Consumer medicine information

Famciclovir Mylan for Genital Herpes

Famciclovir

BRAND INFORMATION

Brand name

Famciclovir Mylan

Active ingredient

Famciclovir

Schedule

What is in this leaflet

This leaflet answers some common questions about FAMCICLOVIR MYLAN.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page.

Some more recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking FAMCICLOVIR MYLAN against the benefits it can provide.

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

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

What FAMCICLOVIR MYLAN is used for

FAMCICLOVIR MYLAN is an antiviral medicine for adults and adolescents. It is used to treat outbreaks of genital herpes and also to suppress (prevent) recurrent outbreaks of the condition.

Genital herpes is a viral infection caused by herpes simplex 1 or herpes simplex 2. It is usually transmitted through sexual contact.

Symptoms include tingling, burning or itching of the genitals, followed by blisters that may be painful.

People who have frequent episodes of genital herpes can also take FAMCICLOVIR MYLAN to help prevent the attacks.

Although FAMCICLOVIR MYLAN does not cure the viral infection, it helps to relieve the symptoms and shorten their duration.

The best results are obtained if the medicine is started as soon as possible after the first symptoms begin to appear.

Taking FAMCICLOVIR MYLAN does not prevent you from spreading the herpes virus to another person.

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.

FAMCICLOVIR MYLAN is only available with a doctor's prescription. It is not addictive.

This medicine is not recommended for use in children under 12 years of age.

Before taking FAMCICLOVIR MYLAN

When you must not take it

Do not take FAMCICLOVIR MYLAN if you have an allergy to:

famciclovir, the active ingredient
penciclovir, a related antiviral medicine
any of the other ingredients of FAMCICLOVIR MYLAN listed at the end of this leaflet (see 'Product Description')

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.

Do not take FAMCICLOVIR MYLAN after the expiry date printed on the pack, or if the packaging is torn or if it shows signs of tampering. In that case, return it to your pharmacist.

Before you start to take it

Tell your doctor if you have a problem with:

your body's immune system, which helps to fight off infections.
your kidneys
your liver

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

Tell your doctor if you are pregnant, intend to become pregnant or if you are breast feeding. FAMCICLOVIR MYLAN should not be used during pregnancy unless necessary. Your doctor will discuss with you the potential risks of taking FAMCICLOVIR MYLAN during pregnancy, and will also advise you if you should take FAMCICLOVIR MYLAN while breast-feeding, based on the benefits and risks of your particular situation.

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives. Your doctor will want to know if you are prone to allergies.

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

Taking other medicines

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

Some medicines and FAMCICLOVIR MYLAN 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

You may need to take different amounts of these medicines or you may need to take different medicines. Your doctor and pharmacist have more information.

If you have not told your doctor about any of these things, tell him/her before you start taking this medicine.

How to take FAMCICLOVIR MYLAN

Swallow the tablets whole with a full glass of water.

The tablets may be taken with or without food.

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

How much to take

Follow your doctor's instructions on how many FAMCICLOVIR MYLAN tablets to take. These instructions may differ from the information contained in this leaflet.

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

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

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

For people who have kidney problems, your doctor may decide to give you a lower dose.

When to take it

There are different ways to take FAMCICLOVIR MYLAN depending on your condition.

TO TREAT AN OUTBREAK OF GENITAL HERPES

To treat an outbreak, take the tablets as soon as possible after the first symptoms of genital herpes appear.
The tablets are best taken within 6 hours of the first symptoms of genital herpes appearing.
There are two ways to take FAMCICLOVIR MYLAN to treat an outbreak of genital herpes and your doctor will tell you which regimen is best for you:

Two 250 mg FAMCICLOVIR MYLAN tablets to start with, followed by one 250 mg tablet every 12 hours for the next 3 doses
or
One 125 mg FAMCICLOVIR MYLAN tablet every 12 hours for 5 days.

Take the second dose (and subsequent doses, if applicable) 12 hours after the first dose, or as close as possible to 12 hours during waking hours.
If you take the first dose in the late morning or early afternoon, you can take the next dose before going to bed, but do not take any doses less than 6 hours apart.
During normal waking hours, take any remaining doses at 12 hourly intervals.
Your doctor may have prescribed a different dose.

TO SUPPRESS (PREVENT) OUTBREAKS OF RECURRENT GENITAL HERPES

Start suppressive treatment to prevent outbreaks of recurrent genital herpes as soon as possible after you have your FAMCICLOVIR MYLAN prescription filled.
Take one 250 mg FAMCICLOVIR MYLAN tablet twice each day.
Continue to take one 250 mg FAMCICLOVIR MYLAN tablet twice each day for as long as your doctor tells you to. Do this even if you do not have an outbreak.

This medicine helps to control your condition but does not cure it. Your doctor will tell you when you can stop.

Fill your next repeat prescription before using all of the tablets in your current carton. This will ensure that your treatment can be continued and give you the best results.

Try to take the tablets at about the same times each day, as directed by your doctor or pharmacist. Taking your tablet at the same times each day will have the best effect. It will also help you remember when to take the tablets.

How long to take it

Continue taking FAMCICLOVIR MYLAN every day for as long as your doctor tells you.

To help clear up your infection, you must keep taking this medicine, even if your symptoms begin to clear up after a few days.

To prevent recurrent episodes of genital herpes, you must take the tablets each day, even if you have no symptoms.

It is important to keep taking your medicine even if you feel well.

If you forget to take it

Take a dose as soon as you remember. Take your next tablet at the usual time, and then go back to taking it as you would normally.

Do not take two doses within a time frame of less than one hour. In that case, skip the missed dose.

Do not take a double dose to make up for the one that you missed. This may increase the chance of you getting an unwanted side effect.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (Overdose)

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

Taking too much FAMCICLOVIR MYLAN 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 MYLAN

Things you must do

If you become pregnant while taking FAMCICLOVIR MYLAN, tell your doctor. Your doctor can discuss with you the risks of taking it while you are pregnant.

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

Tell any other doctor, dentist or pharmacist who treats you that you are taking FAMCICLOVIR MYLAN.

Things you must not do

Do not give this medicine to anyone else even if their condition seems to be the same as yours.

Do not use this medicine to treat any other complaints unless your doctor tells you to.

Do not stop taking your tablets or change the dosage without checking with your doctor first. If you stop your tablets suddenly, your condition may worsen or you may have unwanted side effects.

Things to be careful of

If you are pregnant or breast-feeding, 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 MYLAN affects you.

This medicine can cause dizziness, sleepiness or confusion.

Practice "safer sex", including the use of condoms when symptoms are present, even if you have started taking FAMCICLOVIR MYLAN. This is important to prevent you passing the infection on to others.

Things that may help your condition

Take the following precautions to help manage your condition:

Use condoms between episodes to reduce the risk of infecting your partner
Keep the areas affected by the virus as clean and dry as possible
Wear loose-fitting clothing to avoid irritating the blisters
Avoid touching or scratching the sore area as you may spread the virus on your fingers

Side effects

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by these lists of possible side effects. You may not experience any of them.

Tell your doctor if you notice any of the following side effects and they worry you:

headache
dizziness
nausea (feeling sick) or vomiting
abdominal pain
diarrhoea
itching or an itchy rash (urticaria)
abnormal liver function test results

The above side effects are usually mild.

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

a rash on other parts of your 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
yellowing of the skin /or eyes (signs of jaundice)
palpitations (signs of abnormal heart beat)

The above side effects may need medical attention.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if any of the following side effects happen to you:

swelling below the surface of the skin (e.g. swelling around the face, eye, eyelid or throat)
unexplained bruising, reddish or purplish patches on the skin, or bleeding more easily than usual as it may indicate that the number of platelets (a type of blood cell responsible for blood clotting) in your blood are reduced
severe blistering of the skin or mucous membranes 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)

The above side effects are very rare.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed here or not yet known may happen in some people.

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

After taking FAMCICLOVIR MYLAN

Storage

Keep your medicine in the original container until it is time to take it.

Store it in a dry place where the temperature stays below 25°C.

Do not store FAMCICLOVIR MYLAN or any other in the bathroom or near a sink.

Do not leave the tablets in the car or on window sills. Heat and dampness can destroy some medicines. FAMCICLOVIR MYLAN tablets will keep best if they are stored cool and dry.

Keep the medicine where children cannot reach it. A locked cupboard at least one-and-a-half meters 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 you have left over.

Product description

What it looks like

FAMCICLOVIR MYLAN tablets are available in the following strengths for the treatment of genital herpes:

125mg - white, oval shape, biconvex, film coated, debossed with "FAM 125" on one side and "G" on other side in blister packs of 40.

250mg - white, oval shape, biconvex, film coated, debossed with "FAM 250" on one side and "G" on other side in blister packs of 20, 21 and 56.

Ingredients

The active ingredient in FAMCICLOVIR MYLAN is famciclovir.

Each FAMCICLOVIR MYLAN 125 tablet contains 125 mg of famciclovir

Each FAMCICLOVIR MYLAN 250 tablet contains 250 mg of famciclovir.

The tablets also contain the following inactive ingredients:

hyprolose
sodium starch glycollate
microcrystalline cellulose
silicon dioxide
magnesium stearate
Opadry II white OY-L-28900

This product contains lactose.

Supplier

FAMCICLOVIR MYLAN is supplied in Australia by:

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:

FAMCICLOVIR MYLAN 125 mg - AUST R 157789

FAMCICLOVIR MYLAN 250 mg - AUST R 157788

This leaflet was prepared on
13 May 2021.

FAMCICLOVIR MYLAN for genital herpes_cmi\May21

Published by MIMS August 2021

BRAND INFORMATION

Brand name

Famciclovir Mylan

Active ingredient

Famciclovir

Schedule

1 Name of Medicine

Famciclovir.

2 Qualitative and Quantitative Composition

Each tablet contains 125 mg, 250 mg or 500 mg of famciclovir as the active ingredient.
Famciclovir Mylan tablets contain lactose monohydrate. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Famciclovir Mylan 125 mg.

White, oval shape, biconvex, film coated tablet, debossed with "FAM 125" on one side and "G" on other side.

Famciclovir Mylan 250 mg.

White, oval shape, biconvex, film coated tablet, debossed with "FAM 250" on one side and "G" on other side.

Famciclovir Mylan 500 mg.

White, oval shape, biconvex, film coated tablet, debossed with "FAM 500" on one side and "G" on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Famciclovir Mylan is indicated for:
the 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.
the 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 Mylan 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

Method of administration.

Famciclovir Mylan is intended for oral administration.
Famciclovir can be taken without regard to meals (see Section 5.2 Pharmacokinetic Properties, Effect of food).

Dosage.

Immunocompetent.

Herpes zoster.

The recommended dosage of Famciclovir Mylan 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 Mylan is started within 48 hours.

Recurrent genital herpes infections (HSV).

The recommended dosage is a total dose of 1250 mg famciclovir administered as either: (i) 500 mg statim, then 250 mg 12 hourly for 3 doses or (ii) 125 mg twice each day for 5 days.
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 1500 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 1 hour of symptom onset in the recurrent herpes labialis clinical study.

Immunocompromised.

Herpes zoster.

The recommended dosage of Famciclovir Mylan 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 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 recommended modifications are tabulated in Table 1. 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 creatinine clearance less than 10 mL/min/1.73m².
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 4 hour haemodialysis results in approximately 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).

4.3 Contraindications

Famciclovir Mylan is contraindicated in patients with known hypersensitivity to famciclovir or other constituents of Famciclovir Mylan.
It is also contraindicated in those patients who have shown hypersensitivity to penciclovir, the active metabolite of famciclovir.

4.4 Special Warnings and Precautions for Use

Efficacy has not been studied in ophthalmic zoster, chicken pox or zoster encephalomyelitis patients.

Use in hepatic impairment.

No special precautions are required for elderly patients with normal renal function and patients with mild or moderate 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 Pharmacological Properties).
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 the patients use "safer sex" practices.

Use in renal impairment.

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).

Use in the elderly.

No special precautions are required for elderly patients with normal renal function and well-compensated hepatic impairment.

Paediatric use.

Safety and efficacy in children has 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 (the active metabolite of famciclovir, see Section 5 Pharmacological Properties).

Other drugs that affect renal physiology.

Other drugs the affect renal physiology could affect plasma levels of penciclovir (active metabolite of famciclovir, see Section 5 Pharmacological 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 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.

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 10 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 250 mg famciclovir b.i.d. for 18 weeks. Famciclovir had no effect on fertility in female rats at doses of up to 1000 mg/kg/day, approximately 4 to 27 times the human systemic exposure (AUC).
(Category B1)
Famciclovir was tested for effects on embryo-foetal development in rats and rabbits at oral doses up to 1000 mg/kg/day (approximately 4 to 27 times and 2 to 12 times the human systemic exposure to penciclovir in rats and rabbits, respectively [AUC]), 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 embryo-foetal 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 active metabolite of famciclovir), the safety of famciclovir in human pregnancy has not been established. Famciclovir Mylan 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 nursing 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 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 Mylan 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 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. See Tables 2, 4, 5 and 6.
The following adverse events occurred during the clinical trial in recurrent herpes labialis. See Table 3.
Famciclovir has also been well tolerated in immunocompromised patients. Undesirable effects reported from clinical studies were similar to those reported in the immunocompetent population.

Post-marketing data.

In addition to the adverse events reported in the clinical trials, the following adverse events (Table 7) have been reported in post-marketing surveillance. They are ranked under headings of frequency, according to 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.

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

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 4 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

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.
This triphosphate persists in infected cells 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 1976 total isolates from HSV and VZV (5/1976), and in 0.19% of the 533 virus isolates from immunocompromised patients (1/533).

Clinical trials.

Herpes zoster.

Placebo-controlled trial.

Famciclovir tablet 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 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 7 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 5 days compared to 7 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 (1 day and 2 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 days 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 5 times per day (n=139) for 7 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 5 times per day (n=77) for 10 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 10 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. (n=160), famciclovir 250 mg b.i.d. (n=169), famciclovir 500 mg b.i.d. (n=154) or placebo (n=143) for 5 days. Treatment was initiated within 6 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 4 days compared to 5 days in placebo-treated patients. The median time to cessation of viral shedding was 1.8 vs 3.4 days in 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 vs. 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 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). 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, 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/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 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 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 5 times per day (n=143) for 7 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 7 days, 2 days and 3 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 HSV recurrence for 8 weeks. Famciclovir showed statistically significant superiority over placebo in the efficacy parameters measured. There was an approximate 10-fold 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 1500 mg once (n=227), famciclovir 750 mg b.i.d. (n=220) or placebo (n=254) for 1 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 3 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 breast-feeding women were excluded. Patients were excluded if they had received an investigational drug in the 4 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 1 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 analogs.
Patients were instructed to take the first dose of study medication within 1 hour of symptom onset. However, some patients commenced treatment after 1 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 ITT population compared with placebo. The median time to healing in famciclovir 1500 mg single-dose treated patients was 4.4 days compared to 4.0 days in famciclovir 750 mg bid 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 1500 mg dose of famciclovir 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. Famciclovir is rapidly and extensively absorbed and converted to the antivirally active compound penciclovir. The bioavailability of penciclovir after oral famciclovir is 77%. Mean peak plasma concentrations (C_max) of penciclovir occurred at a median time of 45 minutes following administration of single oral doses of famciclovir (as shown in Table 8). No data is available on the pharmacokinetics of 1500 mg as a 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 2.0 hours. There is no accumulation of penciclovir on repeated dosing with famciclovir.
The pharmacokinetic results of the bioequivalence study (Study #3447) are as follows: C_max 3398.13 + 656.93 nanogram/mL; T_max*0.92 hr (0.50 - 2.50 hr) and t _½ 2.11 + 0.27 hr. *median (min - max).

Effect of food.

Penciclovir C_max was decreased by approximately 50% and T_max was delayed by 1.5 h when a capsule formulation of famciclovir was administered 30 minutes after food. When famciclovir tablets were administered 30 minutes after food, penciclovir C_max was reduced by approximately 20% and T_max was delayed by 0.75 hour. 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.

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 impairment (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 500 mg famciclovir. 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 hour in patients with hepatic impairment 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 body weight 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).

HIV patients.

Extrapolated data from a study (n=8) where famciclovir was given as a single dose resulted in a mean AUC of 24 microgram.h/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 or 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.h/mL in subjects with creatinine clearance greater than 50 mL/min. 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 doses for famciclovir (i.e. penciclovir AUC of 4.5 microgram.h/mL at 125 mg b.i.d. for acute recurrent genital herpes, and a penciclovir AUC of 27 microgram.h/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 IV at doses toxic to bone marrow.

Carcinogenicity.

The carcinogenic potential of famciclovir was evaluated in 2 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.h/mL respectively, or approximately 1 to 8 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.h/mL respectively, or approximately 2 to 12 times the human systemic exposure (AUC).

6 Pharmaceutical Particulars

6.1 List of Excipients

All Famciclovir Mylan tablets also contain hyprolose, sodium starch glycollate, microcrystalline cellulose, silicon dioxide, magnesium stearate, purified water and the film coat, Opadry II OY-L-28900 complete film coating system OY-L-28900 White PI (12591).

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 original container.