Consumer medicine information

Famciclovir Generichealth for Cold Sores

Famciclovir

BRAND INFORMATION

Brand name

Famciclovir Generichealth

Active ingredient

Famciclovir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Famciclovir Generichealth for Cold Sores.

What is in this leaflet

This leaflet answers some common questions about Famciclovir generichealth. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Famciclovir generichealth against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Famciclovir generichealth is used for

Famciclovir generichealth is an antiviral medicine used to treat recurrent outbreaks of cold sores in adults who have a normal immune system (the body system which fights against harmful bacteria, viruses and fungi).

Cold sores are an infection caused by a virus called herpes simplex type 1 (HSV-1). The infection is most commonly acquired as a baby or child from contact with parents or relatives, often from kissing.

Cold sores usually begin on or around the lips, mouth, and nose as small red bumps that turn into fluid-filled blisters. Cold sores can be tender and painful. Many people who get cold sores know when one is coming by a tingling, burning, itchy or painful sensation or redness in the area. This can happen very rapidly.

After redness and swelling develop, blisters form. The blisters may weep or burst, and this can be painful. Then a shallow ulcer and yellow crust form as the cold sore dries. The crust eventually falls off, exposing new pink coloured skin. Generally, the sores heal without scarring. After the initial infection has healed, the virus becomes dormant in nerve cells.

Cold sores can be unpredictable. The virus can become active again in the body, even after many years, resulting in recurrent outbreaks.

Even after many years, some people may experience recurring cold sores due to viral reactivation.

Some common triggers to a cold sore may include:

  • sun exposure;
  • stress;
  • fatigue;
  • menstrual periods;
  • fever;
  • illness;
  • dry chapped lips;
  • skin trauma;
  • a cold.

Although Famciclovir generichealth does not cure the viral infection, it helps to relieve the symptoms and shorten the duration of an outbreak.

The best results are obtained if the medicine is started as soon as possible after the onset of symptoms of a cold sore, such as tingling, itching or burning, or the appearance of the first signs, such as redness or swelling. This is when the virus is reproducing rapidly.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

Famciclovir generichealth for cold sores is not recommended for use in infants, children or adolescents under 18 years of age.

Before you take Famciclovir generichealth

When you must not take it

Do not take Famciclovir generichealth if you have an allergy to:

  • any medicine containing famciclovir (active ingredient);
  • penciclovir, a related antiviral medicine;
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath;
  • wheezing or difficulty breathing;
  • swelling of the face, lips, tongue or other parts of the body;
  • rash, itching or hives on the skin.

If you experience an allergic reaction, stop using the medicine and inform your doctor or pharmacist immediately.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • you have a problem with your body's immune system, which helps to fight off infections.
  • you have a problem with your kidneys or liver.

Your doctor may want to take extra precautions in that case.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Famciclovir generichealth should not be used during pregnancy unless necessary. Your doctor will discuss with you the potential risks of taking Famciclovir generichealth during pregnancy, and will also advise you if you should take Famciclovir generichealth while breastfeeding, based on the benefits and risks of your particular situation.

If you have not told your doctor about any of the above, tell them before you start taking Famciclovir generichealth.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Famciclovir generichealth may interfere with each other. These include:

  • probenecid, a prescription medicine used to treat gout (a disease with painful, swollen joints, caused by uric acid crystals) and to increase blood levels of penicillin-type antibiotics;
  • raloxifene, a medicine used to treat osteoporosis (a disease which causes bones to become less dense, gradually making them weaker, more brittle and likely to break);
  • medicines that can affect your kidneys;
  • medicines that can affect your immune system.

These medicines may be affected by Famciclovir generichealth or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take Famciclovir generichealth

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The usual dose is:

  • three 500 mg tablets taken together as a single dose; or
  • a dose of 750 mg (one 250 mg tablet + one 500 mg tablet), given twice per day.

Your doctor may have prescribed a different dose.

For people whose immune system does not work as well as it should, the dose and duration of treatment may be increased.

For people who have reduced kidney function, the dose may be reduced.

Ask your pharmacist or doctor if you are unsure of the correct dose for you. They will tell you exactly how much to take.

How to take it

Swallow the tablets whole with a full glass of water.

They may be taken with or without food.

Do not change the dose yourself, without your doctor's advice, regardless of how well you may feel.

When to take it

Take Famciclovir generichealth (for cold sores) tablets as soon as possible after the first symptoms (eg. tingling, itching or burning) or signs (eg. redness or swelling) of a cold sore appear.

Do not take the tablets if a hard crust has already formed on the cold sore. Keep the tablets for the next episode.

How long to take it

A single dose of Famciclovir generichealth may be all that is necessary for treating each episode of cold sores. The dose may be repeated if cold sores recur.

Each pack of Famciclovir generichealth contains enough medicine for one dose.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Famciclovir generichealth. Do this even if there are no signs of discomfort or poisoning. Keep the telephone numbers for these places handy. You may need urgent medical attention.

Taking too much Famciclovir generichealth may affect the kidneys. In people who already have kidney problems it may, rarely, lead to kidney failure if their dose is not correctly lowered.

While you are taking Famciclovir generichealth

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Famciclovir generichealth.

Tell any other doctors, dentists and pharmacists who treat you that you are taking Famciclovir generichealth.

If you become pregnant while taking Famciclovir generichealth. tell your doctor. Your doctor can discuss with you the risks of taking it while you are pregnant.

Tell your pharmacist or doctor if your symptoms do not improve within a few days, or if they become worse.

Things you must not do

Do not take Famciclovir generichealth to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your tablets or change the dosage without checking with your doctor first.

Things to be careful of

If you are pregnant or breastfeeding, ask your doctor or pharmacist for advice before taking any medicine.

Be careful driving, operating machinery or doing jobs that require you to be alert until you know how Famciclovir generichealth affects you.

This medicine can cause dizziness, sleepiness or confusion.

Things that may help your condition

Take the following precautions to avoid spreading the virus:

  • Keep the areas affected by the virus as clean and dry as possible.
  • Avoid touching or scratching the sore area as you may spread the virus on your fingers.
  • Do not share any objects that have been in contact with a cold sore (eg. drinking glasses, eating utensils, or towels).
  • Avoid direct skin-to-skin contact of the area with other people (eg. kissing) until the cold sore has healed.

This is important to prevent you passing the infection on to others.

Cold sores are contagious and the virus can be passed on from person to person through close physical contact or saliva, even when blisters are not present. The risk is much higher when the cold sore is visible, as the virus can be shed, making it easy to infect other people.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Famciclovir generichealth.

This medicine helps most people with cold sores, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • headache;
  • dizziness;
  • tiredness, sleepiness
  • nausea (feeling sick) or vomiting;
  • diarrhoea;
  • stomach pain;
  • itching or an itchy rash (urticaria);
  • abnormal liver function test results.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • a rash elsewhere on the body;
  • extreme sleepiness or confusion, usually in older people;
  • hallucinations (seeing or hearing things that are not really there);
  • painful or swollen joints;
  • aching muscles or muscle tenderness or weakness that is not caused by exercise;
  • palpitations (signs of abnormal heart beat).

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • swelling below the surface of the skin (eg. swelling around the face, eye, eyelid or throat);
  • bruising or bleeding more easily than usual (may indicate that the number of platelets (a type of blood cell responsible for blood clotting) in your blood is reduced);
  • widespread red, raised areas, blisters or sores of the lips, eyes, mouth, nasal passages or genitals (signs of a serious skin reaction);
  • purple patches, itching, burning of the skin (signs of inflamed blood vessels);
  • persistent pain in the upper right abdomen, yellowing of the skin and/or eyes, dark urine or pale bowel motions (signs of a possible liver problem);
  • seizures or fits;
  • difficulty breathing or swallowing, wheezing or coughing, light-headedness, changes in alertness, skin reddening, facial/throat swelling, blue discoloration of the lips, tongue or skin (signs of severe allergic reaction).

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people

After taking FAMCICLOVIR GENERICHEALTH

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets. out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store Famciclovir generichealth or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Famciclovir generichealth 125 mg tablets are white, round film coated tablets with "FM" on one side and "125" on the other side.

Famciclovir generichealth 250 mg tablets are white, round film coated tablets, marked with "FM" on one side and "250" on the other side.

Famciclovir generichealth 500 mg tablets are white, oval, film coated tablets with "FM" on one side and “500” on the other side.

Ingredients

Active ingredient

Famciclovir generichealth 125 contain 125 mg famciclovir per tablet.

Famciclovir generichealth 250 contain 250 mg famciclovir per tablet.

Famciclovir generichealth 500 contain 500 mg famciclovir per tablet.

Other ingredients

  • microcrystalline cellulose;
  • crospovidone;
  • colloidal anhydrous silica;
  • copovidone;
  • sodium stearyl fumarate;
  • Opadry White YS-22-18096.

Australian Registration Numbers

Famciclovir generichealth 125 mg: AUST R 177010

Famciclovir generichealth 250 mg: AUST R 177012

Famciclovir generichealth 500 mg: AUST R 177014

Distributor

Famciclovir generichealth is distributed in Australia by:

Generic Health Pty Ltd
Suite 2, Level 2
19-23 Prospect Street
Box Hill, VIC, 3128
Australia

Email: [email protected]
Telephone: +61 3 9809 7900
Website: www.generichealth.com.au

This leaflet was prepared in March 2020.

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Famciclovir Generichealth

Active ingredient

Famciclovir

Schedule

S4

 

Notes

(Distrib. by Generichealth)

1 Name of Medicine

Famciclovir.

2 Qualitative and Quantitative Composition

Each tablet contains 125 mg, 250 mg or 500 mg famciclovir.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Famciclovir Generichealth 125 mg tablets are white round film coated tablets with ‘FM’ on one side and ‘125’ on the other side.
Famciclovir Generichealth 250 mg tablets are white round film coated tablets with ‘FM’ on one side and ‘250’ on the other side.
Famciclovir Generichealth 500 mg tablets are white oval film coated tablets with ‘FM’ on one side and ‘500’ on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Famciclovir is indicated for the following.
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.

4.2 Dose and Method of 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:
(i) 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 Section 5.1 Pharmacodynamic Properties, 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.
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 (see Tables 1 and 2).
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 m2.
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 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 Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties).

Administration.

Famciclovir can be taken without regard to meals (see Section 5.2 Pharmacokinetic Properties, Effect of food).

4.3 Contraindications

Known hypersensitivity to famciclovir or to any of the other ingredients in this medicine.
Hypersensitivity to penciclovir, the active metabolite of famciclovir.

4.4 Special Warnings and Precautions for Use

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 Section 4.2 Dose and Method of 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. Therefore, in addition to therapy with famciclovir, it is recommended that patients use "safer sex" practices.

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 concentrations, and thus possibly a decrease of efficacy of famciclovir (see Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

Safety and efficacy in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties).

Other drugs that affect renal physiology.

Could affect plasma levels of penciclovir (active metabolite of famciclovir, see Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties).
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 coadministered 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.

4.6 Fertility, Pregnancy and Lactation

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).
(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.
 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.

4.7 Effects on Ability to Drive and Use Machines

Patients who experience dizziness, somnolence, confusion or other central nervous system disturbances while taking famciclovir should refrain from driving or operating machinery.

4.8 Adverse Effects (Undesirable 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 and occurred at a similar incidence in patients receiving placebo treatment. Confusion, predominantly in the elderly, has been reported rarely. Table 3 shows adverse events related, possibly related, unassessable or unknown, reported by ≥ 1% of
immunocompetent subjects during clinical trials.
Table 4 shows adverse events related, possibly related, unassessable or unknown, reported by ≥ 1% of immunocompetent subjects during clinical trials in herpes labialis.
Table 5 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.
Table 6 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.
Table 7 shows the frequency of adverse events reported by ≥ 5% of patients receiving famciclovir 500 mg daily or placebo for > ten months.
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.

Uncommon: confusion (predominantly in the elderly). Rare: hallucinations.

Nervous system disorders.

Very common: headache. Common: dizziness. Uncommon: somnolence (predominantly in the elderly). Not known: seizure.

Cardiovascular disorders.

Rare: palpitations.

Gastrointestinal disorders.

Common: nausea, vomiting, abdominal pain, diarrhoea.

Hepatobiliary disorders.

Common: abnormal liver function tests. Rare: cholestatic jaundice.

Immune system disorders.

Not known: anaphylactic shock, anaphylactic reaction.

Skin and subcutaneous tissue disorders.

Common: rash, pruritus. Uncommon: angioedema (e.g. face oedema, eyelid oedema, periorbital oedema, pharyngeal oedema), urticaria. Very rare: serious skin reactions (e.g. erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis). Not known: leukocytoclastic vasculitis, hypersensitivity vasculitis.

Musculoskeletal disorders.

Very rare: arthralgia, myalgia.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdose experience with famciclovir is limited.
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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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

Mechanism of action.

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.
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 triphosphate 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).

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 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 mg 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 over 5 days.

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 nonaborted 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.
In one, randomized (2:1), double blind, placebo controlled 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 nonaborted 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, noninferiority, multicentre 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/microL 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 predefined margin for claiming noninferiority. Noninferiority 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 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 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).

5.2 Pharmacokinetic Properties

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 8). There are no data on the pharmacokinetics of the 1,500 mg single dose.
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 Cmax was decreased by approximately 50% and Tmax was 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 Cmax was reduced by approximately 20% and Tmax 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 Section 4.2 Dose and Method of 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 4.2 Dose and Method of Administration, Hepatic impairment; Section 4.4 Special Warnings and Precautions for Use). 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 4.2 Dose and Method of 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.

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.

5.3 Preclinical Safety Data

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 Section 5.2 Pharmacokinetic Properties). 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.

Genotoxicity.

Famciclovir and penciclovir (the active metabolite of famciclovir) were tested for genotoxic potential in a series of in vitro and 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.

Carcinogenicity.

The carcinogenic potential of famciclovir 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).

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet contains the following excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silica, copovidone, sodium stearyl fumarate and Opadry White YS-22-18096.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C in a dry place. Keep out of the reach of children.

6.5 Nature and Contents of Container

Famciclovir Generichealth 125 mg tablets are packed in blister packs of 10* and 40 and bottles of 40*.
Famciclovir Generichealth 250 mg tablets are packed 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 Generichealth 500 mg tablets are packed in blister packs of 3, 14*, 30*, 56 and bottles of 30*, 56*.
*Not currently marketed in Australia.

Australian registration numbers.

Famciclovir Generichealth 125 mg: AUST R 177010.
Famciclovir Generichealth 250 mg: AUST R 177012.
Famciclovir Generichealth 500 mg: AUST R 177014.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

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

Chemical structure.


Chemical name: 9-(4-acetoxy-3- acetoxymethylbut-1-yl)- 2-aminopurine.
Molecular formula: C14H19N5O4.
Molecular weight: 321.3.

CAS number.

104227-87-4.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes