FAMCICLOVIR: 495 Adverse Event Reports & Safety Profile

Famciclovir Tablets, USP contain famciclovir, USP, an orally administered prodrug of the antiviral agent penciclovir. Chemically, famciclovir, USP is known as 2-[2-(2-amino-9 H -purin-9-yl)ethyl]-1,3-propanediol diacetate. It is a synthetic acyclic guanine derivative and has the following structure: C 14 H 19 N 5 O 4 M.W.

321.3 Famciclovir, USP 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, USP is freely soluble (greater than 25% w/v) in water initially, but rapidly precipitates as the sparingly soluble (2% to 3% w/v) monohydrate. Famciclovir, USP 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. Each white, film-coated tablet contains famciclovir, USP.

The

125 mg and 250 mg tablets are round; the 500 mg tablets are capsule-shaped. Inactive ingredients consist of croscarmellose sodium, hydroxypropyl cellulose, hypromellose, polydextrose, polyethylene glycol, silicified microcrystalline cellulose, sodium starch glycolate, sodium stearyl fumarate, titanium dioxide, and triacetin. Product meets USP Dissolution Test 2.

Chemical

Structure for Famciclovir

1 INDICATIONS & USAGE Famciclovir tablet, a prodrug of penciclovir, is a deoxynucleoside analog DNA polymerase inhibitor indicated for: Immunocompetent Adult Patients ( 1.1 )

• Herpes labialis (cold sores) o Treatment of recurrent episodes
• Genital herpes o Treatment of recurrent episodes o Suppressive therapy of recurrent episodes
• Herpes zoster (shingles)

Human Immunodeficiency

Virus (HIV)-Infected Adult Patients ( 1.2 )

• 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

1.1 Immunocompetent 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.

1.2 HIV-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

AND ADMINISTRATION Famciclovir tablets may be taken with or without food.

Immunocompetent Adult

Patients ( 2.1 ) Herpes labialis (cold sores) 1500 mg as a single dose Genital herpes Treatment of recurrent episodes Suppressive therapy 1000 mg twice daily for 1 day 250 mg twice daily Herpes zoster (shingles) 500 mg every 8 hours for 7 days HIV-Infected Adult Patients ( 2.2 ) Recurrent episodes of orolabial or genital herpes 500 mg twice daily for 7 days Patients with renal impairment: Adjust dose based on creatinine clearance. ( 2.3 )

2.1 Dosing 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.

2.2 Dosing 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).

2.3 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) ] .

Table

1: Dosage Recommendations for Adult Patients with Renal Impairment * Hemodialysis 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 * 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

Famciclovir tablets are 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). ( 4 )

REACTIONS Acute renal failure is discussed in greater detail in other sections of the label [see Warnings and Precautions ( 5 ) ] . 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 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

6.7 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 0.2

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 1.6

0.8 Vomiting 4.8 3.4 1.2 0.6 3.1 1.6 0.7

0.0 Flatulence 1.5 0.7 0.6 0.0 4.8 1.6 0.2

0.0 Abdominal Pain 1.1 3.4 0.0 1.2 7.9 7.9 0.2

0.4 Body as a Whole Fatigue 4.4 3.4 0.6 0.0 4.8 3.2 1.6

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 0.4

0.0 Table 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

0.0 Leukopenia (&lt;0.75 x NRL) 1.3

0.9 Neutropenia (&lt;0.8 x NRL) 3.2

1.5 AST (SGOT) (&gt;2 x NRH) 2.3

1.2 ALT (SGPT) (&gt;2 x NRH) 3.2

1.5 Total Bilirubin (&gt;1.5 x NRH) 1.9

1.2 Serum Creatinine (&gt;1.5 x NRH) 0.2

0.3 Amylase (&gt;1.5 x NRH) 1.5

1.9 Lipase (&gt;1.5 x NRH) 4.9

4.7 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 (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 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 [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

AND PRECAUTIONS 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 )

5.1 Acute renal failure Cases of acute renal failure have been reported in patients with underlying renal disease who have received inappropriately high doses of famciclovir tablets for their level of renal function. Dosage reduction is recommended when administering famciclovir tablets to patients with renal impairment <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ), Use in Specific Populations ( 8.6 )]</span>.

INTERACTIONS Probenecid: May increase penciclovir levels. Monitor for evidence of penciclovir toxicity. ( 7.2 )

7.1 Potential for Famciclovir Tablets to Affect Other Drugs The steady-state pharmacokinetics of digoxin were not altered by concomitant administration of multiple doses of famciclovir (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 famciclovir coadministered with zidovudine or emtricitabine. An in vitro study using human liver microsomes suggests that famciclovir 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 famciclovir after pretreatment 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 famciclovir (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 famciclovir 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.