in male rats receiving 500 mg/kg. There were no significant effects on fertility in female rats given famciclovir. Famciclovir has been shown not to have any significant effects on sperm count, morphology or motility in man.
PHARMACEUTICAL PARTICULARS
6
6.1 List of excipients
Tablet core:
Starch Pregelatinised Sodium Laurilsulfate Cellulose, Microcrystalline Croscarmellose Sodium Silica Colloidal Anhydrous Stearic acid
Film-coating: Hypromellose (E464) Titanium Dioxide (E171) Macrogol 4000 Macrogol 6000
6.2 Incompatibilities
Not applicable
6.3 Shelf life
24 months
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Tablets are provided in blister packs (PVC/PE/PVDC / Aluminium blisters) Pack sizes:
500 mg: 10, 14, 21, 30, 56 tablets Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/0950
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
03/09/2009 01/06/2012