Consumer medicine information

Ezovir Cold Sore Relief

Famciclovir

BRAND INFORMATION

Brand name

Ezovir Cold Sore Relief

Active ingredient

Famciclovir

Schedule

S3

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ezovir Cold Sore Relief.

What is in this leaflet

This leaflet answers some common questions about EZOVIR Cold Sore Relief. It does not contain all the available information and does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your pharmacist or doctor have weighed the risks of you taking EZOVIR Cold Sore Relief 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 this medicine. You may need to read it again.

What EZOVIR Cold Sore Relief is used for

EZOVIR Cold Sore Relief is an antiviral medicine that is 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 I (HSV-1). Cold sores usually begin on or around the lips, mouth, and nose. After redness and swelling develop, the small red bumps turn into fluid-filled blisters.

The blisters may weep or burst, and this can be tender and painful. 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.

The infection is most commonly acquired as a baby or child from physical contact with parents or relatives that have a cold sore, often by kissing. After the initial infection has healed, the virus becomes dormant in nerve cells.

Cold sores can be unpredictable. 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

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.

Although EZOVIR Cold Sore Relief does not cure the viral infection, it helps to relieve the symptoms and shorten their duration of an outbreak.

The best results are obtained if the medicine is started as soon as possible after the onset of symptoms occur. These may include 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 pharmacist or doctor if you have any questions about why this medicine has been prescribed for you.

EZOVIR Cold Sore Relief is only available from your pharmacist. The cold sores pack may be purchased without a doctor's prescription. It is not addictive.

Use in Children

This medicine is not recommended for use in infants, children or adolescents under 18 years of age.

Before taking EZOVIR Cold Sore Relief

When you must not take it

Do not take EZOVIR Cold Sore Relief if you have a problem with your body's immune system, which helps fight off infections. Your pharmacist will refer you to your doctor in that case.

Do not take EZOVIR Cold Sore Relief if you have an allergy to:

  • famciclovir, the active ingredient
  • penciclovir, a related antiviral medicine
  • any of the EZOVIR Cold Sore Relief ingredients 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 this medicine if you have a problem with your body's immune system, which helps to fight off infections. Your pharmacist will refer you to your doctor in that case.

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

Before you start to take it

Tell your pharmacist or doctor if:

  • You are over 50 years of age or if you have or have had any medical conditions especially the following:
    - A problem with your kidneys.
    - Diabetes, high blood pressure, heart problems, liver problems or other medical conditions.
    - Signs of an infection other than your cold sore.

Your pharmacist may want to take extra precautions or refer you to a doctor to determine if this medicine is suitable for you.

Tell your doctor if you are pregnant, intend to become pregnant or if you are breastfeeding.

EZOVIR Cold Sore Relief should not be used during pregnancy unless necessary.

Your pharmacist or doctor will discuss with you the potential risks of taking this medicine during pregnancy and will also advise you if you should take this medicine while breast-feeding, based on the benefits and risks of your particular situation.

Tell your doctor or pharmacist if you are prone to allergies or allergic to any other medicines, foods, dyes or preservatives.

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

Taking other medicines

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

Some medicines and EZOVIR Cold Sore Relief 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 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 immune system
  • medicines that can affect your kidneys

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

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

How to take EZOVIR Cold Sore Relief

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

If you do not understand the instructions on the label, 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.

However, if you have problems with your kidneys and your pharmacist has referred you to your doctor to see if this medicine is suitable for you, your doctor may have recommended a different dose.

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

Follow the instructions that they give you.

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

When to take it

Take EZOVIR Cold Sore Relief tablets as soon as possible after the first symptoms (e.g. tingling, itching or burning) or signs (e.g. 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 to take it

Swallow the tablets whole with a full glass of water.

They may be taken with or without food. It is not necessary to chew or crush the tablet.

How long to take it

A single dose of EZOVIR Cold Sore Relief is all that is necessary for treating each episode of cold sores. Each pack of EZOVIR Cold Sore Relief contains enough medicine for one dose. A repeat dose during this episode is not recommended.

If another episode of cold sores recurs, another dose may be taken. However, do not repeat this treatment within 7 days.

If you take too much (Overdose)

Immediately telephone your doctor or the Poisons Information Centre (Australia telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much EZOVIR Cold Sore Relief. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep the telephone numbers for these places handy.

Taking too much EZOVIR Cold Sore Relief 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 EZOVIR Cold Sore Relief

Things you must do

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

If you become pregnant, tell your doctor before taking any further doses of this medicine to another episode of cold sores. 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 periodically take this medicine to treat recurring episodes of cold sores.

Tell any other doctor, dentist or pharmacist who treats you that you are taking EZOVIR Cold Sore Relief.

Things you must not do

Do not take less than the recommended dose of 3 tablets, unless advised by your doctor.

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.

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 EZOVIR Cold Sore Relief affects you.

This medicine can cause dizziness, sleepiness or confusion in some people.

Things that may help your condition

Cold sores are contagious, and the virus can be passed on from an infected person to an uninfected 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.

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

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking EZOVIR Cold Sore Relief.

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 the below lists of possible side effects. You may not experience any of them. Ask your doctor or pharmacist to answer any questions you may have.

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

  • headache
  • dizziness
  • nausea (feeling sick) or vomiting
  • diarrhoea
  • itching or an itchy rash (urticaria)

The above side effects are usually mild.

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

  • a rash elsewhere on the body, that is separate from the cold sore
  • 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:

  • swelling below the surface of the skin (e.g. swelling around the face, eye, eyelid or throat)
  • unexplained bruising 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)
  • seizures or fits
  • difficulty breathing or swallowing, wheezing or cough, light-headedness, changes in alertness, skin reddening, facial/throat swelling, blue discolouration of the lips, tongue or skin (signs of severe allergic reaction)
  • signs of a possible liver problem such as persistent pain in the upper right abdomen, yellowing of the skin and/or eyes, dark urine or pale bowel motions

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 EZOVIR Cold Sore Relief

Storage

Keep your medicine in the original container until it is time to take it. Store your EZOVIR Cold Sore Relief tablets in a dry place where the temperature stays below 25°C.

Do not leave the tablets in the car or on window sills. Heat and dampness can destroy some medicines. EZOVIR Cold Sore Relief 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 pharmacist or doctor recommended that you take less than the full dose in this pack, told you to stop taking your medicine or if it has expired, ask your pharmacist what to do with any tablets that you may have left over.

Product description

What it looks like

EZOVIR Cold Sore Relief 500 mg tablets are are white, oval, film-coated tablets with "FM" on one side and "500" on the other. Each carton contains 3 tablets.

Ingredients

EZOVIR Cold Sore Relief tablets contains 500 mg of famciclovir as the active ingredient.

The tablets also contain the following inactive ingredients:

  • microcrystalline cellulose
  • crospovidone
  • silicon dioxide
  • copovidone
  • sodium stearylfumarate
  • Opadry II complete film coating system YS-22-18096 White

Supplier

EZOVIR Cold Sore Relief is supplied in Australia by:

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared on
March 2023.

Australian registration numbers:
EZOVIR Cold Sore Relief famciclovir 500 mg tablets
- AUST R 351702

EZOVIR COLD SORE RELIEF_cmi\Mar23/00

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Ezovir Cold Sore Relief

Active ingredient

Famciclovir

Schedule

S3

 

1 Name of Medicine

Famciclovir.

2 Qualitative and Quantitative Composition

Each tablet contains 500 mg famciclovir. Famciclovir is a synthetic guanine derivative. It is a white to pale yellow crystalline solid.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ezovir Cold Sore Relief tablets are white, oval, coated tablets with FM on one side and 500 on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Ezovir Cold Sore Relief is indicated for the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults aged 18 years and over.

4.2 Dose and Method of Administration

Dosage.

Adults 18 years and older.

The recommended dosage is 1500 mg as a single dose. 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.

Renal impairment.

As reduced clearance of penciclovir is related to reduced renal function, as measured by creatinine clearance, patients who have or at-risk of renal impairment should be referred to their medical practitioner for screening for renal impairment and any subsequent dosage adjustment if necessary. Therefore, use of Ezovir Cold Sore Relief in patients with renal impairment should only be under medical advice. The following modifications in dosage are recommended.
If the creatinine clearance is ≥ 60 mL/min/1.73 m2, no dosage adjustment is necessary. If the creatinine clearance is 40-59 mL/min/1.73 m2, the dose is 750 mg as a single dose; 20-39 mL/min/1.73 m2, the dose is 500 mg as a single dose; 10-20 mL/min/1.73 m2 and for patients on haemodialysis, the dose is 250 mg as a single dose.
Ezovir Cold Sore Relief is only available as tablets containing 500 mg of famciclovir.
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/1.73 m2.
Since 4 hours of 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 mild to moderate hepatic impairment.

Administration.

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

4.3 Contraindications

Ezovir Cold Sore Relief is contraindicated in patients with known hypersensitivity to famciclovir or other constituents of Ezovir Cold Sore Relief.
It is also contraindicated in those patients who have shown hypersensitivity to penciclovir, the active metabolite of famciclovir.
Ezovir Cold Sore Relief is not recommended for use in: patients who are immunocompromised; children and adolescents under 18 years of age.

4.4 Special Warnings and Precautions for Use

Use in hepatic impairment.

Famciclovir has not been studied in patients with severe hepatic impairment. Conversion of famciclovir to the active metabolite penciclovir maybe 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).

Use in renal impairment.

As reduced clearance of penciclovir is related to reduced renal function, as measured by creatinine clearance, patients who have or at-risk of renal impairment should be referred to their medical practitioner for screening for renal impairment and any subsequent dosage adjustment if necessary. Appropriate dosage adjustments for renally impaired patients are provided (see Section 4.2 Dose and Method of Administration). Therefore, use of Ezovir Cold Sore Relief in patients with renal impairment should only be under medical advice.

Use in the elderly.

No special precautions are required for elderly patients with normal renal function and patients with mild or moderate hepatic impairment.

Paediatric use.

Safety and efficacy of famciclovir in the treatment of herpes labialis in children and adolescents under 18 years of age has not been established. Therefore, use of Ezovir Cold Sore Relief in this age group is not recommended.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 Pharmacological Properties).

Other drugs that affect renal physiology.

Could affect plasma levels of penciclovir (the 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-deoxypenciclovir 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.
Ezovir Cold Sore Relief should therefore not be used during pregnancy unless the potential benefits are considered to outweigh the potential risks associated with treatment.
 Ezovir Cold Sore Relief 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 Ezovir Cold Sore Relief 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 Table 1).

Post-marketing data.

In addition to the adverse events reported in the clinical trials, the following adverse reactions 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.
Adverse events reported by patients receiving famciclovir during postmarketing (see Table 2):

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 hours of 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.

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.

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 breastfeeding 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. Following oral administration, famciclovir is rapidly and extensively absorbed and converted to the antivirally active compound penciclovir. The bioavailability of penciclovir after oral famciclovir administration is 77%. Mean peak plasma concentrations (Cmax) of penciclovir occurred at a median time of 45 minutes following administration of single oral doses of famciclovir (as shown in Table 3). No data is available on the pharmacokinetics of 1500 mg famciclovir 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.

Effect of food.

Penciclovir Cmax was decreased by approximately 50% and Tmax was delayed by 1.5 hour 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 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.

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 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 maybe 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).

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.

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

Ezovir Cold Sore Relief tablets contain copovidone, crospovidone, microcrystalline cellulose, Opadry II complete film coating system YS-22-18096 White, silicon dioxide, sodium stearylfumarate.

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.

6.5 Nature and Contents of Container

Ezovir Cold Sore Relief 500 mg.

PVC/Al blister pack of 3 tablets.

Australian register of therapeutic goods (ARTG).

AUST R 351702 - Ezovir Cold Sore Relief 500 mg.

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

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)

S3 (Pharmacist Only Medicine).

Summary Table of Changes