Control No. 105102
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 5 DRUG INTERACTIONS 9 DOSAGE AND ADMINISTRATION 9 OVERDOSAGE 10 ACTION AND CLINICAL PHARMACOLOGY 10 STORAGE AND STABILITY 13 DOSAGE FORMS, COMPOSITION AND PACKAGING 13
PHARMACEUTICAL INFORMATION 14 CLINICAL TRIALS 14 TOXICOLOGY 19 REFERENCES 22
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APO-FAMCICLOVIR
Famciclovir Tablets
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablets / 125, 250 and 500 mg | Hydroxypropyl methylcellulose, stearic acid, titanium dioxide and polyethylene glycol. For a complete listing see Dosage Forms, Composition and Packaging section. |
Herpes Zoster
APO-FAMCICLOVIR is indicated for the treatment of acute herpes zoster (shingles).
Genital Herpes
APO-FAMCICLOVIR is indicated to treat or suppress recurrent episodes of genital herpes in immunocompetent adults. Early treatment of acute herpes zoster (shingles) in immune-competent individuals with oral famciclovir resulted in decreased time to loss of vesicles, decreased time to loss of crusts, and decreased viral shedding. In clinical studies of immunocompetent patients with recurrent genital herpes (typically >= 6 episodes in a 12 month period) famciclovir suppressed lesional episodes, slowed the rate to first recurrence and patients were more likely to remain free from recurrences for a 12-month period. Suppressive therapy in patients with fewer than 6 episodes of genital herpes in a 12 month period was not evaluated in these clinical studies. Initiation of famciclovir treatment of recurrent genital herpes during the prodrome or as soon as possible after the onset of lesions resulted in decreased duration of viral shedding, decreased time to lesion healing and decreased time to resolution of symptoms.
APO-FAMCICLOVIR is contraindicated in patients with known hypersensitivity to famciclovir or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of this product monograph.
General
The efficacy of APO-FAMCICLOVIR (famciclovir) has not been established for first episode genital herpes infections, disseminated zoster, or in immunocompromised patients with herpes zoster (see Action and Clinical Pharmacology). Dosage adjustment is required when administering famciclovir to patients with moderate or severe renal dysfunction (see Dosage and Administration). Genital herpes is a sexually transmitted disease with an increased risk of transmission during acute episodes. There are no data evaluating whether APO-FAMCICLOVIR will prevent transmission of infection to others. Patients should be advised to avoid intercourse when lesions and/or symptoms are present (even if treatment with an anti-viral has been initiated) in order to avoid infecting partners. Genital herpes can also be transmitted in the absence of symptoms through asymptotic viral shedding.
Pregnancy: Although animal studies have not shown any embryotoxic or teratogenic effects with famciclovir or penciclovir, the safety of famciclovir in human pregnancy has not been established. Because animal reproductive studies are not always predictive of human response, famciclovir should, therefore, not be used in pregnancy unless the potential benefits are considered to outweigh the potential risks associated with treatment.
Lactation: Following oral administration of famciclovir to lactating rats, penciclovir is excreted in milk. It is not known whether it (penciclovir) is excreted in human milk, thus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Use in Children: Safety and efficacy in children under the age of 18 years has not been established.
Geriatric Use: Of 816 patients with herpes zoster in clinical studies who were treated with famciclovir, 248 (30.4%) were > 65 years of age and 103 (13%) were > 75 years of age. No overall differences were observed in safety between younger and older patients (see Adverse Events).
Impairment of Fertility: As with other drugs of this class, testicular toxicity has been observed in animals receiving both famciclovir and penciclovir. Two placebo-controlled studies in a total of 130 otherwise healthy men with a normal sperm profile over an 8 week baseline period and recurrent genital herpes receiving oral famciclovir (250 mg bid) (n=66) or placebo (n=64) therapy for 18 weeks showed no evidence of significant effects on sperm count, motility or morphology during treatment or during an 8 week follow-up. Preliminary results of another placebo-controlled trial in a total of 117 otherwise healthy men with recurrent genital herpes and a normal sperm profile over an 8 week baseline period receiving famciclovir (250 mg bid, n=59) and placebo (n=58) therapy for 52 weeks showed no evidence of significant effects in sperm concentration, total sperm count, percent motility, percent abnormal morphology and percent dead sperm during treatment or during a 12 week follow-up.
Effects on ability to drive and use machines: Famciclovir can cause dizziness, drowsiness or confusion in very rare cases. Patients who experience any of these symptoms while taking APO-FAMCICLOVIR should take special care when driving or using machines (see Adverse Reactions - Post-market Adverse Drug Reactions).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very special conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Adverse Drug Reaction Overview
Immunocompetent Patients
The most frequent adverse reactions reported during herpes zoster clinical trials with oral famciclovir three times daily were as shown in the following table. Patients (%) reporting A/Es related * to study medication by preferred term in Famciclovir Zoster trials within 30 days of the last dose.
| Famciclovir | Placebo | |
| Patients receiving study medication | 816 | 146 |
| Event | % | % |
| Body as a Whole | ||
| Headache | 7.1 | 6.8 |
| Fatigue | 1.6 | 0.7 |
| Fever | 1.1 | 0.0 |
| Rigors | 0.6 | 1.4 |
| Herpes Zoster Symptoms | 0.5 | 1.4 |
| Central Nervous System | ||
| Dizziness | 1.5 | 0.7 |
| Somnolence | 1.2 | 2.7 |
| Gastrointestinal | ||
| Nausea | 4.3 | 8.2 |
| Diarrhea | 1.8 | 2.1 |
| Abdominal Pain | 1.5 | 0.0 |
| Constipation | 1.0 | 0.0 |
| Vomiting | 1.2 | 0.7 |
| Anorexia | 0.5 | 1.4 |
| Dermatologic | ||
| Pruritis | 1.2 | 0.7 |
| Sweating increased | 1.0 | 0.0 |
| Hepatic | ||
| ALT (SGPT) Increased | 0.6 | 1.4 |
| Gamma GT Increased | 0.6 | 1.4 |
| Hepatic Enzymes Increased | 0.2 | 1.4 |
| Special Senses | ||
| Tinnitus | 0.0 | 1.4 |
*Includes events assessed by the investigator as related, probably related, possibly related and AEs where the
relationship was unassessable or missing.
The most frequent adverse reactions reported within 30 days of the last dose, during genital herpes clinical trials with oral famciclovir were as shown in the following table. Patients (%) reporting A/Es related * to study medication by preferred term in Famciclovir Genital Herpes trials
| Famciclovir | Placebo | |
| Patients receiving study medication | 1500 | 255 |
| Event | % | % |
| Body as a Whole | ||
| Headache | 5.5 | 3.9 |
| Fatigue | 1.5 | 1.6 |
| Central Nervous System | ||
| Dizziness | 2.3 | 3.1 |
| Gastrointestinal | ||
| Nausea | 4.9 | 3.9 |
| Diarrhea | 1.8 | 1.6 |
| Dyspepsia | 1.3 | 1.2 |
| Abdominal Pain | 0.9 | 1.6 |
| Autonomic Nervous System | ||
| Mouth Dry | 0.3 | 1.2 |
*Includes events assessed by the investigator as related, probably related, possibly related or where
relationship was unassessable or not given.
The most frequent adverse events (incidence of > 1% are listed in the following table for patients receiving double-blind famciclovir or placebo for at least 10 months in the two 12-month-long trials. Patients (%) reporting A/Es related * to study medication by preferred term in Famciclovir Genital Herpes Suppression trials.
| Famciclovir | Placebo | |
| Patients receiving study medication | 458 | 63 |
| Event | % | % |
| Body as a Whole | ||
| Headache | 8.7 | 9.5 |
| Central Nervous System | ||
| Dizziness | 1.5 | 0 |
| Gastrointestinal | ||
| Abdominal Pain | 2.4 | 4.8 |
| Dyspepsia | 2.0 | 3.2 |
| Nausea | 1.5 | 3.2 |
| Diarrhea | 1.3 | 0 |
| Flatulence | 1.1 | 0 |
| Enzyme Abnormality+ | 2.2 | 3.2 |
| Bilirubinemia | 1.3 | 1.6 |
| Leukopenia | 1.3 | 0 |
*Includes events assessed by the investigator as related, probably related, possibly related and AEs where the
relationship was unassessable or missing.
+Reports of elevated lipase
Post-Market Adverse Drug Reactions
The following adverse events have been reported during post-approval use of famciclovir (frequency has been estimated from spontaneous and literature reports): rare cases of headache, nausea and confusion (including delirium, disorientation, confusional state, occurring predominantly in the elderly) and very rare cases of rash, urticaria, pruritis, serious skin reactions (e.g. erythema multiforme, Steven Johnson syndrome, toxic epidermal necrolysis), vomiting, dizziness, somnolence (predominantly in the elderly) hallucinations and jaundice. However, reporting rates determined on the basis of spontaneously reported post-marketing adverse events are generally presumed to underestimate the risks associated with drug treatments. Abnormal Hematological and Clinical Chemistry Findings: In post-market experience, thrombocytopenia has been reported very rarely.
No clinically significant alterations in penciclovir pharmacokinetics were observed following single dose administration of 500 mg famciclovir after pretreatment with multiple doses of cimetidine, allopurinol or theophylline. Furthermore, no clinically significant effect on penciclovir pharmacokinetics was observed following multiple-dose (t.i.d.) administration of famciclovir (500 mg) with multiple doses of digoxin. After single dose administration of 0.375 mg digoxin and 500 mg famciclovir in 12 healthy male volunteers, the Cmax of digoxin increased 19 +- 18% as compared to digoxin administered alone. There was no change in digoxin AUC 0-t where t ranged from 10 to 72 hours. The pharmacokinetics of penciclovir or digoxin were not altered by concomitant administration of multiple dose of famciclovir (500 mg t.i.d.) and digoxin to 22 healthy volunteers for 14 days. Probenecid and other drugs that affect renal physiology could affect plasma levels of penciclovir. The conversion of 6-deoxypenciclovir to penciclovir is catalyzed by aldehyde oxidase. No clinically relevant drug interactions mediated via this enzyme are reported in the literature. Interactions with other drugs metabolized by aldehyde oxidase could potentially occur.
Recommended dose
Herpes zoster infections
The recommended dose is 500 mg three times per day for seven days. Therapy should be initiated within 72 hours of the onset of the rash.
Herpes simplex infections
The recommended dosage is 125 mg twice a day for five days. Initiation of treatment is recommended during the prodromal period or as soon as possible after onset of lesions.
The recommended dosage is 250 mg twice daily for up to one year. The safety and efficacy of famciclovir therapy beyond one year of treatment has not been established.
APO-FAMCICLOVIR tablets should be swallowed whole and may be taken with or without food.
Dosage Adjustment
In patients with moderately or severely reduced renal function, dosage reduction is recommended:
| Indication | Creatinine clearance | Dosage |
| (mL/min/1.73m 3 ) | ||
| Herpes Zoster | >= 60 | 500 mg every 8 hours |
| 40-59 | 500 mg every 12 hours | |
| 20-39 | 500 mg every 24 hours | |
| < 20 | 250 mg every 48 hours | |
| Recurrent Genital Herpes | >= 40 | 125 mg every 12 hours |
| 20-39 | 125 mg every 24 hours | |
| < 20 | 125 mg every 48 hours | |
| Suppression of Recurrent | >= 40 | 250 mg every 12 hours |
| Genital Herpes | 20-39 | 125 mg every 12 hours |
| < 20 | 125 mg every 24 hours |
Hemodialysis patients: Following each dialysis treatment, the recommended dose of famciclovir is 250 mg (herpes zoster) or 125 mg (genital herpes) in immunocompetent patients.
Missed Dose
If a dose of APO-FAMCICLOVIR is missed, it should be taken as soon as the patient remembers. The next dose should be taken at the normal time. The patient should carry on as normal until they have finished all the tablets. Do not double-dose.
No acute overdosage has been reported. Appropriate symptomatic and supportive therapy should be given. Penciclovir is dialyzable; plasma concentrations are reduced by approximately 75% following 4h hemodialysis. In patients with underlying renal disease who have received inappropriate high doses of famciclovir for their level of renal function, acute renal failure has been reported frequently.
APO-FAMCICLOVIR (famciclovir) is an orally administered pro-drug of the antiviral agent penciclovir. Studies in volunteers have shown that famciclovir is well absorbed and produces plasma penciclovir concentrations superior to those obtained following oral administration of penciclovir alone. The mean bioavailability of penciclovir after administration of oral famciclovir is 77%. The mean peak plasma concentration of penciclovir, following a 500 mg oral dose of famciclovir was 3.3 mcg/ml and occurred at a mean time of 0.89 hours post-dose. Plasma concentration time curves of penciclovir are similar following single and repeat dosing. The terminal plasma elimination half-life of penciclovir after both single and repeat oral dosing with famciclovir is 2.3 hours. The elimination of famciclovir is by metabolism, principally in penciclovir and its 6- deoxy precursor, which are subsequently excreted in urine (see Pharmacokinetics).
Mechanism of Action
Penciclovir is a substituted guanine analogue with potent and selective antiviral activity against varicella zoster virus and other human herpes viruses (see Virology). Penciclovir is in the same class of antiviral drugs as acyclovir, and both are phosphorylated by viral thymidine kinase and then by cellular enzymes to the active triphosphate form in virus-infected cells. Penciclovir triphosphate inhibits viral DNA polymerase competitively 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. Inhibition of the virus reduces the period of viral shedding, limits the degree of spread and level of pathology, and thereby facilitates healing. Penciclovir is not readily phosphorylated in uninfected cells and does not inhibit cellular DNA synthesis even at concentrations > 20 times those achieved in clinical usage.
Pharmacokinetics
Absorption
Following oral administration, famciclovir is rapidly, extensively and consistently absorbed and converted to the antivirally active compound, penciclovir. The mean bioavailability of penciclovir after oral famciclovir is 77% (69.5 - 84.5%). Food slows the rate of availability of penciclovir after oral famciclovir and reduces Cmax by up to 50%, but total bioavailability is not significantly affected. In a healthy male volunteer study using a single oral dose of famciclovir, the pharmacokinetics of penciclovir were linear over the famciclovir dose range 125 to 750 mg. The mean (range) peak plasma concentration of penciclovir, calculated from dose normalised estimates across all single dose healthy male volunteer studies, following a single 500 mg dose of famciclovir was 3.3 ug/mL (range 1.3 - 6.3 ug/mL) and occurred at a mean time of 0.89 hours post-dose (range 0.5 - 5.0 hours). The mean terminal half-life of penciclovir was 2.3 hours (range 0.99 - 5.26 hours). Pharmacokinetic parameter estimates of penciclovir following oral administration of a single dose of famciclovir to patients with uncomplicated herpes zoster were essentially identical to values reported in healthy volunteers matched for age. Repeated oral dosing of famciclovir every 8 hours for up to 7 days in patients with herpes zoster infections had no significant effect on the pharmacokinetics of penciclovir compared to that described after single doses of famciclovir.
Distribution
Plasma protein binding of penciclovir and its 6-deoxy precursor is low (<20%) and penciclovir distributes freely between plasma and blood cells
Metabolism
Following oral administration little or no famciclovir is detected in plasma or urine since famciclovir is rapidly converted via deacetylation and oxidation to penciclovir. An in-vitro study using human liver microsomes demonstrated that cytochrome P450 does not play an important role in famciclovir metabolism. The conversion of B-deoxy penciclovir is catalyzed by aldehyde oxidase.
Excretion
Little or no famciclovir is detected in plasma or urine since famciclovir undergoes extensive first-pass metabolism to penciclovir. The major metabolites identified in plasma and urine are penciclovir (67 +- 4% of radioactivity in plasma at 1.5 h following a 500 mg oral dose of [14C]famciclovir and 82 +- 2.2% of radioactivity in 0-24 h urine) and, to a lesser extent, its 6- deoxy precursor, which has no antiviral activity (11 +- 4% in plasma and 7 +- 0.5% in urine at the corresponding time point(s). Other minor, virally inactive metabolites identified in human urine are monoacetylated penciclovir and 6-deoxy monoacetylated penciclovir (each < 0.5% of the dose). Renal clearance values for penciclovir exceed creatinine clearance indicating that net active tubular secretion and glomerular filtration contribute to renal elimination. A small but clinically insignificant reduction in mean renal clearance of penciclovir is observed in females compared with males, and in the elderly compared to the young. In both cases the differences observed are thought to relate to gender- and age-related decreases in renal function, respectively. Furthermore, mean elimination half-life estimates for females (2.0 h) and the elderly (2.7 h) do not necessitate a dosage adjustment according to age or gender in those patients with normal or mildly impaired renal function (See DOSAGE AND ADMINISTRATION).
Renal impaired patients:
In a study of volunteers with varying degrees of renal insufficiency given a single oral dose of famciclovir, renal clearance and plasma elimination rate constants for penciclovir decreased linearly with renal function. Mean estimates of systemic exposure and plasma half-life for penciclovir increased and urinary recovery decreased with the severity of renal impairment. There were no apparent changes in the biotransformation of famciclovir to penciclovir in these patients. A dosage adjustment is recommended for patients with moderate or severe renal impairment (see Dosage and Administration).
Hepatically impaired patients:
Following single oral administration of famciclovir to patients with well-compensated hepatic impairment, there was no change in the extent of availability of penciclovir compared with healthy volunteers. There was, however, a decrease in the rate of availability of penciclovir in the hepatically impaired subjects. Mean maximum plasma concentrations of penciclovir were decreased by 43% and the time to maximum plasma concentrations increased by 0.75 hours. However, no dosage adjustment for patients with well-compensated hepatic impairment is recommended. The pharmacokinetics of penciclovir following oral famciclovir in patients with severe uncompensated hepatic impairment has not been studied.
APO-FAMCICLOVIR should be stored at controlled room temperature (between 15degC and 30degC).
Composition
In addition to famciclovir, each tablet contains the following non-medicinal ingredients: Poloxamer 407, hydroxypropyl methylcellulose, stearic acid, titanium dioxide, polyethylene glycol and butylated hydroxy toluene.
Availability:
APO-FAMCICLOVIR 125 mg: each white, round, biconvex, film-coated tablet, engraved "APO" on one side and "FAM" over "125" on the other side, contains 125 mg famciclovir. Available in bottles of 30 and 500. APO-FAMCICLOVIR 250 mg: each white, round, biconvex, film-coated tablet, engraved "APO" on one side and "FAM" over "250" on the other side, contains 250 mg famciclovir. Available in bottles of 30 and 500. APO-FAMCICLOVIR 500 mg: each white, oval, biconvex, film-coated tablet, engraved "APO" on one side and "FAM 500" on the other side, contains 500 mg famciclovir. Available in bottles of 30 and 500.