Famciclovir

Famciclovir tablets, a prodrug of penciclovir, are a deoxynucleoside 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 Herpes zoster (shingles) Human Immunodeficiency Virus (HIV) -Infected Adult Patients Treatment of recurrent episodes of orolabial or genital herpes Limitation of Use The efficacy and safety of famciclovir tablets have not been established for: Patients with first episode of genital herpes Patients with ophthalmic zoster Immunocompromised patients other than for the treatment of recurrent episodes of orolabial or genital herpes in HIV-infected patients Black and African American patients with recurrent genital herpes

1.1Immunocompetent Adult Patients Herpes

labialis (cold sores): Famciclovir tablets are indicated for the treatment of recurrent herpes labialis in adult patients. Genital herpes: Recurrent episodes: Famciclovir tablets are indicated for the treatment of recurrent episodes of genital herpes. The efficacy of famciclovir tablets when initiated more than 6 hours after onset of symptoms or lesions has not been established.

Suppressive therapy: Famciclovir tablets are indicated for chronic suppressive therapy of recurrent episodes of genital herpes in adult patients. The efficacy and safety of famciclovir tablets for the suppression of recurrent genital herpes beyond 1 year have not been established. Herpes zoster (shingles): Famciclovir tablets are indicated for the treatment of herpes zoster in adult patients.

The efficacy of famciclovir tablets when initiated more than 72 hours after onset of rash has not been established.

1.2HIV-Infected Adult Patients Recurrent

orolabial or genital herpes: Famciclovir tablets are indicated for the treatment of recurrent episodes of orolabial or genital herpes in HIV-infected adults. The efficacy of famciclovir tablets when initiated more than 48 hours after onset of symptoms or lesions has not been established. Limitation of Use The efficacy and safety of famciclovir tablets have not been established for: Patients with first episode of genital herpes Patients with ophthalmic zoster Immunocompromised patients other than for the treatment of recurrent orolabial or genital herpes in HIV-infected patients Black and African American patients with recurrent genital herpes

Famciclovir tablets may be taken with or without food. Immunocompetent Adult Patients Herpes labialis (cold sores) 1500 mg as a single dose Genital herpes Treatment of recurrent episodes 1000 mg twice daily for 1 day Suppressive therapy 250 mg twice daily Herpes zoster (shingles) 500 mg every 8 hours for 7 days HIV-Infected Adult Patients Recurrent episodes of orolabial or genital herpes 500 mg twice daily for 7 days Patients with renal impairment: Adjust dose based on creatinine clearance.

2.1Dosing Recommendation in Immunocompetent Adult Patients

Herpes labialis (cold sores): The recommended dosage of famciclovir 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 famciclovir 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 famciclovir tablets for chronic suppressive therapy of recurrent episodes of genital herpes is 250 mg twice daily. Herpes zoster (shingles): The recommended dosage of famciclovir tablets for the treatment of herpes zoster is 500 mg every 8 hours for 7 days.

Therapy should be initiated as soon as herpes zoster is diagnosed.

2.2Dosing Recommendation in HIV-Infected Adult Patients

Recurrent orolabial or genital herpes: The recommended dosage of famciclovir 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 (e.g., tingling, itching, burning, pain, or lesion).

2.3Dosing Recommendation in Patients with Renal Impairment

Dosage recommendations for adult patients with renal impairment are provided in Table 1 . Table 1: Dosage Recommendations for Adult Patients with Renal Impairment 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 to 59 500 every 12 hours for 1 day 20 to 39 500 single dose <20 250 single dose HD Hemodialysis 250 single dose following dialysis Recurrent Herpes Labialis 1500 mg single dose ≥60 1500 single dose 40 to 59 750 single dose 20 to 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 to 59 500 every 12 hours 20 to 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 to 39 125 every 12 hours <20 125 every 24 hours HD 125 following each dialysis Recurrent Orolabial or Genital Herpes in HIV-Infected Patients 500 mg every 12 hours ≥40 500 every 12 hours 20 to 39 500 every 24 hours <20 250 every 24 hours HD 250 following each dialysis

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

5.1Acute Renal Failure Cases of

acute renal failure have been reported in patients with underlying renal disease who have received inappropriately high doses of famciclovir for their level of renal function. Dosage reduction is recommended when administering famciclovir to patients with renal impairment .

Famciclovir is contraindicated in patients with known hypersensitivity to the product, its components, or Denavir ® (penciclovir cream). Known hypersensitivity to the product, its components, or Denavir ® (penciclovir cream).

8.1Pregnancy Risk Summary Available

data from pharmacovigilance reports with famciclovir use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the fetus associated with untreated herpes simplex virus during pregnancy . After oral administration, famciclovir (prodrug) is converted to penciclovir (active drug). In animal reproduction studies with famciclovir, no evidence of adverse developmental outcomes was observed at systemic exposures of penciclovir (AUC) slightly higher than those at the maximum recommended human dose (MRHD) of famciclovir . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo-fetal risk The risk of neonatal herpes infection varies from 30% to 50% for genital herpes simplex virus (HSV) infections that occur in late pregnancy (third trimester), whereas in early pregnancy, infection carries a risk of about 1%. A primary herpes outbreak during the first trimester of pregnancy has been associated with neonatal chorioretinitis, microcephaly and, in rare cases, skin lesions.

In very rare cases, transplacental transmission can occur resulting in congenital infection, including microcephaly, hepatosplenomegaly, intrauterine growth restriction and stillbirth. Co-infection with HSV increases the risk of perinatal HIV transmission in women who had a clinical diagnosis of genital herpes during pregnancy. Data Animal Data Famciclovir was administered orally to pregnant rats and rabbits (up to 1000 mg/kg/day) on gestation Day(s) 6 to 15, and to rats on gestation Day 15 to lactation/post-partum Day 25.

No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed up to the highest dose tested. During organogenesis, systemic exposures of penciclovir (active metabolite) were 3.4 times (rats) and 1.6 times (rabbits) the human systemic exposure of penciclovir based on AUC at the MRHD.

8.2Lactation Risk Summary There

are no data on the presence of famciclovir (prodrug) or penciclovir (active drug) in human milk, the effects on the breastfed infant, or the effects on milk production. Animal data indicate that penciclovir is present in the milk of lactating rats . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for famciclovir and any potential adverse effects on the breastfed infant from famciclovir or from the underlying maternal condition. Data Penciclovir was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 40 mg per kg on lactation Day 12, with milk concentrations of up to approximately 8 times that of maternal plasma concentrations observed 0.5 hours postdose.

Acute renal failure is discussed in greater detail in other sections of the label . The most common adverse events reported in at least 1 indication by greater than 10% of adult patients treated with famciclovir are headache and nausea. The most common adverse events reported in at least 1 indication by greater than 10% of adult patients are headache and nausea. To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 famciclovir has been evaluated in active- and placebo-controlled clinical studies involving 816 famciclovir-treated patients with herpes zoster (famciclovir, 250 mg three times daily to 750 mg three times daily); 163 famciclovir-treated patients with recurrent genital herpes (famciclovir, 1000 mg twice daily); 1,197 patients with recurrent genital herpes treated with famciclovir as suppressive therapy (125 mg once daily to 250 mg three times daily) of which 570 patients received famciclovir (open-labeled and/or double-blind) for at least 10 months; and 447 famciclovir-treated patients with herpes labialis (famciclovir, 1500 mg once daily or 750 mg twice daily). Table 2 lists selected adverse events.

Table 2: Selected Adverse Events (all grades and without regard to causality) Reported by Greater than or Equal to 2% of Patients in Placebo-Controlled Famciclovir Trials Patients may have entered into more than one clinical trial. Incidence Events Herpes Zoster 7 days of treatment Recurrent Genital Herpes 1 day of treatment Genital Herpes- Supression daily treatment Herpes Labialis Famciclovir (n=273) % Placebo (n=146) % Famciclovir (n=163) % Placebo (n=166) % Famciclovir (n=458) % Placebo (n=63) % Famciclovir (n=447) % Placebo (n=254) % Nervous System Headache 22.7 17.8 13.5 5.4 39.3 42.9 8.5

6.7Paresthesia

2.6 0.0 0.0 0.0 0.9 0.0 0.0

0.0Migraine

0.7 0.7 0.6 0.6 3.1 0.0 0.2

0.0Gastrointestinal Nausea

12.5 11.6 2.5 3.6 7.2 9.5 2.2

3.9Diarrhea

7.7 4.8 4.9 1.2 9.0 9.5 1.6

0.8Vomiting

4.8 3.4 1.2 0.6 3.1 1.6 0.7

0.0Flatulence

1.5 0.7 0.6 0.0 4.8 1.6 0.2

0.0Abdominal Pain

1.1 3.4 0.0 1.2 7.9 7.9 0.2

0.4Body as a Whole Fatigue

4.4 3.4 0.6 0.0 4.8 3.2 1.6

0.4Skin and Appendages Pruritus

3.7 2.7 0.0 0.6 2.2 0.0 0.0

0.0Rash

0.4 0.7 0.0 0.0 3.3 1.6 0.0

0.0Reproductive

(Female) Dysmenorrhea 0.0 0.7 1.8 0.6 7.6 6.3 0.4

0.0Table

3 lists selected laboratory abnormalities in genital herpes suppression trials. Table 3: Selected Laboratory Abnormalities in Genital Herpes Suppression Studies Percentage of patients with laboratory abnormalities that were increased or decreased from baseline and were outside of specified ranges. Parameter Famciclovir (n=660) n values represent the minimum number of patients assessed for each laboratory parameter. % Placebo (n=210) % Anemia (<0.8 x NRL) 0.1

0.0Leukopenia

(<0.75 x NRL) 1.3

0.9Neutropenia

(<0.8 x NRL) 3.2

1.5AST

(SGOT) (>2 x NRH) 2.3

1.2ALT

(SGPT) (>2 x NRH) 3.2

1.5Total Bilirubin

(>1.5 x NRH) 1.9

1.2Serum Creatinine

(>1.5 x NRH) 0.2

0.3Amylase

(>1.5 x NRH) 1.5

1.9Lipase

(>1.5 x NRH) 4.9

4.7NRH

= 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 (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%).

6.2Postmarketing Experience The

adverse events listed below have been reported during post-approval use of famciclovir. 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 Immune system disorders: Anaphylactic shock, anaphylactic reaction Nervous system disorders : Dizziness, somnolence, seizure 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), hypersensitivity vasculitis Cardiac disorders: Palpitations To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.