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Famvir
T2006-71
Famvir®
(famciclovir)
Tablets
Rx only
PRESCRIBING INFORMATION
DESCRIPTION
Famvir® (famciclovir) contains famciclovir, an orally administered prodrug of the antiviral agent penciclovir. Chemically, famciclovir is known as 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate. Its molecular formula is C14H19N504; its molecular weight is 321.3. It is a synthetic acyclic guanine derivative and has the following structure
Famciclovir is a white to pale yellow solid. It is freely soluble in acetone and methanol, and sparingly soluble in ethanol and isopropanol. At 25°C famciclovir is freely soluble (>25% w/v) in water initially, but rapidly precipitates as the sparingly soluble (2%-3% w/v) monohydrate. Famciclovir is not hygroscopic below 85% relative humidity. Partition coefficients are: octanol/water (pH 4.8) P=1.09 and octanol/phosphate buffer (pH 7.4) P=2.08.
Tablets for Oral Administration
Each white, film-coated tablet contains famciclovir. The 125-mg and 250-mg tablets are round; the 500-mg tablets are oval. Inactive ingredients consist of hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycols, sodium starch glycolate and titanium dioxide.
MICROBIOLOGY
Mechanism of Antiviral Action
Famciclovir undergoes rapid biotransformation to the active antiviral compound penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2 or VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted to penciclovir triphosphate by cellular kinases. In vitro studies demonstrate that penciclovir triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited.
Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2- and 7 hours in VZV-infected cells grown in culture; however, the clinical significance is unknown.
Antiviral Activity
In cell culture studies, penciclovir is inhibitory to the following herpes viruses (uled in decreasing order of potency): HSV-1, HSV-2 and VZV. Sensitivity test results, expressed as the concentration of the drug required to inhibit the growth of the virus by 50% (EC50) or 99% (EC99) in cell culture, vary greatly depending upon a number of factors, including the assay protocols, and in particular the cell type used. See Table 1.
| Method of Assay | Virus Type | Cell Type | EC50 | EC99 |
| (mcg/mL) | ||||
| Plaque Reduction | VZV (c.i.) | MRC-5 | 5.0 ± 3.0 | |
| VZV (c.i.) | Hs68 | 0.9 ± 0.4 | ||
| HSV-1 (c.i.) | MRC-5 | 0.2 – 0.6 | ||
| HSV-1 (c.i.) | WISH | 0.04 – 0.5 | ||
| HSV-2 (c.i.) | MRC-5 | 0.9 – 2.1 | ||
| HSV-2 (c.i.) | WISH | 0.1 – 0.8 | ||
| Virus Yield | HSV-1 (c.i.) | MRC-5 | 0.4 – 0.5 | |
| Reduction | HSV-2 (c.i.) | MRC-5 | 0.6 – 0.7 | |
| DNA Synthesis | VZV (Ellen) | MRC-5 | 0.1 | |
| Inhibition | HSV-1 (SC16) | MRC-5 | 0.04 | |
| HSV-2 (MS) | MRC-5 | 0.05 | ||
(c.i.) = clinical isolates.
Resistance
Penciclovir-resistant mutants of HSV and VZV can result from mutations in the viral thymidine kinase (TK) and DNA polymerase genes. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). The most commonly encountered acyclovir-resistant mutants that are TK negative are also resistant to penciclovir. The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Drug Interactions
CLINICAL TRIALS
Herpes Zoster
Famvir® (famciclovir) was studied in a placebo-controlled, double-blind trial of 419 immunocompetent adults with uncomplicated herpes zoster. Comparisons included Famvir 500 mg t.i.d., Famvir 750 mg t.i.d., or placebo. Treatment was begun within 72 hours of initial lesion appearance and therapy was continued for 7 days.
The median time to full crusting in Famvir-treated patients was 5 days compared to 7 days in placebo-treated patients. The times to full crusting, loss of vesicles, loss of ulcers, and loss of crusts were shorter for Famvir 500 mg-treated patients than for placebo-treated patients in the overall study population. The effects of Famvir were greater when therapy was initiated within 48 hours of rash onset; it was also more pronounced in patients 50 years of age or older. Among the 65.2% of patients with at least one positive viral culture, Famvir-treated patients had a shorter median duration of viral shedding than placebo-treated patients (1 day and 2 days, respectively).
There were no overall differences in the duration of pain before rash healing between Famvir- and placebo-treated groups. In addition, there was no difference in the incidence of pain after rash healing (postherpetic neuralgia) between the treatment groups. In the 186 patients (44.4% of total study population) who did develop postherpetic neuralgia, the median duration of postherpetic neuralgia was shorter in patients treated with Famvir 500 mg than in those treated with placebo (63 days and 119 days, respectively). No additional efficacy was demonstrated with higher doses of Famvir.
A double-blind controlled trial in 545 immunocompetent adults with uncomplicated herpes zoster treated within 72 hours of initial lesion appearance compared three doses of Famvir to acyclovir 800 mg 5 times per day. Times to full lesion crusting and times to loss of acute pain were comparable for all groups and there were no statistically significant differences in the time to loss of postherpetic neuralgia between Famvir- and acyclovir-treated groups.
Herpes Simplex Infections
INDICATIONS AND USAGE
Herpes Zoster
Famvir® (famciclovir) is indicated for the treatment of acute herpes zoster (shingles).
Herpes Simplex Infections
Famvir is indicated for:
- treatment or suppression of recurrent genital herpes in immunocompetent patients.
- treatment of recurrent herpes labialis (cold sores) in immunocompetent patients.
- treatment of recurrent mucocutaneous herpes simplex infections in HIV-infected patients.
CONTRAINDICATIONS
Famvir® (famciclovir) is contraindicated in patients with known hypersensitivity to the product, its components, and Denavir® (penciclovir cream).
PRECAUTIONS
General
The efficacy of Famvir® (famciclovir) has not been established for initial episode genital herpes infection, ophthalmic zoster, disseminated zoster or in immunocompromised patients with herpes zoster.
Dosage adjustment is recommended when administering Famvir to patients with creatinine clearance values < 60 mL/min. (See DOSAGE AND ADMINISTRATION). In patients with underlying renal disease who have received inappropriately high doses of Famvir for their level of renal function, acute renal failure has been reported.
Famvir 125 mg, 250 mg and 500 mg tablets contain lactose (26.9 mg, 53.7 mg and 107.4 mg, respectively). Patients with rare hereditary problems of galactose intolerance, a severelactase deficiency or glucose-galactose malabsorption should not take Famvir 125 mg, 250mg and 500 mg tablets.
Information for Patients
Patients should be informed that Famvir is not a cure for genital herpes. There are no data evaluating whether Famvir will prevent transmission of infection to others. As genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding. If medical management of recurrent episodes is indicated, patients should be advised to initiate therapy at the first sign or symptom.
There is no evidence that Famvir will affect the ability of a patient to drive or to use machines. However, patients who experience dizziness, somnolence, confusion or other central nervous system disturbances while taking Famvir should refrain from driving or operating machinery.
Drug Interactions
Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may result in increased plasma concentrations of penciclovir.
The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme could potentially occur.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Famciclovir was administered orally unless otherwise stated.
Pregnancy
Nursing Mothers
Following oral administration of famciclovir to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma. It is not known whether it is excreted in human milk. There are no data on the safety of Famvir in infants.
Usage in Children
Safety and efficacy in children under the age of 18 years have not been established.
Geriatric Use
Of 816 patients with herpes zoster in clinical studies who were treated with Famvir, 248 (30.4%) were ≥65 years of age and 103 (13%) were ≥75 years of age. No overall differences were observed in the incidence or types of adverse events between younger and older patients.
Of 610 patients with recurrent herpes simplex (type 1 or type 2) in clinical studies who were treated with Famvir, 26 (4.3%) were > 65 years of age and 7 (1.1%) were > 75 years of age. Clinical studies of Famvir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
In general, appropriate caution should be exercised in the administration and monitoring of FAMVIR in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Immunocompetent Patients
The safety of Famvir® (famciclovir) has been evaluated in clinical studies involving 816 Famvir-treated patients with herpes zoster (Famvir, 250 mg t.i.d. to 750 mg t.i.d.); 163 Famvir-treated patients with recurrent genital herpes (Famvir, 1000 mg b.i.d.); 1,197 patients with recurrent genital herpes treated with Famvir as suppressive therapy (125 mg q.d. to 250 mg t.i.d.) of which 570 patients received Famvir (open-labeled and/or double-blind) for at least 10 months; and 447 Famvir-treated patients with herpes labialis (Famvir, 1500 mg once or 750 mg b.i.d.). Table 5 uls selected adverse events.
| Incidence | ||||||||
| Herpes Zoster† | Recurrent Genital Herpes‡ | Genital Herpes- Suppression§ | Herpes Labialis‡ | |||||
| Event | Famvir® | Placebo | Famvir ® | Placebo | Famvir® | Placebo | Famvir® | Placebo |
| 500 mg | 1 gram | 250 mg | 1500 mg | |||||
| t.i.d* | b.i.d* | b.i.d* | single dose* | |||||
| (n=273) | (n=146) | (n=163) | (n=166) | (n=458) | (n=63) | (n=227) | (n=254) | |
| % | % | % | % | % | % | % | % | |
| Nervous System | ||||||||
| Headache | 22.7 | 17.8 | 13.5 | 5.4 | 39.3 | 42.9 | 9.7 | 6.7 |
| Paresthesia | 2.6 | 0.0 | 0.0 | 0.0 | 0.9 | 0.0 | 0.0 | 0.0 |
| Migraine | 0.7 | 0.7 | 0.6 | 0.6 | 3.1 | 0.0 | 0.0 | 0.0 |
| Gastrointestinal | ||||||||
| Nausea | 12.5 | 11.6 | 2.5 | 3.6 | 7.2 | 9.5 | 2.2 | 3.9 |
| Diarrhea | 7.7 | 4.8 | 4.9 | 1.2 | 9.0 | 9.5 | 1.8 | 0.8 |
| Vomiting | 4.8 | 3.4 | 1.2 | 0.6 | 3.1 | 1.6 | 0.0 | 0.0 |
| Flatulence | 1.5 | 0.7 | 0.6 | 0.0 | 4.8 | 1.6 | 0.0 | 0.0 |
| Abdominal Pain | 1.1 | 3.4 | 0.0 | 1.2 | 7.9 | 7.9 | 0.0 | 0.4 |
| Body as a Whole | ||||||||
| Fatigue | 4.4 | 3.4 | 0.6 | 0.0 | 4.8 | 3.2 | 1.3 | 0.4 |
| Skin and Appendages | ||||||||
| Pruritus | 3.7 | 2.7 | 0.0 | 0.6 | 2.2 | 0.0 | 0.0 | 0.0 |
| Rash | 0.4 | 0.7 | 0.0 | 0.0 | 3.3 | 1.6 | 0.0 | 0.0 |
| Reproductive Female | ||||||||
| Dysmenorrhea | 0.0 | 0.7 | 1.8 | 0.6 | 7.6 | 6.3 | 0.9 | 0.0 |
*Patients may have entered into more than one clinical trial.
†7 days of treatment
‡1 day of treatment
§daily treatment
The following adverse events have been reported during post-approval use of Famvir: urticaria, hallucinations and confusion (including delirium, disorientation, confusional state, occurring predominantly in the elderly). Because these adverse events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. Table 6 uls selected laboratory abnormalities in genital herpes suppression trials.
| Parameter | Famvir® (n = 660)† % | Placebo (n = 210)† % |
| Anemia (<0.8 x NRL) | 0.1 | 0.0 |
| Leukopenia (<0.75 x NRL) | 1.3 | 0.9 |
| Neutropenia (<0.8 x NRL) | 3.2 | 1.5 |
| AST (SGOT) (>2 x NRH) | 2.3 | 1.2 |
| ALT (SGPT) (>2 x NRH) | 3.2 | 1.5 |
| Total Bilirubin (>1.5 x NRH) | 1.9 | 1.2 |
| Serum Creatinine (>1.5 x NRH) | 0.2 | 0.3 |
| Amylase (>1.5 x NRH) | 1.5 | 1.9 |
| Lipase (>1.5 x NRH) | 4.9 | 4.7 |
*Percentage of patients with laboratory abnormalities that were increased or decreased from baseline and were outside of specified ranges.
†n values represent the minimum number of patients assessed for each laboratory parameter.
NRH = Normal Range High.
NRL = Normal Range Low.
HIV-Infected Patients
In HIV-infected patients, the most frequently reported adverse events for famciclovir (500 mg twice daily; n=150) and acyclovir (400 mg, 5x/day; n=143), respectively, were headache (16.7% vs. 15.4%), nausea (10.7% vs. 12.6%), diarrhea (6.7% vs. 10.5%), vomiting (4.7% vs. 3.5%), fatigue (4.0% vs. 2.1%), and abdominal pain (3.3% vs. 5.6%).
Post Marketing Experience
The following adverse events have been reported during post-approval use of Famvir: uticaria, serious skin reactions (e.g. erythema multiforme), jaundice, thrombocytopenia, hallucinations, dizziness, somnolence and confusion (including delirium, disorientation, confusional state, occurring predominantly in the elderly). Because these adverse events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.
OVERDOSAGE
Appropriate symptomatic and supportive therapy should be given. Penciclovir is removed by hemodialysis (see PRECAUTIONS, General).
DOSAGE AND ADMINISTRATION
Herpes Zoster
The recommended dosage is 500 mg every 8 hours for 7 days. Therapy should be initiated promptly as soon as herpes zoster is diagnosed. No data are available on efficacy of treatment started greater than 72 hours after rash onset.
Herpes Simplex Infections
HIV-Infected Patients
For recurrent orolabial or genital herpes simplex infection, the recommended dosage is 500 mg twice daily for 7 days.
Patients with Reduced Renal Function
In patients with reduced renal function, dosage reduction is recommended (see PRECAUTIONS, General).
| Indication and Normal Dosage Regimen | Creatinine Clearance (mL/min.) | Adjusted Dosage Regimen Dose (mg) | Dosing Interval |
| Single-Day Dosing Regimens | |||
| Recurrent Genital Herpes 1000 mg every 12 hours for 1 day | ≥60 | 1000 | every 12 hours for 1 day |
| 40-59 | 500 | every 12 hours for 1 day | |
| 20-39 | 500 | single dose | |
| <20 | 250 | single dose | |
| HD* | 250 | single dose following Dialysis | |
| Recurrent herpes labialis 1500 mg single dose | ≥60 | 1500 | single dose |
| 40-59 | 750 | single dose | |
| 20-39 | 500 | single dose | |
| <20 | 250 | single dose | |
| HD* | 250 | single dose following dialysis | |
| Multiple-Day Dosing Regimens | |||
| Herpes Zoster 500 mg every 8 hours | ≥60 | 500 | every 8 hours |
| 40-59 | 500 | every 12 hours | |
| 20-39 | 500 | every 24 hours | |
| <20 | 250 | every 24 hours | |
| HD* | 250 | following each dialysis | |
| Suppression of Recurrent Genital Herpes 250 mg every 12 hours | ≥40 | 250 | every 12 hours |
| 20-39 | 125 | every 12 hours | |
| <20 | 125 | every 24 hours | |
| HD* | 125 | following each dialysis | |
| Recurrent Orolabial and Genital Herpes Simplex Infection in HIV-Infected Patients 500 mg every 12 hours | ≥40 | 500 | every 12 hours |
| 20-39 | 500 | every 12 hours | |
| <20 | 250 | every 24 hours | |
| HD* | 250 | following each dialysis | |
*Hemodialysis
Administration with Food
When famciclovir was administered with food, penciclovir Cmax decreased approximately 50%. Because the systemic availability of penciclovir (AUC) was not altered, it appears that Famvir may be taken without regard to meals.
HOW SUPPLIED
Famvir® (famciclovir) is supplied as film-coated tablets as follows: 125 mg in bottles of 30; 250 mg in bottles of 30; and 500 mg in bottles of 30 and Single Unit Packages of 50 (intended for institutional use only).
Famvir 125 mg tablet:
White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and “125” on the other.
125 mg 30’s…………………………………………………………...……NDC 0078-0366-15
Famvir 250 mg tablet:
White, round film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and “250” on the other.
250 mg 30’s………………………………………………………………...NDC 0078-0367-15
Famvir 500 mg tablet:
White, oval film-coated, biconvex, beveled edges, debossed with “FAMVIR” on one side and “500” on the other.
500 mg 30’s…………………………………………………………….......NDC 0078-0368-15
500 mg SUP 50’s…………………………………………………………...NDC 0078-0368-64
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
REV: JULY 2006 T2006-71
Distributed by:
Novartis Pharmaceuticals Corp.
East Hanover, NJ 07936
©Novartis