Famciclovir (famciclovir 250 mg) Dailymed

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 > 10% of adult patients treated with famciclovir 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 AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com;  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 ≥ 2% of Patients in Placebo-Controlled Famcicovir Trials Patients may have entered into more than one clinical trial.

Incidence
	Herpes Zoster 7 days of treatment		Recurrent Genital Herpes 1 day of treatment		Genital Herpes- Supression daily treatment		Herpes Labialis
Event	Famciclovir	Placebo	Famciclovir	Placebo	Famciclovir	Placebo	Famciclovir	Placebo
	(n = 273)	(n = 146)	(n = 163)	(n = 166)	(n = 458)	(n = 63)	(n = 447)	(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	0.9	0	0	0
Migraine	0.7	0.7	0.6	0.6	3.1	0	0.2	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
Flatulence	1.5	0.7	0.6	0	4.8	1.6	0.2	0
Abdominal Pain	1.1	3.4	0	1.2	7.9	7.9	0.2	0.4
Body as a Whole
Fatigue	4.4	3.4	0.6	0	4.8	3.2	1.6	0.4
Skin and Appendages
Pruritus	3.7	2.7	0	0.6	2.2	0	0	0
Rash	0.4	0.7	0	0	3.3	1.6	0	0
Reproductive (Female)
Dysmenorrhea	0	0.7	1.8	0.6	7.6	6.3	0.4	0

Table 3 uls 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
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. 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., grace, eyelid, periorbital, and pharyngeal edema.), leukocytoclastic vasculitis. Cardiac disorders: Palpitations

Nursing mothers: Famciclovir should not be used in nursing mothers unless the potential benefits outweigh the potential risks associated with treatment. ( 8.3)

8.1 Pregnancy

Teratogenic Effects

Pregnancy category B

After oral administration, famciclovir (prodrug) is converted to penciclovir (active drug). There are no adequate and well-controlled studies of famciclovir or penciclovir use in pregnant women. No adverse effects on embryofetal development were observed in animal reproduction studies using famciclovir 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, famciclovir should be used during pregnancy only if needed.

In animal reproduction studies, pregnant rats and rabbits received oral famciclovir 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 famciclovir 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 famciclovir (prodrug) or penciclovir (active drug) are excreted in human milk. Following oral administration of famciclovir 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 famciclovir in infants. Famciclovir 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 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 < 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 < 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 < 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 < 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 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. 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 < 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 ≥ 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 < 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 ≥ 65 years of age and 103 (13%) were ≥ 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 > 65 years of age and 7 (1.1%) were > 75 years of age. Clinical studies of famciclovir 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 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.)	CL CR CL CR is measured creatinine clearance. ≥ 60 (mL/min) (n = 15)	CL CR 40 to 59 (mL/min) (n = 5)	CL CR 20 to 39 (mL/min) (n = 4)	CL CR < 20 (mL/min) (n = 3)
CL CR (mL/min)	88.1 ± 20.6	49.3 ± 5.9	26.5 ± 5.3	12.7 ± 5.9
CL R (L/hr)	30.1 ± 10.6	13.0 ± 1.3 n = 4.	4.2 ± 0.9	1.6 ± 1.0
CL/F CL/F consists of bioavailability factor and famciclovir to penciclovir conversion factor. (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 section 12 Clinical Pharmacology).

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) ].