FAMCICLOVIR SCP

Main information

  • Trade name:
  • FAMCICLOVIR SCP
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FAMCICLOVIR SCP
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 176991
  • Last update:
  • 22-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

176991

FAMCICLOVIR SCP famciclovir 500 mg tablet bottle

ARTG entry for

Medicine Registered

Sponsor

Southern Cross Pharma Pty Ltd

Postal Address

PO Box 2037,MALUA BAY, NSW, 2536

Australia

ARTG Start Date

14/08/2012

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. FAMCICLOVIR SCP

Product Type

Single Medicine Product

Effective date

11/02/2013

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Famciclovir is indicated for:

òTreatment of herpes zoster infection in adult patients who commence therapy within 72 hours of the onset of rash. Greatest benefit occurs if the drug

is started within 48 hours. Efficacy has not been demonstrated in patients less than 50 years of age, although the occasional younger patient with severe

herpes zoster may benefit from therapy with famciclovir. Herpes zoster infection is generally a milder condition in younger patients.

òTreatment of recurrent episodes of genital herpes in adults and adolescents 12 years of age and older.

òSuppression of recurrent genital herpes.

òTreatment of recurrent herpes labialis (cold sores) in immunocompetent adult patients.,Famciclovir is also indicated in immunocompromised patients

for:

òTreatment of uncomplicated herpes zoster.

òTreatment of recurrent herpes simplex.

òSuppression of recurrent herpes simplex.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Bottle

HDPE

3 Years

Store below 25

degrees Celsius

Not recorded

Not recorded

Pack Size/Poison information

Pack Size

Poison Schedule

56 tablets

(S4) Prescription Only Medicine

30 tablets

(S4) Prescription Only Medicine

Components

1.

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

White oval film coated tablets with FM on one side and 500 on the other

side

Active Ingredients

Famciclovir

500 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 29.11.2017 at 12:08:05 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

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PRODUCT INFORMATION

Famciclovir SCP Tablets 125, 250 and 500 mg

NAME OF THE MEDICINE

Active ingredient: famciclovir

Chemical name: 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine

CAS number: 104227-87-4

Molecular weight: 321.3

Molecular formula: C

The chemical structure of famciclovir is:

DESCRIPTION

Famciclovir is a synthetic guanine derivative. It is a white to pale yellow crystalline

solid. Excipients in Famciclovir SCP tablets are microcrystalline cellulose,

crospovidone, colloidal anhydrous silica, copovidone, sodium stearylfumarate and

Opadry White YS-22-18096.

PHARMACOLOGY

Pharmacodynamic properties

Famciclovir is a synthetic guanine derivative antiviral agent, ATC code: JO5A B09.

Virology.

Famciclovir is the oral form of the antiviral compound penciclovir.

Famciclovir is rapidly converted in vivo into penciclovir, which has demonstrable in

vitro activity against herpes simplex viruses (HSV types 1 and 2) and varicella zoster

virus (VZV). The antiviral effect of orally administered famciclovir has been

demonstrated in several animal models. This effect is due to in vivo conversion to

penciclovir.

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Penciclovir targets virus infected cells where it is rapidly converted into penciclovir

triphosphate (mediated via virus induced thymidine kinase). The triphosphate inhibits

viral DNA polymerase by competition with deoxyguanosine triphosphate and is

incorporated into the extending DNA chain, preventing significant chain elongation.

Consequently, viral DNA synthesis and, therefore, viral replication are inhibited.

The triphosphate persists in infected cells for in excess of 12 hours. The long

intracellular half-life of penciclovir triphospate ensures prolonged antiviral activity, as

demonstrated in cell cultures with HSV-1 and HSV-2 and in animal studies.

Penciclovir is only readily phosphorylated in virus infected cells. In uninfected cells

treated with penciclovir, concentrations of penciclovir triphosphate are only barely

detectable. Accordingly, uninfected cells are unlikely to be affected by therapeutic

concentrations of penciclovir.

The most common form of resistance encountered with aciclovir among HSV strains

is a deficiency in the production of the thymidine kinase (TK) enzyme. Such TK

deficient strains would be expected to be cross resistant to both penciclovir and

aciclovir. However, penciclovir has been shown to be active against a clinically

isolated aciclovir resistant herpes simplex type 1 strain with an altered DNA

polymerase.

The results from penciclovir and famciclovir patient studies, including studies of up to

four months treatment with famciclovir, showed that no resistance occurred as a result

of treatment with either famciclovir or penciclovir. Penciclovir resistant isolates were

found at the start of treatment or in the placebo groups in 0.25% of the 1,976 total

isolates from HSV and VZV (5/1,976), and in 0.19% of the 533 virus isolates from

immunocompromised patients (1/533).

Pharmacokinetics

Famciclovir is the oral prodrug of penciclovir. Following oral administration,

famciclovir is rapidly and extensively absorbed and converted to the antivirally active

compound penciclovir. Bioavailability of penciclovir after oral famciclovir is 77%.

Mean peak plasma concentrations of penciclovir following 125, 250, 500, 750 and

1000 mg oral doses of famciclovir were 0.8, 1.6, 3.3,5.1 and 6.6 microgram/mL,

respectively, and occurred at a median time of 45 minutes postdose (see Table 1).

There are no data on the pharmacokinetics of the 1,500 mg single dose.

Table 1:

Mean peak plasma concentrations (C

max

) of penciclovir after

administration of single oral doses of famciclovir

Famciclovir single oral dose (mg)

Cmax (µg/mL)

1000

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Plasma concentration time curves of penciclovir are similar following single and

repeat (b.i.d. and t.i.d.) dosing and there is no accumulation of penciclovir on repeated

dosing. Penciclovir and its 6-deoxy precursor are poorly (< 20%) bound to plasma

proteins. Famciclovir is eliminated principally as penciclovir and its 6-deoxy

precursor, which are excreted in urine. No unchanged famciclovir has been detected

in urine. Tubular secretion and glomerular filtration contribute to renal elimination of

the compound. The terminal plasma half-life of penciclovir after both single and

repeat dosing with famciclovir is approximately two hours. There is no accumulation

of penciclovir on repeated dosing with famciclovir.

Effect of food.

Penciclovir C

was decreased by approximately 50% and T

delayed by 1.5 hours when a capsule formulation of famciclovir was administered 30

minutes after food. When Famciclovir tablets were administered 30 minutes after

food, penciclovir C

was reduced by approximately 20% and T

was delayed by

0.75 hours. The systemic availability (AUC) of penciclovir following either

preparation was unaffected. The clinical consequences of these effects on plasma

concentration are unknown.

Characteristics in special populations.

Patients with Herpes Zoster infection.

Uncomplicated Herpes virus infection does

not significantly alter the pharmacokinetics of penciclovir measured after the oral

administration of famciclovir.

Renal impairment.

Plasma clearance, renal clearance and plasma elimination rate

constant decreased linearly with reductions in renal function. A dosage interval

adjustment is recommended for patients with renal insufficiency (see Dosage and

Administration).

Hepatic impairment.

Well compensated chronic liver disease (chronic hepatitis (n =

6), chronic ethanol abuse (n = 8) or biliary cirrhosis (n = 1)) has no effect on the

extent of availability (AUC) of penciclovir following a single dose of famciclovir 500

mg. No dose adjustment is recommended for patients with well-compensated hepatic

impairment (see section Dosage and Administration, Hepatic impairment and

Precautions). However, there was a 43% decrease in penciclovir mean maximum

plasma concentration, and the time to maximum plasma concentration was increased

by a median of 0.75 hours in patients with hepatic insufficiency compared to normal

volunteers. The pharmacokinetics have not been evaluated in patients with severe

uncompensated hepatic impairment.

Elderly patients.

Based on cross study comparisons of single dose studies, the mean

penciclovir AUC was approximately 30% higher, half-life 23% longer and penciclovir

bodyweight adjusted renal clearance reduced by 19% in healthy elderly male

volunteers (n = 18, aged 65 to 79 years) compared to younger volunteers. Some of

this difference may be due to differences in renal function between the two groups.

No dose adjustment based on age is recommended unless renal function is impaired

(see section Dosage and Administration).

Human immunodeficiency virus patients

. Extrapolated data from a study (n = 8)

where famciclovir was given as a single dose resulted in a mean AUC of 24

microgram.hour/mL which is similar to that obtained in healthy subjects.

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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 famciclovir 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 relevant differences in the

pharmacokinetics of penciclovir between Black and Caucasian subjects.

Transplant patients.

In a study of allogeneic bone marrow transplant, peripheral

blood stem cell transplant or allogeneic renal transplant patients (n = 21), intravenous

penciclovir for one month was followed by oral use of famciclovir. The doses of

penciclovir and famciclovir were adjusted according to creatinine clearance. During

repeat dosing with famciclovir, the AUC of penciclovir was found to be 66

microgram.hour/mL in subjects with creatinine clearance greater than 50 mL/minute.

No safety concerns were identified despite the higher than normal AUCs reported, and

additional dosage adjustment in renal transplant patients is not recommended.

CLINICAL TRIALS

Herpes zoster.

Placebo controlled trial.

Famciclovir was studied in a placebo

controlled, double blind trial of 419 otherwise healthy patients with uncomplicated

herpes zoster who were treated with famciclovir 500 mg three times daily (t.i.d.) (n =

138), famciclovir 750 mg t.i.d. (n = 135) or placebo (n = 146). Treatment was begun

within 72 hours of initial lesion appearance and therapy was continued for seven days.

Dermatology and virology. The times to full crusting, loss of vesicles, loss of ulcers

and loss of crusts were shorter for famciclovir 500 mg treated patients than for

placebo treated patients in the overall study population. The median time to full

crusting in famciclovir 500 mg treated patients was five days compared to seven days

in placebo treated patients. No additional efficacy was demonstrated with the higher

dose of famciclovir (750 mg t.i.d.) when compared to famciclovir 500 mg t.i.d. In the

total population, 65.2% of patients had a positive viral culture at some time during

their acute infection. Patients treated with famciclovir 500 mg had a shorter median

duration of viral shedding (time to last positive viral culture) than did placebo treated

patients (one and two days, respectively).

Acute pain and postherpetic neuralgia. There were no overall differences in the

duration of acute pain (i.e. pain before rash healing) between famciclovir and placebo

treated groups. In addition, there was no difference in the incidence of postherpetic

neuralgia (i.e. pain after rash healing) between the treatment groups. In the 186

patients (44.4% of total study population) who did develop postherpetic neuralgia, the

median duration of postherpetic neuralgia was shorter in patients treated with

famciclovir 500 mg than in those treated with placebo (63 and 119 days, respectively).

Active control trial.

A second double blind controlled trial in 545 otherwise healthy

patients with uncomplicated herpes zoster, treated within 72 hours of initial lesion

appearance, compared famciclovir 250 mg t.i.d. (n = 134), famciclovir 500 mg t.i.d.

(n = 134), famciclovir 750 mg t.i.d. (n = 138) and aciclovir 800 mg five times per day

(n = 139) for seven days. In this study, patients treated with famciclovir at each dose

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and aciclovir had comparable times to full lesion crusting and times to loss of acute

pain. There were no statistically significant differences in the time to loss of

postherpetic neuralgia between famciclovir and aciclovir treated groups.

Higher doses of famciclovir (500 t.i.d.; 750 mg t.i.d.) have not been shown to confer

greater benefit. The minimum effective dose of famciclovir in the treatment of herpes

zoster has not been established.

Immunocompromised.

A double blind, controlled clinical trial was conducted in 148

oncology and transplant patients with herpes zoster infections who received

famciclovir 500 mg t.i.d. (n = 71) or aciclovir 800 mg five times per day (n = 77) for

ten days. Patients started study medication within 72 hours of rash onset. Overall

famciclovir and aciclovir showed comparable efficacy. The median times to full

crusting and complete healing were 8 and 20 days for the famciclovir group and 9 and

21 days for the aciclovir group. The median times to loss of all pain were 14 and 17

days for the famciclovir and aciclovir groups, respectively. Withdrawal due to

dissemination of zoster and continued new lesion formation beyond ten days of onset

was reported in 7% of the famciclovir group and 9% of the aciclovir group.

Genital herpes.

Placebo controlled trials (episodic therapy).

5-day treatment:

In two double-blind, placebo controlled trials, 626 otherwise

healthy patients with a recurrence of genital herpes were treated with famciclovir 125

mg b.i.d. (twice daily) (n = 160), famciclovir 250 mg b.i.d. (n = 169), famciclovir 500

mg b.i.d. (n = 154) or placebo (n = 143) for five days. Treatment was initiated within

six hours of either symptom onset or lesion appearance. In the two studies combined,

the median time to healing in famciclovir 125 mg treated patients was four days

compared to five days in placebo treated patients. The median time to cessation of

viral shedding was 1.8 versus 3.4 days in the famciclovir 125 mg and placebo

recipients, respectively. The median time to loss of all symptoms was 3.2 days in

famciclovir 125 mg treated patients versus 3.8 days in placebo treated patients. When

used to treat acute recurrent genital herpes, no additional efficacy was demonstrated

with higher doses of famciclovir (250 mg b.i.d. or 500 mg b.i.d.) when compared to

famciclovir 125 mg b.i.d.

1-day treatment:

In one double-blind, placebo-controlled trial, 329

immunocompetent patients with a recurrence of genital herpes were treated with

famciclovir 1 g b.i.d. (n=163) or placebo (n=166) for 1 day. Treatment was initiated

within 6 hours of either symptom onset or lesion appearance. Among patients with

non-aborted lesions, the median time to healing in famciclovir 1 g-treated patients

(n=125) was 4.3 days 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 - 2.0). Twenty three percent (23 %) of famciclovir-

treated patients had aborted lesions (no development beyond erythema) compared to

13 % in placebo-treated patients. The median time to loss of all symptoms (e.g.,

burning, itching, pain, tenderness, tingling), was 3.3 days in famciclovir-treated

patients vs. 5.4 days in placebo-treated patients.

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In one, randomized (2:1), double-blind, placebo-controlled, double-blind study to

assess the safety and efficacy of patient-initiated, single-day treatment, 304 black

immunocompetent patients with recurrent genital herpes were treated with famciclovir

1 g b.i.d. (n= 206) or placebo (n=98) 1 g b.i.d. The study was conducted in 43 centres

in the USA and South Africa, in patients with a history of at least four recurrences of

genital herpes in the past 12 months and laboratory confirmation of HSV-2 infection.

The median time to healing among patients with non-aborted lesions was 5.4 days in

famciclovir-treated patients (n=152) as compared to 4.8 days in placebo-treated

patients (n=78). The median difference in time to healing between the

placebo and famciclovir-treated groups was -0.26 days (95% CI: -0.98 . 0.40). There

were no unexpected or new safety findings in this trial.

Active-control trial (episodic therapy):

2-day treatment:

In a randomised, double-blind, non-inferiority, multi-centre study

(59 sites in Australia and 7 in Canada), famciclovir 500 mg statim then 250 mg bd for

2 days (short course) was compared to the standard regimen of 125 mg bd for 5 days

in the treatment of adult patients with recurrent genital herpes. HIV-infected patients

were eligible if CD4 ≥ 500 cells/µL and/or CD4% ≥ 25%.

The study was designed to treat and follow each eligible patient for two complete and

consecutive recurrences. A total of 1038 recurrences occurred in 616 patients that

were randomised and treated. Treatment was initiated by patients within 12 hours of

development of a lesion or onset of symptoms.

Patients attended for assessment within 24 hours and then 5.5 days following

initiation of treatment. A daily diary was used to record treatment compliance,

progression of lesions and symptoms, functional impact and side effects from the

treatment.

The primary endpoint was the estimated probability of being not lesion-free at 5.5

elapsed days (132 hours) after patient self-initiation of therapy. The estimated

probability was 24.4% for recurrences treated with the 2-day regimen and was 27.6 %

for recurrences treated with the 5-day regimen. The upper one-sided 97.5%

confidence limit of the treatment difference was 1.7 % which was within the pre-

defined margin for claiming non-inferiority. Non-inferiority was maintained in five

sensitivity analyses, confirming a robust result.

Over the course of treatment, there were no differences between the mean symptom

and functional impact scores for either the famciclovir short-course or the standard-

course treatment groups.

The study concluded that the 2-day famciclovir regimen was equivalent to the 5-day

regimen in the treatment of adult patients with recurrent genital herpes.

Placebo controlled trials (suppressive therapy).

In two placebo controlled suppression studies, immunocompetent patients (n = 934)

with at least six recurrences of genital herpes per year received 125 mg t.i.d. (n =

233), 250 mg b.i.d. (n = 236), 250 mg t.i.d. (n = 232) or placebo (n = 233) for 52

weeks. Treatment was initiated during an asymptomatic period. Among those who

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received famciclovir 250 mg b.i.d., the proportion of patients who remained free from

virologically confirmed recurrence at the 12 month end point was 68% in one trial and

72% in the second trial compared with approximately 21% in the placebo groups.

Median days to first clinically confirmed recurrence for the famciclovir 250 mg b.i.d.

treatment groups were >365 days for the famciclovir 250 mg b.i.d. treatment groups

compared to 67 days for the placebo treated group in one of the studies and 336 days

for the famciclovir groups compared to 47 days for the placebo group in the second

study.

Immunocompromised.

A randomised, double blind, controlled trial in 293 HIV

infected patients with a recurrence of genital herpes compared famciclovir 500 mg

b.i.d. (n = 150) and aciclovir 400 mg five times per day (n = 143) for seven days.

Treatment was initiated within 48 hours of lesion onset. Famciclovir and aciclovir

were equally effective in prevention of new lesion formation while patients were

receiving treatment. Efficacy in the three main time to event parameters were also

comparable. The median times to complete healing of lesions, cessation of viral

shedding and loss of lesion pain were seven, two and three days for both the

famciclovir and aciclovir treatment groups, respectively.

A further double blind, placebo controlled, crossover study was conducted in 48

patients with HIV to assess famciclovir (500 mg b.i.d.) in the suppression of herpes

simplex (HSV) recurrence for eight weeks. Famciclovir showed statistically

significant superiority over placebo in the efficacy parameters measured. There was

an approximate tenfold reduction in the percentage of days with HSV shedding (p =

0.0003) and a 6.7-fold reduction in the proportion of patients with HSV shedding

from anogenital sites (p = 0.0065) in the famciclovir treated group. There was also an

8.7-fold reduction in the proportion of patients with HSV shedding from any site.

Overall, in the famciclovir group the proportion of days of asymptomatic,

symptomatic, subclinical or lesional HSV shedding from any site was significantly

reduced compared to placebo (p = 0.0012).

In the famciclovir treatment group there was a 2.6-fold reduction in the percentage of

days with lesions (p = 0.0101), and a 3.6-fold reduction in the percentage of days with

lesions/ symptoms (p = 0.0089) over the placebo group.

Herpes labialis (cold sores).

Placebo controlled trial

In one large placebo controlled trial, 701 immunocompetent adults with recurrent

herpes labialis were treated with famciclovir 1,500 mg once (n = 227), famciclovir

750 mg b.i.d. (n = 220) or placebo (n = 254) for one day. As well, patients also had to

be in good general health, aged at least 18 years, have normal renal and hepatic

function, had prior pregnancy tests if they were females of reproductive age and have

experienced three or more episodes of cold sores in the preceding 12 months. Patients

were required to have a history of prodromal symptoms preceding at least 50% of the

recurrent episodes and at least 50% of these episodes had to have progressed to the

vesicular lesion stage. Women of childbearing potential had to agree to use reliable

birth control measures during the study. Pregnant or breastfeeding women were

excluded. Patients were excluded if they had received an investigational drug in the

four weeks prior to the study, had been previously vaccinated against herpes or were

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using a topical immunosuppressive agent on or near the face or a systemic

immunosuppressive agent within one month of screening. Patients were also excluded

if they were immunosuppressed due to underlying disease or concomitant treatment,

had a recent history of drug or alcohol abuse, were suffering from inflammatory skin

diseases (e.g. eczema or dermatitis) that would interfere with the assessment of

lesions or were allergic or hypersensitive to products containing aciclovir, penciclovir,

famciclovir or other nucleoside analogues.

Patients were instructed to take the first dose of study medication within one hour of

symptom onset. However, some patients commenced treatment after one hour of onset

of symptoms. Both famciclovir regimens significantly reduced time to healing of

primary vesicular herpes labialis lesions (the primary efficacy variable) in the

modified intention to treat (ITT) population compared with placebo. The median time

to healing in famciclovir 1,500 mg single dose treated patients was 4.4 days compared

to 4.0 days in famciclovir 750 mg b.i.d. and 6.2 days in placebo treated patients.

This translates to treatment effects of 1.8 (CI 95% 0.9, 2.7) and 2.2 (CI 95% 1.3, 3.1)

days, respectively. A single famciclovir 1,500 mg dose reduced the time to resolution

of pain and tenderness (median time 1.7 days versus 2.9 days) compared with placebo

and was marginally more effective than famciclovir 750 mg b.i.d. (median time 2.1

days).

INDICATIONS

Famciclovir is indicated for:

Treatment of herpes zoster infection in adult patients who commence therapy

within 72 hours of the onset of rash. Greatest benefit occurs if the drug is

started within 48 hours. Efficacy has not been demonstrated in patients less

than 50 years of age, although the occasional younger patient with severe

herpes zoster may benefit from therapy with famciclovir. Herpes zoster

infection is generally a milder condition in younger patients.

Treatment of recurrent episodes of genital herpes in adults and adolescents 12

years of age and older.

Suppression of recurrent genital herpes.

Treatment of recurrent herpes labialis (cold sores) in immunocompetent adult

patients.

Famciclovir is also indicated in immunocompromised patients for:

Treatment of uncomplicated herpes zoster.

Treatment of recurrent herpes simplex.

Suppression of recurrent herpes simplex.

CONTRAINDICATIONS

Known hypersensitivity to famciclovir or other constituents of famciclovir.

Hypersensitivity to penciclovir.

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PRECAUTIONS

Efficacy has not been studied in ophthalmic zoster, chickenpox or zoster

encephalomyelitis patients.

Special attention should be paid to patients with impaired renal function and dosage

adjustment may be necessary. Appropriate dosage adjustments for renally impaired

patients are provided (see “

DOSAGE AND ADMINISTRATION

”).

Genital herpes is a sexually transmitted disease. The risk of transmission is increased

during acute episodes. Patients should be advised to use condoms between episodes to

reduce the risk of transmission and to avoid sexual intercourse when symptoms are

present even if treatment with an antiviral has been initiated. Genital herpes can also

be transmitted in the absence of symptoms through asymptomatic viral shedding.

Patients should therefore take appropriate steps for protected intercourse.

Carcinogenesis, mutagenesis, impairment of fertility

Data presented below include reference to area under the plasma concentration curve

(24 hour AUC) for penciclovir in humans following the lowest and highest

recommended dose for famciclovir (i.e. penciclovir AUC of 4.5 microgram.hour/mL

at 125 mg b.i.d. for acute recurrent genital herpes, and a penciclovir AUC of 27

microgram.hour/mL at 500 mg t.i.d. for herpes infections in immunocompromised

patients). This is based on the assumption that the pharmacokinetics in

immunocompetent subjects are similar to the pharmacokinetics in

immunocompromised subjects, as shown in the study on HIV patients (see

Pharmacokinetics). If the higher values of AUC obtained in the renal transplant

patients were used as a basis for comparison, the multiples specified here would be

decreased. Exposures in animal studies are expressed as multiples of human

exposures at the highest and lowest dosing schedules based on penciclovir AUC or

body surface area.

Carcinogenesis.

The carcinogenic potential of famiclovir was evaluated in two year

dietary studies in rats and mice. A significant increase in the incidence of mammary

adenocarcinoma was seen in female rats receiving 600 mg/kg/day. No increases in

tumour incidences were reported for male rats treated at doses of up to 240 mg/kg/day

or in mice of either sex at doses of up to 600 mg/kg/day. At the no effect levels of 240

and 200 mg/kg/day in male and female rats, the daily exposures to penciclovir, based

on AUC, were about 40 and 29 microgram.hour/mL respectively, or approximately

one to eight times the human systemic exposures at 500 mg t.i.d. or 125 mg b.i.d.

Systemic exposures at the no-effect dose in male and female mice were 65 and 46

microgram.hour/mL, respectively, or approximately 2 to 12 times the human systemic

exposure (AUC).

Genotoxicity.

Famciclovir and penciclovir (the active metabolite of famciclovir) were

tested for genotoxic potential in a series of

in vitro

in vivo

assays. Famciclovir

showed no genotoxic potential in a series of assays for gene mutations, chromosomal

damage and DNA damage. Penciclovir was positive in the L5178Y mouse lymphoma

assay for gene mutations/ chromosomal damage, caused chromosomal aberrations in

human lymphocytes

in vitro

and was positive in a mouse micronucleus assay

in vivo

when administered intravenously at doses toxic to bone marrow.

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Effects on fertility.

Testicular toxicity was observed in rats, mice and dogs following

repeated administration of famciclovir or penciclovir. Testicular changes included

atrophy of seminiferous tubules, reduction in sperm count and/or increased incidence

of sperm with abnormal morphology or reduced motility. The degree of testicular

toxicity was related to dose and duration of exposure and tended to reverse after the

cessation of dosing. In male rats, decreased fertility was observed after ten weeks

dosing at 500 mg/kg/day, or approximately 3 to 20 times the human systemic

exposure (AUC). Testicular toxicity was also seen in mice and dogs following chronic

administration at exposures to penciclovir ranging from 2 to 14 times the human

systemic exposure (AUC). However, there were no clinically significant effects on

sperm count, morphology and motility in male patients receiving famciclovir 250 mg

b.i.d. for 18 weeks. Famciclovir had no effect on fertility in female rats at doses of up

to 1,000 mg/kg/day, approximately 4 to 27 times the human systemic exposure

(AUC).

Use in pregnancy

(Category B1)

Famciclovir was tested for effects on embryofoetal development in rats and rabbits at

oral doses up to 1,000 mg/kg/day (approximately 4 to 27 times and 2 to 12 times the

human systemic exposure to penciclovir (AUC) in rats and rabbits, respectively) and

intravenous doses of 360 mg/kg/day in rats (1.9 to 12 times the human dose based on

body surface area (BSA) comparisons) or 120 mg/kg/day in rabbits (1.2 to 7.1 times

the human dose (BSA)). No adverse effects were observed on embryofoetal

development. Similarly, no adverse effects were observed following intravenous

administration of penciclovir to rats (80 mg/kg/day, 0.4 to 2.6 times the human dose

(BSA)) or rabbits (60 mg/kg/day, 0.6 to 3.6 times the human dose (BSA)). Although

animal studies have not shown any embryotoxic or teratogenic effects with

famciclovir or penciclovir, the safety of famciclovir in human pregnancy has not been

established. Famciclovir should therefore not be used during pregnancy unless the

potential benefits are considered to outweigh the potential risks associated with

treatment.

Use in lactation

Famciclovir should not be used by breastfeeding mothers unless the potential benefits

are considered to outweigh the potential risks associated with treatment. Following

oral administration of famciclovir to lactating rats, penciclovir was excreted in breast

milk at concentrations higher than those seen in plasma. There is no information on

excretion in human milk.

Use in children

Safety and efficacy in children have not been established.

Use in the elderly

No special precautions are required for elderly patients with normal renal function and

well-compensated hepatic impairment. Famciclovir has not been studied in patients

with severe hepatic impairment. Conversion of famciclovir to the active metabolite

penciclovir may be impaired in these patients resulting in lower penciclovir plasma

C:Products/Famciclovir/PI SCP TGA Aprvd 25/6/12

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concentrations, and thus possibly a decrease of efficacy of famciclovir (see

PHARMACOLOGY

”).

Effect on ability to drive or operate machinery

Patients who experience dizziness, somnolence, confusion or other central nervous

system disturbances while taking famciclovir should refrain from driving or operating

machinery.

INTERACTIONS WITH OTHER MEDICINES

Effects of other medicinal products on famciclovir.

No clinically significant

interactions have been identified with famciclovir or penciclovir.

Probenecid:

Concurrent use of probenecid may result in increased plasma

concentrations of penciclovir (active metabolite of famciclovir, see

PHARMACOLOGY

”).

Other drugs that affect renal physiology:

could affect plasma levels of penciclovir

(active metabolite of famciclovir, see “

PHARMACOLOGY

”).

Evidence from preclinical studies has shown no potential for induction of cytochrome

P450.

Zidovudine:

In a phase I study, no significant drug interactions were observed after

coadministration of zidovudine and famciclovir.

The conversion of the inactive metabolite 6-deoxy penciclovir to penciclovir is

catalysed 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.

However, raloxifene, the most potent aldehyde oxidase inhibitor observed

in vitro

could affect the formation of penciclovir and thus the efficacy of famciclovir. When

raloxifene is co-administered with famciclovir, the clinical efficacy should be

monitored.

Effects of famciclovir on other medicinal products

Although famciclovir is only a weak inhibitor of aldehyde oxidase

in vitro

interactions with drugs metabolized by aldehyde oxidase could potentially occur.

Evidence from preclinical studies has shown no potential for induction of cytochrome

P450 enzymes or inhibition of CYP3A4.

ADVERSE EFFECTS

Famciclovir has been well tolerated in human studies. Headache, fatigue and nausea

have been reported in clinical trials. These events were generally mild or moderate

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and occurred at a similar incidence in patients receiving placebo treatment. Confusion,

predominantly in the elderly, has been reported rarely.

Table 2 shows adverse events related, possibly related, unassessable or unknown,

reported by ≥ 1% of immunocompetent subjects during clinical trials.

Famciclovir Table 2

Adverse events (related, possibly related, unassessable or unknown) reported by ≥ 1% of

immunocompetent subjects during clinical trials:

Adverse event

Famciclovir

(n=3996)

Placebo

(n=880)

Headache

Nausea

Dizziness

Diarrhoea

Fatigue

Abdominal pain

Vomiting

Somnolence

5.3%

4.6%

1.5%

1.5%

1.2%

1.1%

1.1%

0.6%

4.8%

4.5%

1.5%

1.3%

0.9%

1.3%

0.5%

1.1%

Table 3 shows adverse events related, possibly related, unassessable or unknown,

reported by ≥ 1% of immunocompetent subjects during clinical trials in

Herpes

labialis

Famciclovir Table 3

Adverse events (related, possibly related, unassessable or unknown) reported by ≥ 1% of

immunocompetent subjects during clinical trials in Herpes labialis

Famciclovir 1,500 mg

q.d

n = 227

n (%)

Famciclovir 750 mg

b.i.d

n = 220

n (%)

Placebo

n = 254

n (%)

Patients with AE(s)

AE preferred term

Headache

Diarrhoea

Nausea

Nasopharyngitis

63 (27.8)

22 (9.7)

4 (1.8)

5 (2.2)

6 (2.6)

54 (24.5)

16 (7.3)

3 (1.4)

5 (2.3)

3 (1.4)

53 (20.9)

17 (6.7)

2 (0.8)

10 (3.9)

2 (0.8)

AE: adverse event

q.d: daily

b.i.d: twice daily

Table 4 shows adverse events (related, possibly related, unassessable or unknown)

reported by ≥ 1% of immunocompetent subjects during the clinical trial comparing

the 2-day and 5-day recurrent genital herpes treatments

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Famciclovir Table 4

Adverse events (related, possibly related, unassessable or unknown) reported by ≥ 1%

of immunocompetent subjects during the clinical trial comparing the 2-day and 5-day

recurrent genital herpes treatments

Famciclovir 2‐day course

(n=521 recurrences)

N (%)

Famciclovir 5‐day course

(n=517 recurrences)

N (%)

Recurrences with ≥ 1 AE(s)

No. of AEs

185 (35.5)

176 (34.0)

MedDRA preferred term

b,c

:

Headache

Nausea

Diarrhoea

Abdominal pain

Dizziness

Fatigue

83 (15.9)

15 (2.9)

12 (2.3)

12 (2.3)

10 (1.9)

9 (1.7)

94 (18.2)

22 (4.3)

16 (3.1)

5 (1.0)

10 (1.9)

13 (2.5)

On or for 4 days after date of starting study medication

The denominator is the number of recurrences in the safety recurrence population for each treatment group

If a patient had more than 1 recurrence of a specific AE during a recurrence, the AE is counted only once for that

recurrence

2‐day course: 2‐day famciclovir regimen (500 mg loading dose then 250 mg 12‐hourly)

5‐day course: 5‐day famciclovir regimen (125 mg 12‐hourly)

Table 5 shows the frequency of adverse events (related, possibly related, unassessable

or unknown) reported by ≥1% of immunocompetent subjects during a clinical trial of

1 g b.i.d. for 1 day vs placebo in recurrent genital herpes.

Famciclovir Table 5

Adverse events (related, possibly related, unassessable or unknown) reported by ≥1% of

immunocompetent subjects during a clinical trial of 1 g b.i.d. for 1 day vs placebo in

recurrent genital herpes

Adverse event

Famciclovir (n=163)

N(%)

Placebo (n=166)

N(%)

Patients with AE(s)

AE preferred term

Headache

Diarrhoea

Nausea

Insomnia

Dysmenorrhoea

Pharyngolaryngeal pain

Back pain

Anxiety

Dry mouth

Palpitation

Stomach discomfort

Vomiting

Abdominal pain upper

Dizziness

Abdominal pain

Fungal infection

Nasopharyngitis

43 (26.4)

22 (13.5)

8 (4.9)

4 (2.5)

3 (1.8)

3 (1.8)

3 (1.8)

2 (1.2)

2 (1.2)

2 (1.2)

2 (1.2)

2 (1.2)

2 (1.2)

1 (0.6)

40 (24.1)

9 (5.4)

2 (1.2)

6 (3.6)

2 (1.2)

1 (0.6)

1 (0.6)

1 (0.6)

1 (0.6)

1 (0.6)

4 (2.4)

4 (2.4)

2 (1.2)

2 (1.2)

2 (1.2)

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Table 6 shows the frequency of adverse events reported by ≥ 5% of patients receiving

famciclovir 500 mg daily or placebo for > ten months.

Famciclovir Table 6

Frequency of adverse events (≥ 5%) for patients receiving famciclovir 500 mg daily of

placebo for >10 months

Adverse event

Famciclovir (n=154)

Placebo (n=63)

Headache

URTI

Infection (viral)

Injury

Sinusitis

Back pain

Pharyngitis

Dyspepsia

37.7%

31.8%

24.7%

18.8%

19.5%

12.3%

11.0%

7.1%

5.2%

42.9%

31.7%

25.4%

23.8%

15.9%

14.3%

14.3%

4.8%

11.1%

Famciclovir has also been well tolerated in immunocompromised patients.

Undesirable effects reported from clinical studies were similar to those reported in the

immunocompetent population.

Postmarketing data

In addition to the adverse events reported in the clinical trials, the following events

have been reported rarely in postmarketing surveillance.

Adverse reactions are ranked under headings of frequency, using the following

convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥

1/1,000, < 1/100); rare (≥ 10,000, < 1/1,000); very rare (< 1/10,000), including

isolated reports.

Blood and lymphatic system disorders.

Very rare:

thrombocytopenia.

Psychiatric disorders.

Rare:

confusion (predominantly in the elderly).

Very rare:

hallucinations.

Nervous system disorders.

Rare:

headache.

Very rare:

dizziness, somnolence (predominantly in the elderly).

Gastrointestinal disorders.

Rare:

nausea.

Very rare:

vomiting.

Hepatobiliary disorders.

Very rare:

cholestatic jaundice and abnormal liver function tests.

Skin and subcutaneous tissue disorders.

Very rare:

rash, pruritus, urticaria, serious skin reactions (e.g. erythema

multiforme, Stevens-Johnson syndrome and toxic epidermal

necrolysis).

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Uncommon:

angioedema (e.g. face oedema, eyelid oedema, periorbital

oedema, pharyngeal oedema), urticaria.

Musculoskeletal disorders

Very rare:

arthralgia, myalgia.

DOSAGE AND ADMINISTRATION

Dosage

Immunocompetent patients

Herpes zoster.

The recommended dosage of famciclovir is 250 mg three times daily

for seven days. Treatment should be initiated as soon as possible after herpes zoster is

diagnosed. Studies have shown famciclovir to be of benefit when started within 72

hours of the onset of rash. Greatest benefit occurs if famciclovir is started within 48

hours.

Recurrent genital herpes (HSV).

The recommended dosage is either:

125 mg twice each day for 5 days or

(ii)

500 mg statim, then 250 mg 12 hourly for 3 doses or

(iii)

1000 mg twice daily for 1 day.

Initiation of treatment is recommended during the prodromal period or as soon as

possible after onset of lesions.

Suppression of recurrent genital herpes (HSV).

The recommended dose for the

suppression of recurrent genital herpes is 250 mg twice daily. As studies conducted to

date have not extended beyond 12 months, therapy should be re-evaluated after this

period in order to observe possible changes in the natural history of the disease.

Recurrent Herpes labialis (cold sores).

The recommended dosage is 1,500 mg as a

single dose or 750 mg twice daily at 12 hourly intervals for one day (see Clinical

Trials,

Herpes labialis

(cold sores)). Initiate therapy at the earliest sign or symptom of

a cold sore (e.g. tingling, itching or burning). Treatment was initiated within one hour

of symptom onset in the recurrent herpes labialis clinical study.

Immunocompromised

Herpes zoster.

The recommended dosage of famciclovir is 500 mg three times daily

for ten days. Initiation of treatment is recommended as soon as possible after rash

onset. Studies have shown famciclovir to be of benefit when started within 72 hours

of the onset of rash.

Recurrent HSV infections.

For treating herpes simplex infections in

immunocompromised adults, the recommended dose is 500 mg twice daily for seven

days.

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Initiation of treatment is recommended during the prodromal period or as soon as

possible after the onset of lesions.

Suppression of recurrent genital herpes (HSV) in HIV.

For suppression of recurrent

genital herpes infections, a dose of 500 mg twice a day has been shown to be

efficacious in HIV patients.

Renal Impairment

As reduced clearance of penciclovir is related to reduced renal function as measured

by creatinine clearance, special attention should be given to dosages in patients with

impaired renal function. The following modifications in dosage are recommended.

Creatinine Clearance Dosage

(mL/min/1.73 m

2

)

Immunocompetent

For the treatment of herpes

zoster infection

≥ 30

10 - 29

No dosage adjustment necessary

250 mg / 24 hours

For the treatment or

suppression of recurrent

genital herpes infections

≥ 30

10 - 29

No dose adjustment necessary

125 mg / 12 hours

For the treatment of

recurrent herpes labialis

≥ 60

40 – 59

20 - 39

10 - 20

For patients on

haemodialysis

No dose adjustment necessary

750 mg single dose

500 mg single dose

250 mg single dose

250 mg single dose

Creatinine Clearance Dosage

(mL/min/1.73 m

2

)

Immunocompromised

For the treatment of herpes

zoster infection

≥ 50

30 – 49

10 - 29

No dose adjustment necessary

250 mg / 8 hours

250 mg / 24 hours

For the treatment or

suppression of recurrent

herpes simplex infections

≥ 50

30 – 49

10 - 29

No dose adjustment necessary

250 mg / 12 hours

125 mg / 24 hours

For suppression of genital

herpes infections

≥ 50

30 – 49

10 - 29

No dose adjustment necessary

250 mg / 12 hours

125 mg / 12 hours

As these recommendations are not based on repeated dose data, patients with impaired

renal function should be closely monitored for adverse effects. There are insufficient

data to recommend a dosage for patients with a creatinine clearance of less than 10

mL/min/1.73 m

For a patient on haemodialysis, who has been prescribed famciclovir for conditions

other than herpes labialis, a dosage interval of 48 hours is recommended for periods

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Page 17 of 18

between dialysis. Since four hour haemodialysis results in approximately a 75%

reduction in plasma concentrations of penciclovir, the full adjusted dose (for patients

with severe renal impairment) of famciclovir should be administered immediately

following dialysis.

Hepatic Impairment

Dosage modification is not required for patients with well compensated hepatic

impairment.

Black patients with recurrent genital herpes

A placebo-controlled study in immunocompetent Black patients with recurrent genital

herpes showed no difference in efficacy between patients receiving famciclovir 1 g

b.i.d. for 1 day and placebo. There were no unexpected or new safety findings in this

trial in Black patients. The relevance of these study results to other indications in

Black patients is unknown (see CLINICAL TRIALS and Pharmacokinetics).

Administration

Famciclovir can be taken without regard to meals (see Pharmacokinetics - Effect of

food in PHARMACOLOGY).

OVERDOSAGE

Contact the Poisons Information Centre on 131 126 for advice on management.

Symptomatic and supportive therapy should be given as appropriate. Acute renal

failure has been reported rarely in patients with underlying renal disease. The

famciclovir dosage in these patients had not been appropriately reduced for the level

of renal function.

Penciclovir, the active metabolite of famciclovir, is dialysable; plasma concentrations

are reduced by approximately 75% following four hour haemodialysis.

PRESENTATION

Famciclovir SCP Tablets 125 containing famciclovir 125 mg are white round film

coated tablets with FM on one side and 125 on the other side in blister packs of 10*

and 40 and bottles of 40*.

Famciclovir SCP Tablets 250 containing famciclovir 250 mg are white round film

coated tablets with FM on one side and 250 on the other side in blister packs of 3*

(herpes zoster samples), 5* (episodic genital herpes samples), 14*, 20, 21, 56 and

bottles of 14*, 20*, 21*; 56*.

Famciclovir SCP Tablets 500 containing famciclovir 500 mg are white oval film

coated tablets with FM on one side and 500 on the other side in blister packs of 3,

14*, 30*, 56 and bottles of 30*, 56*.

*Not currently marketed in Australia

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Page 18 of 18

STORAGE

Store below 25°C in a dry place. Shelf life: 3 years. Keep out of the reach of children.

POISON SCHEDULE

SPONSOR

Southern Cross Pharma Pty Ltd

56 Illabunda Drive

Malua Bay NSW 2536

ARTG START DATE

14 August 2012