Famvir for Genital Herpes

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Famvir for Genital Herpes uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Famvir for Genital Herpes reviews

1 INDICATIONS AND USAGE

Famvir for Genital Herpes tablets, a prodrug of penciclovir, is a nucleoside analog DNA polymerase inhibitor indicated for:

Immunocompetent Adult Patients

• Herpes labialis (cold sores)
  

  ○ Treatment of recurrent episodes

• Genital herpes
  

  ○ Treatment of recurrent episodes
  

  ○ Suppressive therapy of recurrent episodes

HIV-Infected Adult Patients (1.2)

• Treatment of recurrent episodes of orolabial or genital herpes

Limitation of Use (1.3)

The efficacy and safety of Famvir for Genital Herpes tablets have not been established for:

• Patients <18 years of age
• Immunocompromised patients other than for the treatment of recurrent episodes of orolabial or genital herpes in HIV-infected patients

1.1 Immunocompetent Adult Patients

Herpes labialis (cold sores): Famvir for Genital Herpes tablets are indicated for the treatment of recurrent herpes labialis.

Genital herpes:

Recurrent episodes: Famvir for Genital Herpes tablets are indicated for the treatment of recurrent episodes of genital herpes. The efficacy of Famvir for Genital Herpes tablets when initiated more than 6 hours after onset of symptoms or lesions has not been established.

Suppressive therapy: Famvir for Genital Herpes tablets are indicated for chronic suppressive therapy of recurrent episodes of genital herpes. The efficacy and safety of Famvir for Genital Herpes tablets for the suppression of recurrent genital herpes beyond 1 year have not been established.

1.2 HIV-Infected Adult Patients

Recurrent orolabial or genital herpes: Famvir for Genital Herpes tablets are indicated for the treatment of recurrent episodes of orolabial or genital herpes in HIV-infected adults. The efficacy of Famvir for Genital Herpes tablets when initiated more than 48 hours after onset of symptoms or lesions has not been established.

1.3 Limitation of Use

The efficacy and safety of Famvir for Genital Herpes tablets have not been established for:

• Patients <18 years of age
• Patients with first episode of genital herpes
• Immunocompromised patients other than for the treatment of recurrent orolabial or genital herpes in HIV-infected patients

2 DOSAGE AND ADMINISTRATION

Famvir for Genital Herpes tablets may be taken with or without food.

Patients with renal impairment: Adjust dose based on creatinine clearance (2.3)

2.1 Dosing Recommendation in Immunocompetent Adult Patients

Herpes labialis (cold sores): The recommended dosage of Famvir for Genital Herpes tablets for the treatment of recurrent herpes labialis is 1500 mg as a single dose. Therapy should be initiated at the first sign or symptom of herpes labialis (e.g., tingling, itching, burning, pain, or lesion).

Genital herpes:

Recurrent episodes: The recommended dosage of Famvir for Genital Herpes tablets for the treatment of recurrent episodes of genital herpes is 1000 mg twice daily for 1 day. Therapy should be initiated at the first sign or symptom of a recurrent episode (e.g., tingling, itching, burning, pain, or lesion).

Suppressive therapy: The recommended dosage of Famvir for Genital Herpes tablets for chronic suppressive therapy of recurrent episodes of genital herpes is 250 mg twice daily.

2.2 Dosing Recommendation in HIV-Infected Adult Patients

Recurrent orolabial or genital herpes: The recommended dosage of Famvir for Genital Herpes tablets for the treatment of recurrent orolabial or genital herpes in HIV-infected patients is 500 mg twice daily for 7 days. Therapy should be initiated at the first sign or symptom of a recurrent episode.

2.3 Dosing Recommendation in Patients with Renal Impairment

Dosage recommendations for adult patients with renal impairment are provided in Table 1 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Famvir for Genital Herpes tablets are available in 3 strengths:

• 125 mg: White, round film-coated, biconvex, beveled edges, debossed with WPI on one side and 3271 on the other side.

• 250 mg: White, round film-coated, biconvex, beveled edges, debossed with WPI on one side and 3272 on the other side

• 500 mg: White, capsule shaped film-coated, biconvex, debossed with WPI on one side and 3273 on the other side

Tablets: 125 mg, 250 mg, 500 mg (3)

4 CONTRAINDICATIONS

Famvir for Genital Herpes tablets are contraindicated in patients with known hypersensitivity to the product, its components, or penciclovir cream.

Known hypersensitivity to the product, its components, or penciclovir cream (4)

5 WARNINGS AND PRECAUTIONS

Acute renal failure: Cases of acute renal failure have been reported in patients with underlying renal disease who have received inappropriately high doses of Famvir for Genital Herpes for their level of renal function. Dosage reduction is recommended when administering Famvir for Genital Herpes to patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

Acute renal failure: May occur in patients with underlying renal disease who receive higher than recommended doses of Famvir for Genital Herpes tablets for their level of renal function. Reduce dosage in patients with renal impairment (2.3, 8.6)

6 ADVERSE REACTIONS

Acute renal failure is discussed in greater detail in other sections of the label [see Warnings and Precautions ].

The most common adverse events reported in at least 1 indication by >10% of adult patients treated with Famvir for Genital Herpes tablets are headache and nausea.

The most common adverse events reported in at least one indication by >10% of adult patients are headache and nausea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Cipla Limited, Inc. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience in Adult Patients

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Immunocompetent patients: The safety of Famvir for Genital Herpes tablets has been evaluated in active-and placebo-controlled clinical studies involving 163 Famvir for Genital Herpes tablets -treated patients with recurrent genital herpes (famciclovir tablets, 1000 mg twice daily); 1,197 patients with recurrent genital herpes treated with Famvir for Genital Herpes tablets as suppressive therapy (125 mg once daily to 250 mg three times daily) of which 570 patients received Famvir for Genital Herpes tablets (open-labeled and/or double-blind) for at least 10 months; and 447 Famvir for Genital Herpes tablets -treated patients with herpes labialis (famciclovir tablets, 1500 mg once daily or 750 mg twice daily). Table 2 lists selected adverse events.

Table 3 lists selected laboratory abnormalities in genital herpes suppression trials.

HIV-infected patients: In HIV-infected patients, the most frequently reported adverse events for Famvir for Genital Herpes (500 mg twice daily; n=150) and acyclovir (400 mg, 5x/day; n=143), respectively, were headache (17% vs. 15%), nausea (11% vs. 13%), diarrhea (7% vs. 11%), vomiting (5% vs. 4%), fatigue (4% vs. 2%), and abdominal pain (3% vs. 6%).

6.2 Postmarketing Experience

The adverse events listed below have been reported during post approval use of Famvir for Genital Herpes tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Blood and lymphatic system disorders: Thrombocytopenia

Hepatobiliary disorders: Abnormal liver function tests, cholestatic jaundice

Nervous system disorders: Dizziness, somnolence

Psychiatric disorders: Confusion (including delirium, disorientation, and confusional state occurring predominantly in the elderly), hallucinations

Skin and subcutaneous tissue disorders: Urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema (e.g., face, eyelid, periorbital, and pharyngeal edema), leukocytoclastic vasculitis

Cardiac disorders: Palpitations

7 DRUG INTERACTIONS

Probenecid: May increase penciclovir levels. Monitor for evidence of penciclovir toxicity

7.1 Potential for Famvir for Genital Herpes Tablets to Affect Other Drugs

The steady-state pharmacokinetics of digoxin were not altered by concomitant administration of multiple doses of Famvir for Genital Herpes (500 mg three times daily). No clinically significant effect on the pharmacokinetics of zidovudine, its metabolite zidovudine glucuronide, or emtricitabine was observed following a single oral dose of 500 mg Famvir for Genital Herpes coadministered with zidovudine or emtricitabine.

An in vitro study using human liver microsomes suggests that Famvir for Genital Herpes is not an inhibitor of CYP3A4 enzymes.

7.2 Potential for Other Drugs to Affect Penciclovir

No clinically significant alterations in penciclovir pharmacokinetics were observed following single-dose administration of 500 mg Famvir for Genital Herpes after pre-treatment with multiple doses of allopurinol, cimetidine, theophylline, zidovudine, promethazine, when given shortly after an antacid (magnesium and aluminum hydroxide), or concomitantly with emtricitabine. No clinically significant effect on penciclovir pharmacokinetics was observed following multiple-dose (three times daily) administration of Famvir for Genital Herpes (500 mg) with multiple doses of digoxin.

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 and/or inhibiting this enzyme could potentially occur. Clinical interaction studies of Famvir for Genital Herpes with cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir. Raloxifene, a potent aldehyde oxidase inhibitor in vitro, could decrease the formation of penciclovir. However, a clinical drug-drug interaction study to determine the magnitude of interaction between penciclovir and raloxifene has not been conducted.

8 USE IN SPECIFIC POPULATIONS

Nursing mothers: Famciclovir tablets should not be used in nursing mothers unless the potential benefits outweigh the potential risks associated with treatment.

8.1 Pregnancy

Pregnancy category B. After oral administration, Famvir for Genital Herpes (prodrug) is converted to penciclovir (active drug). There are no adequate and well-controlled studies of Famvir for Genital Herpes or penciclovir use in pregnant women. No adverse effects on embryofetal development were observed in animal reproduction studies using Famvir for Genital Herpes and penciclovir at doses higher than the maximum recommended human dose (MRHD) and human exposure. Because animal reproduction studies are not always predictive of human response, Famvir for Genital Herpes should be used during pregnancy only if needed.

In animal reproduction studies, pregnant rats and rabbits received oral Famvir for Genital Herpes at doses (up to 1000 mg/kg/day) that provided 2.7 to 10.8 times (rats) and 1.4 to 5.4 times (rabbits) the human systemic exposure based on AUC. No adverse effects were observed on embryo-fetal development. In other studies, pregnant rats and rabbits received intravenous Famvir for Genital Herpes at doses (360 mg/kg/day) 1.5 to 6 times (rats) and (120 mg/kg/day) 1.1 to 4.5 times (rabbits) or penciclovir at doses (80 mg/kg/day) 0.3 to 1.3 times (rats) and (60 mg/kg/day) 0.5 to 2.1 times (rabbits) the MRHD based on body surface area comparisons. No adverse effects were observed on embryo-fetal development.

8.3 Nursing Mothers

It is not known whether Famvir for Genital Herpes or penciclovir (active drug) are excreted in human milk. Following oral administration of Famvir for Genital Herpes to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma. There are no data on the safety of Famvir for Genital Herpes in infants. Famvir for Genital Herpes should not be used in nursing mothers unless the potential benefits are considered to outweigh the potential risks associated with treatment.

8.4 Pediatric Use

The efficacy and safety of Famvir for Genital Herpes have not been established in pediatric patients.

Labeling describing additional clinical pharmacokinetic studies in pediatric patients (ages of 1 month to <12 years) is approved for Novartis Pharmaceuticals Corporation’s Famvir® Tablets. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, a description of those clinical pharmacokinetic studies is not approved for this Famvir for Genital Herpes tablet product.

8.5 Geriatric Use

Of 610 patients with recurrent herpes simplex in clinical studies who were treated with Famvir for Genital Herpes, 26 (4.3%) were >65 years of age and 7 (1.1%) were >75 years of age. Clinical studies of Famvir for Genital Herpes in patients with recurrent genital herpes did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects.

No Famvir for Genital Herpes dosage adjustment based on age is recommended unless renal function is impaired [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. In general, appropriate caution should be exercised in the administration and monitoring of Famvir for Genital Herpes in elderly patients reflecting the greater frequency of decreased renal function and concomitant use of other drugs.

8.6 Patients with Renal Impairment

Apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal function. After the administration of a single 500 mg Famvir for Genital Herpes oral dose (n=27) to healthy volunteers and to volunteers with varying degrees of renal impairment (CL_CR ranged from 6.4 to 138.8 mL/min), the following results were obtained (Table 4):

In a multiple-dose study of Famvir for Genital Herpes conducted in subjects with varying degrees of renal impairment (n=18), the pharmacokinetics of penciclovir were comparable to those after single doses.

A dosage adjustment is recommended for patients with renal impairment [see Dosage and Administration (2.3)].

8.7 Patients with Hepatic Impairment

Mild or moderate hepatic impairment (chronic hepatitis [n=6], chronic ethanol abuse [n=8], or primary biliary cirrhosis [n=1]) had no effect on the extent of availability (AUC) of penciclovir following a single dose of 500 mg Famvir for Genital Herpes. However, there was a 44% decrease in penciclovir mean maximum plasma concentration (C_max) and the time to maximum plasma concentration (t_max) was increased by 0.75 hours in patients with hepatic impairment compared to normal volunteers. No dosage adjustment is recommended for patients with mild or moderate hepatic impairment. The pharmacokinetics of penciclovir has not been evaluated in patients with severe hepatic impairment. Conversion of Famvir for Genital Herpes to the active metabolite penciclovir may be impaired in these patients resulting in a lower penciclovir plasma concentrations, and thus possibly a decrease of efficacy of Famvir for Genital Herpes.

10 OVERDOSAGE

Appropriate symptomatic and supportive therapy should be given. Penciclovir is removed by hemodialysis.

11 DESCRIPTION

The active ingredient in Famvir for Genital Herpes tablets is Famvir for Genital Herpes, an orally administered prodrug of the antiviral agent penciclovir. Chemically, Famvir for Genital Herpes is known as 2-[2-(2-amino-9H-purin-9-yl) ethyl]-1, 3-propanediol diacetate. Its molecular formula is C₁₄H₁₉N₅O₄; its molecular weight is 321.3. It is a synthetic acyclic guanine derivative and has the following structure

Famvir for Genital Herpes 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 Famvir for Genital Herpes is freely soluble (>25% w/v) in water initially, but rapidly precipitates as the sparingly soluble (2%-3% w/v) monohydrate. Famvir for Genital Herpes 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.

Famvir for Genital Herpes tablets contain 125 mg, 250 mg or 500 mg of Famvir for Genital Herpes, together with the following inactive ingredients: croscarmellose sodium, crospovidone, hypromellose 2910, lactose monohydrate, magnesium stearate, polyethylene glycols 6000 and titanium dioxide.

Famvir for Genital Herpes structural formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Famvir for Genital Herpes is an orally administered prodrug of the antiviral agent penciclovir [see Clinical Pharmacology ].

12.3 Pharmacokinetics

Famvir for Genital Herpes is the diacetyl 6-deoxy analog of the active antiviral compound penciclovir. Following oral administration Famvir for Genital Herpes undergoes rapid and extensive metabolism to penciclovir and little or no Famvir for Genital Herpes is detected in plasma or urine. Penciclovir is predominantly eliminated unchanged by the kidney. Therefore, the dose of Famvir for Genital Herpes needs to be adjusted in patients with different degrees of renal impairment [see Dosage and Administration (2.3)].

Pharmacokinetics in adults:

Absorption and Bioavailability: The absolute bioavailability of penciclovir is 77 ± 8% as determined following the administration of a 500 mg Famvir for Genital Herpes oral dose and a 400 mg penciclovir intravenous dose to 12 healthy male subjects.

Penciclovir concentrations increased in proportion to dose over a Famvir for Genital Herpes dose range of 125 mg to 1000 mg administered as a single dose. Table 5 shows the mean pharmacokinetic parameters of penciclovir after single administration of Famvir for Genital Herpes to healthy male volunteers.

There is no accumulation of penciclovir after the administration of 500 mg Famvir for Genital Herpes three times daily for 7 days.

Penciclovir C_max decreased approximately 50% and t_max was delayed by 1.5 hours when a capsule formulation of Famvir for Genital Herpes was administered with food (nutritional content was approximately 910 Kcal and 26% fat). There was no effect on the extent of availability (AUC) of penciclovir. There was an 18% decrease in C_max and a delay in t_max of about 1 hour when Famvir for Genital Herpes was given 2 hours after a meal as compared to its administration 2 hours before a meal. Because there was no effect on the extent of systemic availability of penciclovir, Famvir for Genital Herpes can be taken without regard to meals.

Distribution: The volume of distribution (Vdβ) was 1.08±0.17 L/kg in 12 healthy male subjects following a single intravenous dose of penciclovir at 400 mg administered as a 1-hour intravenous infusion. Penciclovir is <20% bound to plasma proteins over the concentration range of 0.1 to 20 mcg/mL. The blood/plasma ratio of penciclovir is approximately 1.

Metabolism: Following oral administration, Famvir for Genital Herpes is deacetylated and oxidized to form penciclovir. Metabolites that are inactive include 6-deoxy penciclovir, monoacetylated penciclovir, and 6-deoxy monoacetylated penciclovir (5%, <0.5% and <0.5% of the dose in the urine, respectively). Little or no Famvir for Genital Herpes is detected in plasma or urine. An in vitro study using human liver microsomes demonstrated that cytochrome P450 does not play an important role in Famvir for Genital Herpes metabolism. The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir in vivo [see Drug Interactions (7.2)].

Elimination: Approximately 94% of administered radioactivity was recovered in urine over 24 hours (83% of the dose was excreted in the first 6 hours) after the administration of 5 mg/kg radiolabeled penciclovir as a 1-hour infusion to 3 healthy male volunteers. Penciclovir accounted for 91% of the radioactivity excreted in the urine.

Following the oral administration of a single 500 mg dose of radiolabeled Famvir for Genital Herpes to 3 healthy male volunteers, 73% and 27% of administered radioactivity were recovered in urine and feces over 72 hours, respectively. Penciclovir accounted for 82% and 6-deoxy penciclovir accounted for 7% of the radioactivity excreted in the urine. Approximately 60% of the administered radiolabeled dose was collected in urine in the first 6 hours.

After intravenous administration of penciclovir in 48 healthy male volunteers, mean ± SD total plasma clearance of penciclovir was 36.6±6.3 L/hr (0.48±0.09 L/hr/kg). Penciclovir renal clearance accounted for 74.5±8.8% of total plasma clearance.

Renal clearance of penciclovir following the oral administration of a single 500 mg dose of Famvir for Genital Herpes to 109 healthy male volunteers was 27.7±7.6 L/hr. Active tubular secretion contributes to the renal elimination of penciclovir.

The plasma elimination half-life of penciclovir was 2.0±0.3 hours after intravenous administration of penciclovir to 48 healthy male volunteers and 2.3±0.4 hours after oral administration of 500 mg Famvir for Genital Herpes to 124 healthy male volunteers.

Special populations:

Geriatric patients: Based on cross study comparison, penciclovir AUC was 40% higher and penciclovir renal clearance was 22% lower in elderly subjects (n=18, age 65-79 years) as compared with younger subjects Some of this difference may be due to differences in renal function between the 2 groups. No Famvir for Genital Herpes dosage adjustment based on age is recommended unless renal function is impaired [see Dosage and Administration (2.3), Use in Specific Populations (8.5).]

Patients with renal impairment: In subjects with varying degrees of renal impairment, apparent plasma clearance, renal clearance, and the plasma-elimination rate constant of penciclovir decreased linearly with reductions in renal function, after both single and repeated dosing [see Use in Specific Populations (8.6)]. A dosage adjustment is recommended for patients with renal impairment [see Dosage and Administration (2.3)].

Patients with hepatic impairment: Mild or moderate hepatic impairment had no effect on the extent of availability (AUC) of penciclovir [see Use in Specific Populations (8.7)]. No dosage adjustment is recommended for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of penciclovir has not been evaluated.

HIV-infected patients: Following oral administration of a single dose of 500 mg Famvir for Genital Herpes to HIV-positive patients, the pharmacokinetic parameters of penciclovir were comparable to those observed in healthy subjects.

Gender: The pharmacokinetics of penciclovir were evaluated in 18 healthy male and 18 healthy female volunteers after single-dose oral administration of 500 mg Famvir for Genital Herpes. AUC of penciclovir was 9.3±1.9 mcg hr/mL and 11.1±2.1 mcg hr/mL in males and females, respectively. Penciclovir renal clearance was 28.5±8.9 L/hr and 21.8±4.3 L/hr, respectively. These differences were attributed to differences in renal function between the 2 groups. No Famvir for Genital Herpes dosage adjustment based on gender is recommended.

Race: 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 Famvir for Genital Herpes 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 significant differences in the pharmacokinetics of penciclovir between black and Caucasian subjects.

12.4 Virology

Mechanism of action: Famvir for Genital Herpes is a prodrug of penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). In cells infected with HSV-1, HSV-2 the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical 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- infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown.

Antiviral activity: In cell culture studies, penciclovir is inhibitory to the following herpes viruses: HSV-1 and HSV-2. The antiviral activity of penciclovir against wild type strains grown on human foreskin fibroblasts was assessed with a plaque reduction assay and staining with crystal violet 3 days postinfection for HSV. The median EC₅₀ values of penciclovir against laboratory and clinical isolates of HSV-1 and HSV-2 were 2 μM (range 1.2 to 2.4 μM, n = 7) and 2.6 μM (range 1.6 to 11 μM, n = 6), respectively.

Resistance: Penciclovir-resistant mutants of HSV 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 median EC₅₀ values observed in a plaque reduction assay with penciclovir resistant HSV-1 and HSV-2 were 69 μM (range 14 to 115 μM, n = 6) and 46 μM (range 4 to >395 μM, n = 9), respectively. The possibility of viral resistance to penciclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.

Cross-resistance: Cross-resistance has been observed among HSV DNA polymerase inhibitors. The most commonly encountered acyclovir resistant mutants that are TK negative are also resistant to penciclovir.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Two-year dietary carcinogenicity studies with Famvir for Genital Herpes were conducted in rats and mice. An increase in the incidence of mammary adenocarcinoma (a common tumor in animals of this strain) was seen in female rats receiving the high dose of 600 mg/kg/day (1.1 to 4.5x the human systemic exposure at the recommended total daily oral dose ranging between 500 mg and 2000 mg, based on area under the plasma concentration curve comparisons [24 hr AUC] for penciclovir). No increases in tumor incidence were reported in male rats treated at doses up to 240 mg/kg/day (0.7 to 2.7x the human AUC), or in male and female mice at doses up to 600 mg/kg/day (0.3 to 1.2x the human AUC).

Mutagenesis: Famvir for Genital Herpes and penciclovir (the active metabolite of Famvir for Genital Herpes) were tested for genotoxic potential in a battery of in vitro and in vivo assays. Famvir for Genital Herpes and penciclovir were negative in in vitro tests for gene mutations in bacteria (S. typhimurium and E. coli) and unscheduled DNA synthesis in mammalian HeLa 83 cells (at doses up to 10,000 and 5,000 mcg/plate, respectively). Famvir for Genital Herpes was also negative in the L5178Y mouse lymphoma assay (5000 mcg/mL), the in vivo mouse micronucleus test (4800 mg/kg), and rat dominant lethal study (5000 mg/kg). Famvir for Genital Herpes induced increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage (1200 mcg/mL). Penciclovir was positive in the L5178Y mouse lymphoma assay for gene mutation/chromosomal aberrations, with and without metabolic activation (1000 mcg/mL). In human lymphocytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation (250 mcg/mL). Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when administered intravenously at doses highly toxic to bone marrow (500 mg/kg), but not when administered orally.

Impairment of fertility: Testicular toxicity was observed in rats, mice, and dogs following repeated administration of Famvir for Genital Herpes or penciclovir. Testicular changes included atrophy of the seminiferous tubules, reduction in sperm count, and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of toxicity to male reproduction was related to dose and duration of exposure. In male rats, decreased fertility was observed after 10 weeks of dosing at 500 mg/kg/day (1.4 to 5.7x the human AUC). The no observable effect level for sperm and testicular toxicity in rats following chronic administration (26 weeks) was 50 mg/kg/day (0.15 to 0.6 x the human systemic exposure based on AUC comparisons). Testicular toxicity was observed following chronic administration to mice (104 weeks) and dogs (26 weeks) at doses of 600 mg/kg/day (0.3 to 1.2x the human AUC) and 150 mg/kg/day (1.3 to 5.1x the human AUC), respectively.

Famvir for Genital Herpes had no effect on general reproductive performance or fertility in female rats at doses up to 1000 mg/kg/day (2.7 to 10.8x the human AUC).

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 Famvir for Genital Herpes (250 mg twice daily) (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.

14 CLINICAL STUDIES

14.1 Herpes Labialis

A randomized, double-blind, placebo-controlled trial was conducted in 701 immunocompetent adults with recurrent herpes labialis. Patients self-initiated therapy within 1 hour of first onset of signs or symptoms of a recurrent herpes labialis episode with Famvir for Genital Herpes 1500 mg as a single dose (n=227), Famvir for Genital Herpes 750 mg twice daily (n=220) or placebo (n=254) for 1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule stage) was 4.4 days in the Famvir for Genital Herpes 1500 mg single-dose group (n=152) as compared to 6.2 days in the placebo group (n=168). The median difference in time to healing between the placebo and Famvir for Genital Herpes 1500 mg treated groups was 1.3 days (95% CI: 0.6 – 2.0). No differences in proportion of patients with aborted lesions (not progressing beyond the papule stage) were observed between patients receiving Famvir for Genital Herpes or placebo: 33% for Famvir for Genital Herpes 1500 mg single dose and 34% for placebo. The median time to loss of pain and tenderness was 1.7 days in Famvir for Genital Herpes 1500 mg single dose-treated patients vs. 2.9 days in placebo-treated patients.

14.2 Genital Herpes

Recurrent episodes: A randomized, double-blind, placebo-controlled trial was conducted in 329 immunocompetent adults with recurrent genital herpes. Patients self-initiated therapy within 6 hours of the first sign or symptom of a recurrent genital herpes episode with either Famvir for Genital Herpes 1000 mg twice daily or placebo (n=166) for 1 day. The median time to healing among patients with non-aborted lesions (progressing beyond the papule stage) was 4.3 days in famciclovir-treated patients (n=125) as compared to 6.1 days in placebo-treated patients (n=145). The median difference in time to healing between the placebo and famciclovir-treated groups was 1.2 days (95% CI: 0.5 to 2.0). Twenty-three percent of famciclovir-treated patients had aborted lesions (no lesion development beyond erythema) vs. 13% in placebo-treated patients. The median time to loss of all symptoms (e.g., tingling, itching, burning, pain, or tenderness) was 3.3 days in famciclovir-treated patients vs. 5.4 days in placebo-treated patients.

Suppressive therapy: Two randomized, double-blind, placebo-controlled, 12-month trials were conducted in 934 immunocompetent adults with a history of 6 or more recurrences of genital herpes episodes per year. Comparisons included Famvir for Genital Herpes 125 mg three times daily, 250 mg twice daily, 250 mg three times daily, and placebo. At 12 months, 60% to 65% of patients were still receiving Famvir for Genital Herpes and 25% were receiving placebo treatment. Recurrence rates at 6 and 12 months in patients treated with the 250 mg twice daily dose are shown in Table 6.

Famciclovir-treated patients had approximately 1/5 the median number of recurrences as compared to placebo-treated patients. Higher doses of Famvir for Genital Herpes were not associated with an increase in efficacy.

14.3 Recurrent Orolabial or Genital Herpes in HIV-Infected Patients

A randomized, double-blind trial compared Famvir for Genital Herpes 500 mg twice daily for 7 days (n=150) with oral acyclovir 400 mg 5 times daily for 7 days (n=143) in HIV-infected patients with recurrent orolabial or genital herpes treated within 48 hours of lesion onset. Approximately 40% of patients had a CD₄ ⁺ count below 200 cells/mm³, 54% of patients had anogenital lesions and 35% had orolabial lesions. Famvir for Genital Herpes therapy was comparable to oral acyclovir in reducing new lesion formation and in time to complete healing.

16 HOW SUPPLIED/STORAGE AND HANDLING

Famvir for Genital Herpes tablets are 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.

Famvir for Genital Herpes 125 mg tablet:

White, round film-coated, biconvex, beveled edges, debossed with WPI on one side and 3271 on the other.

125 mg 30’s…………………..…………………………………………… NDC 0591-3271-30

Famvir for Genital Herpes 250 mg tablet:

White, round film-coated, biconvex, beveled edges, debossed with WPI on one side and 3272 on the other.

250 mg 30’s………..……………………………………………………… NDC 0591-3272-30

Famvir for Genital Herpes 500 mg tablet:

White, capsule shaped film-coated, biconvex, debossed with WPI on one side and 3273 on the other.

500 mg 30’s……………………..………………………………………… NDC 0591-3273-30

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

There is no evidence that Famvir for Genital Herpes tablets 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 for Genital Herpes tablets should refrain from driving or operating machinery.

Because Famvir for Genital Herpes tablets contains lactose (famciclovir tablets 125 mg, 250 mg and 500 mg tablets contain lactose 11 mg, 22 mg and 44 mg, respectively), patients with rare hereditary problems of galactose intolerance, a severe lactase deficiency or glucose-galactose malabsorption should be advised to discuss with their healthcare provider before taking Famvir for Genital Herpes tablets.

17.1 Herpes Labialis (Cold Sores)

Patients should be advised to initiate treatment at the earliest sign or symptom of a recurrence of cold sores (e.g., tingling, itching, burning, pain, or lesion). Patients should be instructed that treatment for cold sores should not exceed 1 dose. Patients should be informed that Famvir for Genital Herpes tablets are not a cure for cold sores.

17.2 Genital Herpes

Patients should be informed that Famvir for Genital Herpes tablets are not a cure for genital herpes. There are no data evaluating whether Famvir for Genital Herpes tablets will prevent transmission of infection to others. Because 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 is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices.

If episodic therapy for recurrent genital herpes is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode.

There are no data on safety or effectiveness of chronic suppressive therapy of longer than 1-year duration.

Disclaimer: Other Brands listed are the registered trademarks of their respective owners and are not trademarks of Cipla Limited.

Manufactured for:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Manufactured by:

Cipla Ltd.

Verna Goa, INDIA

Revised: 9/2015

Famvir for Genital Herpes (fam sye' kloe vir) Tablets

Rx Only

Read this Patient Information before you start taking Famvir for Genital Herpes tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

What are Famvir for Genital Herpes tablets?

Famvir for Genital Herpes tablets are a prescription antiviral medicine used to:

• treat outbreaks of cold sores (fever blisters) in healthy adults.
• treat outbreaks of genital herpes in healthy adults.
• decrease the number of outbreaks of genital herpes in healthy adults.
• treat outbreaks of herpes simplex lesions in or around the mouth, genitals, and anal area in people infected with HIV.

It is not known if Famvir for Genital Herpes tablets are safe and effective in children younger than 18 years of age.

Famvir for Genital Herpes tablets are not a cure for herpes. It is not known if Famvir for Genital Herpes tablets can stop the spread of herpes to others. If you are sexually active, you can pass herpes to your partner even if you are taking Famvir for Genital Herpes tablets. Herpes can be transmitted even if you do not have active symptoms. You should continue to practice safer sex to lower the chances of spreading genital herpes to others. Do not have sexual contact with your partner during an outbreak of genital herpes or if you have any symptoms of genital herpes. Use a condom made of latex or polyurethane when you have a sexual contact. Ask your healthcare provider for more information about safer sex practices.

Who should not take Famvir for Genital Herpes tablets?

Do not take Famvir for Genital Herpes tablets if you are allergic to any of its ingredients or to penciclovir cream. See the end of this Patient Information leaflet for a complete list of ingredients in Famvir for Genital Herpes tablets.

What should I tell my healthcare provider before taking Famvir for Genital Herpes tablets?

Before you start taking Famvir for Genital Herpes tablets, tell your healthcare provider if you:

• have kidney or liver problems
• have a rare genetic problem with galactose intolerance, a severe lactase deficiency or you do not absorb glucose-galactose (malabsorption)
• are pregnant or planning to become pregnant. It is not known if Famvir for Genital Herpes tablets will harm your unborn baby
• are breastfeeding or plan to breastfeed

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take:

• any other medicines and products you use to treat herpes outbreaks
• probenecid (Probalan)

Know the medicines you take. Keep a list of them with you to show to your healthcare provider and pharmacist every time you get a new medicine.

How should I take Famvir for Genital Herpes tablets?

• Take Famvir for Genital Herpes tablets exactly as prescribed
• Your healthcare provider will tell you how many Famvir for Genital Herpes tablets to take and when to take them. Your dose of Famvir for Genital Herpes tablets and how often you take it may be different depending on your condition
• Famvir for Genital Herpes tablets can be taken with or without food
• It is important for you to finish all of the medicine as prescribed, even if you begin to feel better
• Your symptoms may continue even after you finish all of your Famvir for Genital Herpes tablets. This does not mean that you need more medicine, since you have already finished a full course of Famvir for Genital Herpes tablets and it will continue to work in your body. Talk to your healthcare provider if you have any questions about your condition and your treatment

What are the possible side effects of Famvir for Genital Herpes tablets?

The most common side effects of Famvir for Genital Herpes tablets include:

• headache
• nausea
• Talk to your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Famvir for Genital Herpes tablets. Ask your healthcare provider or pharmacist for more information.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Famvir for Genital Herpes tablets?

• Store Famvir for Genital Herpes tablets at 20° to 25°C (68° to 77°F).

Keep Famvir for Genital Herpes tablets and all medicines out of reach from children.

General information about Famvir for Genital Herpes tablets

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Famvir for Genital Herpes tablets for a condition for which it was not prescribed. Do not give Famvir for Genital Herpes tablets to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Famvir for Genital Herpes tablets. If you would like more information, talk with your healthcare provider. Your healthcare provider or pharmacist can give you information about Famvir for Genital Herpes tablets that is written for health professionals. For more information, call 1-866-604-3268.

What are the ingredients in Famvir for Genital Herpes tablets?

Active ingredient: Famvir for Genital Herpes

Inactive ingredients: croscarmellose sodium, crospovidone, hypromellose 2910, lactose monohydrate, magnesium stearate, polyethylene glycols 6000 and titanium dioxide.

Disclaimer: Other Brands listed are the registered trademarks of their respective owners and are not trademarks of Cipla Limited.

Manufactured for:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Manufactured by:

Cipla Ltd.

Verna Goa, INDIA

Revised: 9/2015

Famvir for Genital Herpes pharmaceutical active ingredients containing related brand and generic drugs:

• Famciclovir

Famvir for Genital Herpes available forms, composition, doses:

• Tablets, Film-Coated; Oral; Famciclovir 500 mg
• Tablets; Oral; Famciclovir 125 mg
• Tablets; Oral; Famciclovir 250 mg

Famvir for Genital Herpes destination | category:

• Human:
• Antivirals
• Nucleosides and nucleotides

Famvir for Genital Herpes Anatomical Therapeutic Chemical codes:

• J05AB09 - Famciclovir

Famvir for Genital Herpes pharmaceutical companies:

• Novartis

References

1. Dailymed."FAMCICLOVIR TABLET, FILM COATED [ACTAVIS PHARMA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."FAMCICLOVIR: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "famciclovir". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Famvir for Genital Herpes after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Famvir for Genital Herpes not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology