Active ingredient: famciclovir Chemical names: 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine CAS number: 104227-87-4 Molecular weight: 321.3 Molecular formula C14H19N5O4 Chemical structure: N N O
N N NH2 O CH3 O
Famciclovir is a synthetic guanine derivative. It is a white to pale yellow crystalline solid. Famvir for Cold Sores are film-coated tablets that also contain hydroxypropyl cellulose, sodium starch glycollate and magnesium stearate as excipients. The film coating, Opadry OY-S-28924, contains titanium dioxide, hypromellose and macrogol.
Pharmacodynamic properties
Pharmacotherapeutic group: Oral antiviral agent, ATC code: JO5A B09
Famciclovir is the oral form of the antiviral compound: penciclovir. Famciclovir is rapidly converted in vivo into penciclovir, which has demonstrable in vitro activity against herpes simplex viruses (HSV types 1 and 2) and varicella zoster virus (VZV). The antiviral effect of orally administered famciclovir has been demonstrated in several animal models: this effect is due to in vivo conversion to penciclovir. Penciclovir targets virus-infected cells where it is rapidly converted into penciclovir- triphosphate (mediated via virus-induced thymidine kinase). The triphosphate inhibits viral DNA polymerase by competition with deoxyguanosine triphosphate and is incorporated into the extending DNA chain, preventing significant chain elongation. Consequently, viral DNA synthesis and, therefore, viral replication are inhibited. This triphosphate persists in infected cells in excess of 12 hours. The long intracellular half- life of penciclovir triphosphate ensures prolonged antiviral activity, as demonstrated in cell cultures with HSV-1 and HSV-2 and in animal studies. Penciclovir is only readily phosphorylated in virus-infected cells. 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 against a clinically isolated aciclovir-resistant herpes simplex type 1 strain with an altered DNA polymerase. The results from penciclovir and famciclovir patient studies, including studies of up to four months' treatment with famciclovir, showed that no resistance occurred as a result of treatment with either famciclovir or penciclovir. Penciclovir-resistant isolates were found at the start of treatment or in the placebo groups in 0.25% of the 1976 total isolates from HSV and VZV (5/1976), and in 0.19% of the 533 virus isolates from immunocompromised patients (1/533).
Pharmacokinetics
Famciclovir is the oral prodrug of penciclovir. Following oral administration, famciclovir is rapidly and extensively absorbed and converted to the antivirally active compound penciclovir. The bioavailability of penciclovir after oral famciclovir administration is 77 %. Mean peak plasma concentrations (Cmax) of penciclovir occurred at a median time of 45 minutes following administration of single oral doses of famciclovir (as shown in Table 1). No data is available on the pharmacokinetics of 1500 mg famciclovir as a single dose.
| famciclovir single oral dose (mg) | C max (ug/mL) |
| 125 | 0.8 |
| 250 | 1.6 |
| 500 | 3.3 |
| 750 | 5.1 |
| 1000 | 6.6 |
Plasma concentration-time curves of penciclovir are similar following single and repeat (b.i.d. and t.i.d.) dosing and there is no accumulation of penciclovir on repeated dosing. 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 has been detected in urine. Tubular secretion and glomerular filtration contribute to renal elimination of the compound. 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 Cmax was decreased by approximately 50 % and Tmax was delayed by 1.5 hour when a capsule formulation of famciclovir was administered 30 minutes after food. When Famvir tablets were administered 30 minutes after food, penciclovir Cmax was reduced by approximately 20 % and Tmax was delayed by 0.75 hour. The systemic availability (AUC) of penciclovir following either preparation was unaffected. The clinical consequences of these effects on plasma concentration are unknown.
Characteristics in special populations
Plasma clearance, renal clearance and plasma elimination rate constant decreased linearly with reductions in renal function. A dosage interval adjustment is recommended for patients with renal insufficiency (see "DOSAGE AND ADMINISTRATION").
Well-compensated chronic liver disease (chronic hepatitis [n=6], chronic ethanol abuse [n=8] or biliary cirrhosis [n=1]) has no effect on the extent of availability (AUC) of penciclovir following a single dose of 500 mg famciclovir. No dose adjustment is recommended for patients with well-compensated hepatic impairment (see section "DOSAGE AND ADMINISTRATION - Hepatic impairment" and "PRECAUTIONS"). However, there was a 43% decrease in penciclovir mean maximum plasma concentration and the time to maximum plasma concentration was increased by a median of 0.75 hour in patients with hepatic insufficiency compared to normal volunteers. The pharmacokinetics have not been evaluated in patients with severe uncompensated hepatic impairment.
Based on cross-study comparisons of single dose studies, the mean penciclovir AUC was approximately 30 % higher, half-life 23 % longer and penciclovir body weight adjusted renal clearance reduced by 19% in healthy elderly male volunteers (n=18, aged 65 to 79 years) compared to younger volunteers. Some of this difference may be due to differences in renal function between the two groups. No dose adjustment based on age is recommended unless renal function is impaired (see section "DOSAGE AND ADMINISTRATION").
A retrospective evaluation was performed to compare the pharmacokinetic parameters obtained in Black and Caucasian subjects after single and repeat once-daily, twice-daily, or three times-daily administration of famciclovir 500 mg. Data from a study in healthy volunteers (single dose), a study in subjects with varying degrees of renal impairment (single and repeat dose) and a study in subjects with hepatic impairment (single dose) did not indicate any relevant differences in the pharmacokinetics of penciclovir between Black and Caucasian subjects.
In one large placebo-controlled trial, 701 immunocompetent adults with recurrent herpes labialis were treated with Famvir 1500 mg once (n=227), Famvir 750 mg b.i.d. (n=220) or placebo (n=254) for 1 day. As well, patients also had to be in good general health, aged at least 18 years, have normal renal and hepatic function, had prior pregnancy tests if they were females of reproductive age, and have experienced 3 or more episodes of cold sores in the preceding 12 months. Patients were required to have a history of prodromal symptoms preceding at least 50% of the recurrent episodes, and at least 50% of these episodes had to have progressed to the vesicular lesion stage. Women of childbearing potential had to agree to use reliable birth control measures during the study. Pregnant or breast-feeding women were excluded. Patients were excluded if they had received an investigational drug in the 4 weeks prior to the study, had been previously vaccinated against herpes, or were using a topical immunosuppressive agent on or near the face or a systemic immunosuppressive agent within 1 month of screening. Patients were also excluded if they were immunosuppressed due to underlying disease or concomitant treatment, had a recent history of drug or alcohol abuse, were suffering from inflammatory skin diseases (e.g. eczema or dermatitis) that would interfere with the assessment of lesions, or were allergic or hypersensitive to products containing aciclovir, penciclovir, famciclovir or other nucleoside analogs. Patients were instructed to take the first dose of study medication within 1 hour of symptom onset. However, some patients commenced treatment after 1 hour of onset of symptoms. Both famciclovir regimens significantly reduced time to healing of primary vesicular herpes labialis lesions (the primary efficacy variable) in the modified ITT population compared with placebo. The median time to healing in Famvir 1500 mg single-dose treated patients was 4.4 days compared to 4.0 days in Famvir 750 mg bid and 6.2 days in placebo-treated patients. This translates to treatment effects of 1.8 (CI95% 0.9, 2.7) and 2.2 (CI95% 1.3, 3.1) days, respectively. A single 1500 mg dose of Famvir reduced the time to resolution of pain and tenderness (median time 1.7 days versus 2.9 days) compared with placebo and was marginally more effective than Famvir 750 mg b.i.d. (median time 2.1 days).
Famvir for Cold Sores is indicated for the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults aged 18 years and over.
Famvir for Cold Sores is contraindicated in patients with known hypersensitivity to famciclovir or other constituents of Famvir for Cold Sores. It is also contraindicated in those patients who have shown hypersensitivity to penciclovir, the active metabolite of famciclovir. Famvir for Cold Sores is not recommended for use in:
Patients who are immunocompromised
Children and adolescents under 18 years of age
As reduced clearance of penciclovir is related to reduced renal function, as measured by creatinine clearance, patients who have or at-risk of renal impairment should be referred to their medical practitioner for screening for renal impairment and any subsequent dosage adjustment if necessary. Appropriate dosage adjustments for renally impaired patients are provided (see "DOSAGE AND ADMINISTRATION"). Therefore, use of Famvir for Cold Sores in patients with renal impairment should only be under medical advice.
Famciclovir has not been studied in patients with severe hepatic impairment. Conversion of famciclovir to the active metabolite penciclovir may be impaired in these patients resulting in lower penciclovir plasma concentrations, and thus possibly a decrease of efficacy of famciclovir (see "PHARMACOLOGY").
No special precautions are required for elderly patients with normal renal function and patients with mild or moderate hepatic impairment.
Safety and efficacy of famciclovir in the treatment of herpes labialis in children and adolescents under 18 years of age has not been established. Therefore, use of Famvir for Cold Sores in this age group is not recommended.
Patients who experience dizziness, somnolence, confusion or other central nervous system disturbances while taking Famvir for Cold Sores should refrain from driving or operating machinery.
Data presented below include reference to area under the plasma concentration curve (24 hour AUC) for penciclovir in humans following the lowest and highest recommended doses for famciclovir (i.e. penciclovir AUC of 4.5 microgram.h/mL at 125 mg b.i.d. for acute recurrent genital herpes, and a penciclovir AUC of 27 microgram.h/mL at 500 mg t.i.d. for herpes infections in immunocompromised patients). This is based on the assumption that the pharmacokinetics in immunocompetent subjects are similar to the pharmacokinetics in immunocompromised subjects, as shown in the study on HIV patients (see "Pharmacokinetics"). If the higher values of AUC obtained in the renal transplant patients were used as a basis for comparison, the multiples specified here would be decreased. Exposures in animal studies are expressed as multiples of human exposures at the highest and lowest dosing schedules based on penciclovir AUC or body surface area.
Carcinogenesis
The carcinogenic potential of famciclovir was evaluated in 2 year dietary studies in rats and mice. A significant increase in the incidence of mammary adenocarcinoma was seen in female rats receiving 600 mg/kg/day. No increases in tumour incidences were reported for male rats treated at doses of up to 240 mg/kg/day or in mice of either sex at doses of up to 600 mg/kg/day. At the no effect levels of 240 and 200 mg/kg/day in male and female rats, the daily exposures to penciclovir based on AUC were about 40 and 29 microgram.h/mL respectively, or approximately 1 to 8 times the human systemic exposures at 500 mg t.i.d or 125 mg b.i.d. Systemic exposures at the no effect dose in male and female mice were 65 and 46 microgram.h/mL respectively, or approximately 2 to 12 times the human systemic exposure (AUC).
Genotoxicity
Famciclovir and penciclovir (the active metabolite of famciclovir) were tested for genotoxic potential in a series of in vitro and in vivo assays. Famciclovir showed no genotoxic potential in a series of assays for gene mutations, chromosomal damage and DNA damage. Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutations/ chromosomal damage, caused chromosomal aberrations in human lymphocytes in vitro and was positive in a mouse micronucleus assay in vivo when administered IV at doses toxic to bone marrow.
Effects on fertility
Testicular toxicity was observed in rats, mice and dogs following repeated administration of famciclovir or penciclovir. Testicular changes included atrophy of seminiferous tubules, reduction in sperm count and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of testicular toxicity was related to dose and duration of exposure and tended to reverse after the cessation of dosing. In male rats, decreased fertility was observed after 10 weeks dosing at 500 mg/kg/day, or approximately 3 to 20 times the human systemic exposure (AUC). Testicular toxicity was also seen in mice and dogs following chronic administration at exposures to penciclovir ranging from 2 to 14 times the human systemic exposure (AUC). However, there were no clinically significant effects on sperm count, morphology and motility in male patients receiving 250 mg famciclovir b.i.d. for 18 weeks. Famciclovir had no effect on fertility in female rats at doses of up to 1000 mg/kg/day, approximately 4 to 27 times the human systemic exposure (AUC).
Famciclovir was tested for effects on embryo-foetal development in rats and rabbits at oral doses up to 1000 mg/kg/day (approximately 4 to 27 times and 2 to 12 times the human systemic exposure to penciclovir in rats and rabbits, respectively [AUC]), and intravenous doses of 360 mg/kg/day in rats (1.9 to 12 times the human dose based on body surface area [BSA] comparisons) or 120 mg/kg/day in rabbits (1.2 to 7.1 times the human dose [BSA]). No adverse effects were observed on embryo-foetal development. Similarly, no adverse effects were observed following intravenous administration of penciclovir to rats (80 mg/kg/day, 0.4 to 2.6 times the human dose [BSA]) or rabbits (60 mg/kg/day, 0.6 to 3.6 times the human dose [BSA]). Although animal studies have not shown any embryotoxic or teratogenic effects with famciclovir or penciclovir (the active metabolite of famciclovir), the safety of famciclovir in human pregnancy has not been established. Famvir for Cold Sores should therefore not be used during pregnancy unless the potential benefits are considered to outweigh the potential risks associated with treatment.
Famvir for Cold Sores should not be used by nursing mothers unless the potential benefits are considered to outweigh the potential risks associated with treatment. Following oral administration of famciclovir to lactating rats, penciclovir was excreted in milk at concentrations higher than those seen in plasma. There is no information on excretion in human milk.
Effects of other medicinal products on famciclovir
No clinically significant interactions have been identified with famciclovir or penciclovir.
Concurrent use of Probenecid may result in increased plasma concentrations of penciclovir (active metabolite of famciclovir, see
).
could affect plasma levels of penciclovir (the active metabolite of famciclovir, see
).
Evidence from preclinical studies has shown no potential for induction of cytochrome P450.
: In a phase I study, no significant drug interactions were observed after coadministration of zidovudine and famciclovir.
The conversion of the inactive metabolite 6-deoxy penciclovir 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 and thus the efficacy of famciclovir. When raloxifene is co-administered with famciclovir, the clinical efficacy should be monitored.
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 or inhibition of CYP3A4.
Famvir for Cold Sores has been well tolerated in human studies. Headache, fatigue and nausea have been reported in clinical trials. These were generally mild or moderate and occurred at a similar incidence in patients receiving placebo treatment. Confusion, predominantly in the elderly, has been reported rarely.
Table 2: Adverse Events (related, possibly related, unassessable or unknown) reported by 1% of immunocompetent subjects during clinical trials in Herpes labialis:
| Adverse Event | Famvir for Cold Sores 1500 mg q.d. N=227 N (%) | Famvir for Cold Sores 750 mg b.i.d. N=220 N (%) | Placebo N=254 N (%) |
| Patients with AE(s) | 63 (27.8) | 54 (24.5) | 53 (20.9) |
| AE preferred term | |||
| Headache | 22 (9.7) | 16 (7.3) | 17 (6.7) |
| Diarrhoea | 4 (1.8) | 3 (1.4) | 2 (0.8) |
| Nausea | 5 (2.2) | 5 (2.3) | 10 (3.9) |
| Nasopharyngitis | 6 (2.6) | 3 (1.4) | 2 (0.8) |
Post-marketing Data
In addition to the adverse events reported in the clinical trials, the following adverse reactions (Table 3) have been reported in post-marketing surveillance. They are ranked under headings of frequency, according to the following convention: very common ( 1/10); common ( 1/100, < 1/10); uncommon ( 1/1,000, <1/100); rare ( 10,000, < 1/1,000); very rare (<1/10,000), including isolated reports.
Table 3: Adverse Events reported by patients receiving famciclovir during post- marketing
Blood and lymphatic system disorders
Very rare : Thrombocytopenia
Psychiatric disorders
Uncommon : Confusional state (predominantly in the elderly) Rare : Hallucination
Nervous system disorders
Very common : Headache Common : Dizziness Uncommon : Somnolence (predominantly in the elderly)
Cardiac disorders
Rare : Palpitations
Gastrointestinal disorders
Common : Vomiting, nausea, abdominal pain, diarrhoea
Hepatobiliary disorders
Common : Liver function test abnormal Rare : Jaundice cholestatic
Skin and subcutaneous tissue disorders
Common : Rash, pruritus Uncommon : Angioedema (e.g. face oedema, eyelid oedema, periorbital oedema, pharyngeal oedema), urticaria. Very rare : Serious skin reactions (e.g. erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) Not known : Leukocytoclastic vasculitis
Musculoskeletal disorders
Very rare : arthralgia, myalgia
The recommended dosage is 1500 mg as a single dose. Initiate therapy at the earliest sign or symptom of a cold sore (e.g. tingling, itching or burning). Treatment was initiated within 1 hour of symptom onset in the recurrent herpes labialis clinical study.
Renal impairment
As reduced clearance of penciclovir is related to reduced renal function, as measured by creatinine clearance, patients who have or at-risk of renal impairment should be referred to their medical practitioner for screening for renal impairment and any subsequent dosage adjustment if necessary. Therefore, use of Famvir for Cold Sores in patients with renal impairment should only be under medical advice. The following modifications in dosage are recommended: Creatinine Clearance (mL/min/1.73m2) Dosage
60 No dose adjustment necessary
40 - 59 750 single dose 20 - 39 500 single dose 10 - 20 250 single dose for patients on haemodialysis 250 single dose Famvir for Cold Sores is only available as unscored tablets containing 500mg of famciclovir. As these recommendations are not based on repeated dose data, patients with impaired renal function should be closely monitored for adverse effects. There are insufficient data to recommend a dosage for patients with creatinine clearance less than 10 mL/min/1.73m2. Since 4 hour haemodialysis results in approximately 75 % reduction in plasma concentrations of penciclovir, the full adjusted dose (for patients with severe renal impairment) of famciclovir should be administered immediately following dialysis.
Hepatic impairment
Dosage modification is not required for patients with mild to moderate hepatic impairment.
Famciclovir can be taken without regard to meals (see "Pharmacokinetics - Effect of food" section in PHARMACOLOGY).
Contact the Poisons Information Centre on 131 126 for advice on management. Symptomatic and supportive therapy should be given as appropriate. Acute renal failure has been reported rarely in patients with underlying renal disease. The famciclovir dosage in these patients had not been appropriately reduced for the level of renal function. Penciclovir, the active metabolite of famciclovir, is dialysable; plasma concentrations are reduced by approximately 75% following 4 hour haemodialysis.
Presentation
Blister packs of 3 white, oval, film coated, biconvex tablets debossed with "FV 500" on one side and no markings on the reverse side.
Storage
Famvir for Cold Sores tablets should be stored below 30degC in a dry place. The shelf life under these conditions is three years. Keep out of the reach of children.
NOVARTIS Pharmaceuticals Australia Pty Limited ABN 18 004 244 160 54 Waterloo Road NORTH RYDE NSW 2113
= Registered Trademark
Schedule 3 - Pharmacist Only Medicine
24 September 2012
07 February 2013
:
(famcs070213i.doc) is based on CDS dated 21-Nov-2012