Famciclovir (famciclovir 125 mg) Dailymed

3 Dosage Forms & Strengths

Famciclovir tablets, USP are available in 3 strengths: •125 mg: White to off white, round, film-coated, biconvex, engraved with "ML 67" on one side and plain on the other side. •250 mg: White to off white, round, film-coated, biconvex, engraved with "ML 70" on one side and plain on the other side. •500 mg: White to off white, oval, film-coated, biconvex, engraved with "ML 72" on one side and plain on the other side.


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

4 Contraindications

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)

5 Warnings 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 for their level of renal function. Dosage reduction is recommended when administering famciclovir tablets to patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

6 Adverse 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 Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 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 uls 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 TrialsPatients may have entered into more than one clinical trial
 Incidence
  Events Â	Herpes Zoster7 days of treatment		Recurrent Genital Herpes1 day of treatment		Genital Herpes- Suppressiondaily 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: selected laboratory abnormalities in genital herpes suppression trials

 Table 3 Selected Laboratory Abnormalities in Genital Herpes Suppression StudiesPercentage 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 (<0.75 x NRL)	1.3	0.9
Neutropenia (<0.8 x NRL)	3.2	1.5
AST (SGOT) (>2 x NRH)	2.3	1.2
ALT (SGPT) (>2 x NRH)	3.2	1.5
Total Bilirubin (>1.5 x NRH)	1.9	1.2
Serum Creatinine (>1.5 x NRH)	0.2	0.3
Amylase (>1.5 x NRH)	1.5	1.9
Lipase (>1.5 x NRH)	4.9	4.7

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 uled below have been reported during post-approval use of famciclovir 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 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

8.1 Pregnancy

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 (see Clinical Considerations). 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 (see Data). 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 2-4% and 15- 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.

8.2 Lactation

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 (see Data). 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.

8.3 Females and Males of Reproductive Potential

Infertility

Decreased fertility, due to testicular toxicity, was observed in male animals following repeated administration of famciclovir or penciclovir [see Nonclinical Toxicology (13.1)].

In two placebo-controlled studies, 130 men with a history of recurrent genital herpes received either oral famciclovir (250 mg twice daily; n=66) or placebo (n=64) therapy for 18 weeks. The men were otherwise healthy and had a normal sperm profile prior to treatment. There was no evidence of significant effects on sperm count, motility or morphology during famciclovir treatment or during an 8-week follow-up.

8.4 Pediatric Use

The efficacy of famciclovir tablets has not been established in pediatric patients. The pharmacokinetic profile and safety of famciclovir (experimental granules mixed with OraSweet^® or tablets) were studied in 3 open-label studies. Study 1 was a single-dose pharmacokinetic and safety study in infants 1 month to less than 1 year of age who had an active herpes simplex virus (HSV) infection or who were at risk for HSV infection. Eighteen subjects were enrolled and received a single dose of famciclovir experimental granules mixed with OraSweet based on the patient’s body weight (doses ranged from 25 mg to 175 mg). These doses were selected to provide penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. The efficacy and safety of famciclovir have not been established as suppressive therapy in infants following neonatal HSV infections. In addition, the efficacy cannot be extrapolated from adults to infants because there is no similar disease in adults. Therefore, famciclovir is not recommended in infants. Study 2 was an open-label, single-dose pharmacokinetic, multiple-dose safety study of famciclovir experimental granules mixed with OraSweet in children 1 to less than 12 years of age with clinically suspected HSV or varicella zoster virus (VZV) infection. Fifty-one subjects were enrolled in the pharmacokinetic part of the study and received a single body weight adjusted dose of famciclovir (doses ranged from 125 mg to 500 mg). These doses were selected to provide penciclovir systemic exposures similar to the penciclovir systemic exposures observed in adults after administration of 500 mg famciclovir. Based on the pharmacokinetic data observed with these doses in children, a new weight-based dosing algorithm was designed and used in the multiple-dose safety part of the study. Pharmacokinetic data were not obtained with the revised weight-based dosing algorithm. A total of 100 patients were enrolled in the multiple-dose safety part of the study; 47 subjects with active or latent HSV infection and 53 subjects with chickenpox. Patients with active or latent HSV infection received famciclovir twice a day for 7 days. The daily dose of famciclovir ranged from 150 mg to 500 mg twice daily depending on the patient’s body weight. Patients with chickenpox received famciclovir three times daily for 7 days. The daily dose of famciclovir ranged from 150 mg to 500 mg three times daily depending on the patient’s body weight. The clinical adverse events and laboratory test abnormalities observed in this study were similar to these seen in adults. The available data are insufficient to support the use of famciclovir for the treatment of children 1 to less than 12 years of age with chickenpox or infections due to HSV for the following reasons: Chickenpox: The efficacy of famciclovir for the treatment of chickenpox has not been established in either pediatric or adult patients. Famciclovir is approved for the treatment of herpes zoster in adult patients. However, extrapolation of efficacy data from adults with herpes zoster to children with chickenpox would not be appropriate. Although chickenpox and herpes zoster are caused by the same virus, the diseases are different. Genital herpes: Clinical information on genital herpes in children is limited. Therefore, efficacy data from adults cannot be extrapolated to this population. Further, famciclovir has not been studied in children 1 to less than 12 years of age with recurrent genital herpes. None of the children in Study 2 had genital herpes. Herpes labialis: There are no pharmacokinetic and safety data in children 1 to less than 12 years of age to support a famciclovir dose that provides penciclovir systemic exposures comparable to the penciclovir systemic exposures in adults after a single dose administration of 1500 mg. Moreover, no efficacy data have been obtained in children 1 to less than 12 years of age with recurrent herpes labialis. Study 3 was an open-label, single-arm study to evaluate the pharmacokinetics, safety, and antiviral activity of a single 1500 mg dose (three 500 mg tablets) of famciclovir in children 12 to less than 18 years of age with recurrent herpes labialis. A total of 53 subjects were enrolled in the study; 10 subjects in the pharmacokinetic part of the study and 43 subjects in the non-pharmacokinetic part of the study. All enrolled subjects weighed greater than or equal to 40 kg. The 43 subjects enrolled in the non-pharmacokinetic part of the study had active recurrent herpes labialis and received a single 1500 mg dose of famciclovir within 24 hours after the onset of symptoms (median time to treatment initiation was 21 hours). The safety profile of famciclovir observed in this study was similar to that seen in adults. The median time to healing of patients with non-aborted lesions was 5.9 days.

In a phase 3 trial in adults in which patients received a single 1500 mg dose of famciclovir or placebo, the median time to healing among patients with non-aborted lesions was 4.4 days in the famciclovir 1500 mg single-dose group and 6.2 days in the placebo group. Of note, in the adult study treatment was initiated by patients within 1 hour after the onset of symptoms [see Clinical Studies (14.1)]. Based on the efficacy results in Study 3, famciclovir is not recommended in children 12 to less than 18 years of age with recurrent herpes labialis.

8.5 Geriatric Use

Of 816 patients with herpes zoster in clinical studies who were treated with famciclovir, 248 (30.4%) were greater than or equal to 65 years of age and 103 (13%) were greater than or equal to 75 years of age. No overall differences were observed in the incidence or types of adverse events between younger and older patients. Of 610 patients with recurrent herpes simplex (type 1 or type 2) in clinical studies who were treated with famciclovir, 26 (4.3%) were greater than 65 years of age and 7 (1.1%) were greater than 75 years of age. Clinical studies of famciclovir in patients with recurrent genital herpes did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently compared to younger subjects. No famciclovir 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 famciclovir 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 famciclovir 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): Table 4: Pharmacokinetic Parameters of Penciclovir in Subjects with Different Degrees of Renal Impairment

 Parameter (mean ± S.D.)	 CLCR ≥60 (mL/min) (n=15)	 CLCR 40-59 (mL/min)  (n=5)	 CLCR 20-39 (mL/min) (n=4)	 CLCR <20  (mL/min) (n=3)
CLCR (mL/min)	 88.1 ± 20.6	 49.3 ± 5.9	 26.5 ± 5.3	 12.7 ± 5.9
CLR (L/hr)	 30.1 ± 10.6	13.0 ± 1.3	 4.2 ± 0.9	 1.6 ± 1.0
CL/F (L/hr)	 66.9 ± 27.5	 27.3 ± 2.8	 12.8 ± 1.3	 5.8 ± 2.8
 Half-life (hr)	 2.3 ± 0.5	 3.4 ± 0.7	 6.2 ± 1.6	 13.4 ± 10.2

In a multiple-dose study of famciclovir 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 famciclovir. 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 famciclovir 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 famciclovir [ see Clinical Pharmacology (12)].

8.8 Black and African American Patients

In a randomized, double-blind, placebo-controlled trial conducted in 304 immunocompetent black and African American adults with recurrent genital herpes there was no difference in median time to healing between patients receiving famciclovir or placebo. In general, the adverse reaction profile was similar to that observed in other famciclovir clinical trials for adult patients [see Adverse Reactions (6.1)]. The relevance of these study results to other indications in black and African American patients is unknown [see Clinical Studies (14.2)].