Consumer medicine information

GenRx Aciclovir Tablets

Aciclovir

BRAND INFORMATION

Brand name

GenRx Aciclovir Tablets

Active ingredient

Aciclovir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using GenRx Aciclovir Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about aciclovir. 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 last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is GenRx Aciclovir. It contains the active ingredient aciclovir.

The 200mg strength is used to

  • treat genital herpes. It makes an outbreak of genital herpes shorter and less severe
  • prevent or reduce the number of outbreaks and/or severity of genital herpes in people who experience them often.

The 800mg strength is used:

  • to treat shingles, also known as herpes zoster. Shingles is caused by the same virus which causes chicken pox. It usually involves nerve pain and a blistery rash, limited to one area of the body. If taken within 72 hours of first getting the rash, aciclovir makes an outbreak of shingles shorter and less severe
  • as part of the management program for certain infections in people who have the human immunodeficiency virus (HIV). HIV is the virus that causes acquired immune deficiency syndrome (AIDS). Aciclovir does not cure AIDS or get rid of the HIV virus from your body, but it may prevent further damage to the immune system by stopping production of the herpes viruses.

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

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

How it works

Aciclovir belongs to a group of medicines called "anti-virals". It works by stopping the production of the virus that causes herpes and shingles.

Aciclovir does not get rid of the virus from your body.

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You are hypersensitive to, or have had an allergic reaction to, aciclovir, valaciclovir or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body, rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • kidney or liver problems
  • neurological disorders such as muscle weakness, paralysis, seizures, confusion, etc
  • an imbalance of electrolytes (salts) in your body
  • severe lack of oxygen from any part of your body
  • neurological reactions from a cytotoxic (anti-cancer) medicine.
  1. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  2. You are currently breastfeeding or you plan to breastfeed. Do not take this medicine whilst breastfeeding until you and your doctor have discussed the risks and benefits involved.
  3. You are planning to have surgery or an anaesthetic.
  4. You are currently receiving or are planning to receive dental treatment.
  5. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with aciclovir. These include:

  • probenecid, a medicine commonly used to treat gout
  • cimetidine, used for stomach problems
  • diuretics, also called fluid tablets
  • interferon, used to treat multiple sclerosis, hepatitis, leukaemia, Hodgkin's lymphoma and other diseases
  • methotrexate given by injection into the spine to treat cancer and leukaemia
  • mycophenolate mofetil, used by people with organ transplants.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with aciclovir.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

The doses below may be lower if you have problems with your kidneys.

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

Initial genital herpes
The usual dose is one 200mg tablet every four hours, while awake, for a total of five tablets daily for ten days.

Recurrent genital herpes
The usual dose is one 200mg tablet three times a day for up to six months.
Or
One 200mg tablet every four hours, while awake, for a total of five tablets daily for five days.

Shingles
The usual dose is one 800mg tablet every four hours, while awake, for a total of five tablets daily for seven days (or up to ten days if your eyes are affected by shingles).

Management of HIV
The usual dose is one 800mg tablet four times a day at six hourly intervals.

How to take it

The tablets should be swallowed whole with a glass of water.

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take it before, with or after food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses.

This may increase the chance of you experiencing side effects.

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively go to the Accident and Emergency Department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much of this medicine, you may feel or be sick, have a headache and/or feel confused.

While you are taking this medicine

Things you must do

If you feel that your condition is not improving or is getting worse, see your doctor.

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breastfeed
  • you are about to have any blood tests
  • you are going to have surgery or are going into hospital.

Your doctor may occasionally do tests on your blood or urine to check for side effects and see how your kidneys are working. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor or pharmacist tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Genital herpes and HIV can be transmitted to your partner during sexual activity. It is important to remember that this medicine will not keep you from transmitting herpes or HIV to others.

Be careful when driving or operating machinery until you know how this medicine affects you.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking aciclovir or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

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

  • stomach problems such as nausea (feeling sick), vomiting (being sick), diarrhoea, constipation, stomach pain
  • changes in taste sensation, loss of appetite, weight loss
  • dizziness/giddiness or headache
  • difficulty sleeping
  • increased hair loss
  • weakness, fatigue, lack of energy, tiredness
  • aching, leg pains, muscles pains, joint pain, muscle cramps
  • menstrual problems.

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

These may be serious side effects. You may need medical attention.

  • confusion
  • depression, agitation, irritability
  • unusual thoughts or actions, hallucinations (seeing, feeling or hearing things that are not there)
  • shakiness/trembling
  • difficulty speaking
  • uncoordinated movements, i.e. unsteady walking
  • fever, sore throat, swollen glands
  • blood problems (e.g. feeling tired and weak, fever, frequent infections, unusual bruising or bleeding or swelling around wounds)
  • fluid retention
  • eye problems (inflamed eye).

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation.

  • yellowing of the skin and/or eyes (jaundice) or other liver problems with a collection of symptoms which may include: mental confusion, drowsiness, restlessness, itching and unconsciousness
  • kidney problems e.g. too much or too little urine, or pain when urinating, or pain in the kidneys
  • troubled breathing
  • chest pain, fast heart beat (palpitations)
  • convulsion (fits)
  • losing consciousness or in a coma
  • signs of a blood clot such as a swollen and painful area in your leg, and swelling in your foot or ankle.

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to aciclovir, tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, 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
  • fainting
  • hayfever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

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

Keep this medicine where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or they have passed their expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What GenRx Aciclovir looks like

GenRx Aciclovir 200mg tablets are round, blue, flat-faced, bevel-edged tablets, engraved "APO" over "200" on one side and the other side plain.

Blister packs of 25, 50 and 90 tablets.*

GenRx Aciclovir 800mg tablets are oval, blue, biconvex tablet. Engraved APO partial bisect 800 on one side, plain on the other side.

Blister packs of 35 tablets.

* Not all strengths, pack types and/or pack sizes may be available

Ingredients

Each tablet contains 200mg or 800mg of aciclovir as the active ingredient.

It also contains the following inactive ingredients:

  • lactose (for the 200mg strength only)
  • magnesium stearate
  • colloidal anhydrous silica
  • croscarmellose sodium
  • microcrystalline cellulose
  • indigo carmine
  • brilliant blue FCF (for the 800mg strength only).

The 200 mg tablets are gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

The 800 mg tablets are lactose-free, gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

GenRx Aciclovir 200mg tablets: AUST R 71816.

GenRx Aciclovir 800mg tablets: AUST R 71817.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

GenRx is a registered trademark of Apotex Pty Ltd.

This leaflet was last updated in:
October 2016

BRAND INFORMATION

Brand name

GenRx Aciclovir Tablets

Active ingredient

Aciclovir

Schedule

S4

 

1 Name of Medicine

Aciclovir.

6.7 Physicochemical Properties

Chemical name: 9-((2-hydroxyethoxy) methyl)guanine. Molecular Formula: C8H11N5O3. Molecular Weight: 225.2.

Chemical structure.


CAS number.

59277-89-3.

2 Qualitative and Quantitative Composition

Aciclovir is a synthetic acyclic purine nucleoside analogue. It is a white crystalline powder slightly soluble in water and practically insoluble in most organic solvents.
Each tablet contains 200 mg or 800 mg of acyclovir as the active ingredient.
In addition, each tablet contains the following inactive ingredients: lactose monohydrate (200 mg tablet only), magnesium stearate, colloidal anhydrous silica, croscarmellose sodium, microcrystalline cellulose, brilliant blue FCF (800 mg tablet only) and indigo carmine.
Aciclovir 200 mg tablets contains sugars as lactose.
Aciclovir tablets are gluten free.

3 Pharmaceutical Form

200 mg tablets are round, blue flat faced, bevel-edged tablets, engraved "APO" over "200" on one side and the other side plain.
800 mg tablets are oval, blue, biconvex tablets, scored. Engraved APO partial bisect 800 on one side, plain in the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Aciclovir is an antiviral agent which is active in vitro against herpes simplex virus (HSV) types I and II and varicella zoster virus (VZV), the latter being considerably less sensitive. The relationship between the level of in vitro sensitivity of herpes viruses to aciclovir and clinical response to therapy has not been adequately established. Development of resistance by HSV to aciclovir has been documented. Aciclovir needs to be phosphorylated to the active compound, aciclovir triphosphate, in order to become active against the virus. Such conversion is very limited in normal cells and in addition cellular DNA polymerase is not very sensitive to the active compound. However, in infected cells HSV or VZV coded thymidine kinase facilitates the conversion of aciclovir to aciclovir monophosphate which is then converted to aciclovir triphosphate by cellular enzymes. Aciclovir triphosphate acts as an inhibitor of and substrate for the herpes specified DNA polymerase, preventing further viral DNA synthesis.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Aciclovir is only partially and variably absorbed from the gut. Estimated bioavailability following a dose of 200 mg is about 20%, and decreases to about half of this with an 800 mg dose. Mean steady-state peak and trough concentrations during dosage of 200 mg administered four hourly were 0.49 (range 0.47-0.54) microgram/mL and 0.31 (range 0.18-0.41) microgram/mL respectively, and after 800 mg six hourly were 1.43 (range 0.66-1.8) microgram/mL and 0.55 (range 0.14-10) microgram/mL respectively. Both peak and trough levels following repeated doses in adults over 60 years of age are considerably higher than in young adults, apparently because of the reduced renal function in the elderly.

Distribution.

Plasma protein binding is low (9 to 33%).

Excretion.

Following oral administration, the mean plasma half-life of aciclovir in volunteers and patients with normal renal function ranges from 2.5 to 3.3 hours. Approximately 60% of the drug is excreted unchanged by the kidney by glomerular filtration and tubular excretion. When aciclovir is given after probenecid the terminal half-life and the area under the plasma concentration time curve are extended. 9-Carboxymethoxymethyl guanine is the major metabolite of aciclovir and accounts for 10-15% of the dose excreted in the urine following i.v. administration.
In children aged 0-3 months the terminal plasma half-life is approximately four hours. However, experience is insufficient at present to recommend therapy for this age group.
Because aciclovir is excreted mainly by the kidneys its total body clearance in the elderly (> 60 years of age) declines due to decreased renal function. The terminal half-life of aciclovir in the elderly is approximately 4.6 hours. It is important to maintain adequate hydration in elderly patients taking high oral doses.
In patients with chronic renal failure the mean terminal half-life following intravenous administration was found to be 19.5 ± 5.9 SD hours. The mean aciclovir half-life during haemodialysis was 5.7 hours. Plasma aciclovir levels dropped approximately 60% during dialysis.
Studies have shown no apparent changes in the pharmacokinetic properties of aciclovir or zidovudine when both are administered simultaneously to HIV infected patients.
Dosage adjustment for aciclovir is recommended in renal impairment (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Aciclovir was clastogenic in Chinese hamster cells in vivo, at exposure levels also causing nephrotoxicity (500 and 1,000 mg/kg parenteral dose). There was also an increase, though not statistically significant, in chromosomal damage at maximum tolerated doses (100 mg/kg) of aciclovir in rats. No activity was found in a dominant lethal study in mice or in 4 microbial assays. Positive results were obtained in 2 of 7 genetic toxicity assays using mammalian cells in vitro (positive in human lymphocytes in vitro and one locus in mouse lymphoma cells, negative at 2 other loci in mouse lymphoma cells, and 3 loci in a Chinese hamster ovary cell line).
The results of these mutagenicity tests in vitro and in vivo suggest that aciclovir is unlikely to pose a genetic threat to man at therapeutic dose levels.

Carcinogenicity.

Aciclovir was positive in one of two mouse cell transformation systems in vitro. Inoculation of the transformed cells into immune suppressed mice resulted in tumours. These data are suggestive of an oncogenic potential. However, the validity of this type of study is unclear. Lifetime oral dosing studies in mice and rats gave no evidence of tumourogenicity but in these species the absorption of oral aciclovir is poor and possibly self limiting.

4 Clinical Particulars

4.1 Therapeutic Indications

Aciclovir tablets are indicated for use in adult patients for:
the treatment of first episode (primary or nonprimary) genital herpes and the management of recurrent episodes of genital herpes in certain patients;
the treatment of acute attacks of herpes zoster (shingles) when the duration of rash is less than 72 hours;
the management of patients with advanced symptomatic HIV disease (CD4+ counts < 150 x 106/L).

Genital herpes.

Initial episodes.

The duration of viral shedding is reduced very significantly; the duration of pain and time to healing are also reduced. The promptness of initiation of therapy and/or the patient's prior exposure to herpes simplex virus may influence the degree of benefit from therapy.
Intravenous aciclovir should be considered in patients in whom prostration, central nervous system involvement or inability to take oral medication requires hospitalisation and initiation of more aggressive management.
Aciclovir does not prevent the establishment of latency in primary episodes.

Recurrent episodes.

a) Suppression.

In patients with frequent recurrences, suppressive therapy prevents or reduces the frequency and/or severity of recurrences in a high proportion of patients. Abortive episodes (prodromal symptoms without vesicle formation) and occasional breakthrough episodes may, however, continue to occur during suppressive therapy.
Suppressive therapy is not considered appropriate for patients in whom attacks are mild, last for short periods and/or occur infrequently (for example less frequently than once a month).
Aciclovir is effective only during the period of intake and has no residual beneficial effect. It does not eradicate the body viral pool. Following cessation of therapy the time to onset of recurrences, their frequency, severity and duration remain generally unaffected. Some patients may experience increased severity of the first episode following cessation of therapy.
The risk of inducing viral resistance and of potential long-term adverse effects (see Section 4.6 Fertility, Pregnancy and Lactation, Effects on fertility and Section 5.3 Preclinical Safety Data, Genotoxicity and Carcinogenicity) should be weighed carefully before initiating suppressive therapy.
Asymptomatic cases of genital herpes are known to shed the virus with a high frequency. However, at present only limited data are available on the extent and frequency of viral shedding in patients receiving suppressive therapy. Therefore, if therapy with aciclovir tablets is being used in the prenatal period (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy) it should not be assumed that viral shedding has ceased. Pregnancy should be managed according to considerations normally applicable to patients with genital herpes.
In view of the complex and variable natural history of genital herpes, suppressive therapy should be interrupted periodically to ascertain whether the disease has undergone spontaneous change in frequency or severity (see Section 4.2 Dose and Method of Administration).

b) Intermittent treatment.

For certain patients intermittent short-term treatment of recurrences is effective. Although the average patient would derive limited benefits from such treatment, a minority of patients who have experienced severe, prolonged recurrent episodes or recurrences complicated by eczema, burns or immunosuppression may experience more appreciable benefits. In those patients, intermittent treatment may be more appropriate than suppressive therapy when recurrences are infrequent.

Herpes zoster.

In controlled trials aciclovir was shown to reduce acute pain and rash progression in adult patients of all ages with herpes zoster, in whom the duration of rash was less than 72 hours. The same treatment appeared to be relatively less effective in younger adults, in whom herpes zoster is generally a milder disease.
In ophthalmic zoster, oral aciclovir has been shown to reduce the incidence of stromal keratitis and both the incidence and severity of anterior uveitis, but not other ocular complications or acute pain.

Note.

In immunocompetent patients with very severe herpes zoster, immunocompromised patients or in patients with impaired absorption from the gut, consideration should be given to intravenous dosing.

Patients with advanced symptomatic HIV disease (CD4+ counts < 150 x 106/L).

Studies have shown that oral aciclovir reduced mortality in patients with advanced HIV disease. In addition, oral aciclovir provided effective prophylaxis for herpes virus disease. No significant effect was seen on the prophylaxis of CMV disease or EBV disease.

4.3 Contraindications

Aciclovir tablets are contraindicated in patients known to be hypersensitive to aciclovir or valaciclovir.

4.4 Special Warnings and Precautions for Use

Hydration status.

Care should be taken to maintain adequate hydration in patients receiving high oral doses of aciclovir.

Development of resistant strains.

Resistant strains have been isolated in vitro and in animals following treatment with aciclovir. HSV strains resistant in vitro to aciclovir have also been isolated from immunocompromised as well as immunocompetent patients receiving aciclovir for herpes simplex infections. Therefore the potential for the development of resistant HSV strains in patients treated with aciclovir should be borne in mind. The relationship between the level of in vitro sensitivity of herpes viruses to aciclovir and clinical response to therapy has not been adequately established.

Other conditions.

As aciclovir has been associated with reversible encephalopathic changes, it should be used with caution in patients with underlying neurological abnormalities, significant hypoxia or serious renal, hepatic or electrolyte abnormalities. It should also be used with caution in patients who have manifested neurological reactions to cytotoxic drugs or are receiving concomitantly interferon or intrathecal methotrexate. Animal studies indicate that at high doses aciclovir is cytotoxic.

Use in renal impairment and in elderly patients.

Aciclovir is eliminated by renal clearance, therefore the dose must be reduced in patients with renal impairment (see Section 4.2 Dose and Method of Administration). Elderly patients are likely to have reduced renal function and therefore the need for dose reduction must be considered in this group of patients. Both elderly patients and patients with renal impairment are at increased risk of developing neurological side effects and should be closely monitored for evidence of these effects. In the reported cases, these reactions were generally reversible on discontinuation of treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). The dosage should be adjusted in patients with renal impairment (see Section 4.2 Dose and Method of Administration).

Paediatric use.

Safety and effectiveness in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Aciclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase aciclovir plasma concentrations. Probenecid and cimetidine increase the AUC of aciclovir by this mechanism and reduce aciclovir renal clearance. However, no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.
In patients receiving aciclovir, caution is required during concurrent administration with drugs which compete with aciclovir for elimination, because of the potential for increased plasma levels of one or both drugs or their metabolites. Increase in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplants, have been shown when the drugs are coadministered. However, no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.
In patients over 60 years of age concurrent use of diuretics increases plasma levels of aciclovir very significantly. It is not known whether a similar effect occurs in young adults. In patients receiving zidovudine no significant overall increase in toxicity was associated with the addition of aciclovir. No data are available on interactions between aciclovir and other antiretroviral therapies.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There is no information on the effect of aciclovir on human female fertility.
(Category B3)
Animal studies show that aciclovir crosses the placenta readily. Aciclovir was not teratogenic in the mouse (450 mg/kg/day orally), rabbit (50 mg/kg/day subcutaneously and intravenously) or rat (50 mg/kg/day subcutaneously) when dosed throughout the period of major organogenesis. This exposure in the rat resulted in plasma levels 11-fold the mean steady-state peak concentration in humans after doses of 800 mg every 4 hours. In additional studies in which rats were given 3 subcutaneous doses of 100 mg/kg aciclovir on gestation day 10, foetal abnormalities, such as head and tail anomalies, were reported (exposure was 63-fold human levels after 800 mg every four hours).
There have been no adequate and well controlled studies concerning the safety of aciclovir in pregnant women. It should not be used during pregnancy unless the benefits to the patient clearly outweigh the potential risks to the foetus. If suppressive therapy is used in the perinatal period it should not be assumed that viral shedding has ceased, or that the risk to foetus/neonate has decreased. Pregnancy should be managed according to considerations normally applicable to patients with genital herpes.
 Limited human data show that aciclovir does pass into breast milk. Aciclovir should only be administered to nursing mothers if the benefits to the mother outweigh the potential risks to the baby. Caution is therefore advised if aciclovir is to be administered to a nursing woman.

4.8 Adverse Effects (Undesirable Effects)

Aciclovir tablets appear to be generally very well tolerated. Adverse effects are usually mild. However the following have been noted.

Short-term administration for treatment for genital herpes.

Nausea and/or vomiting and headache were the most frequent adverse effects.
Less frequent (< 1%) reactions included diarrhoea, dizziness, anorexia, fatigue, oedema, skin rashes, leg pain, inguinal adenopathy, medication taste and sore throat. Occasional changes in liver enzymes and changes in haematological parameters were also noted.

Long-term suppressive therapy for genital herpes.

Nausea and/or vomiting, headache, diarrhoea, vertigo and arthralgia were the most frequent adverse effects. Less frequent adverse effects included skin rash, insomnia, fatigue, fever, palpitation, sore throat, superficial thrombophlebitis, muscle cramps, pars planitis, menstrual abnormalities, lymphadenopathy, irritability, accelerated hair loss, depression and occasional increases in liver enzymes.

Treatment of herpes zoster.

The most commonly reported adverse effect in clinical trials was gastrointestinal disturbance. Other reports included aching, chest pain, confusion, constipation, diarrhoea, giddiness, hallucinations, headache, insomnia, nausea, rash, shaking, taste disturbance, tremor, vertigo and malaise, vomiting and mental status alteration. Significantly, the overall incidence of side effects reported was the same in patients on placebo.

Patients with advanced symptomatic HIV disease.

In patients receiving antiretroviral therapy (mainly oral zidovudine) no significant overall increase in toxicity was associated with the addition of aciclovir. However, moderate increases in anaemia and neutropenia were seen in some studies in patients with advanced HIV disease.
The frequency categories associated with the adverse events below are estimates. For most events, suitable data for estimating incidence were not available. In addition, adverse events may vary in their incidence depending on the indication.
The following convention has been used for the classification of undesirable effects in terms of frequency: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1,000 and < 1/100); rare (≥ 1/10,000 and < 1/1,000); very rare (< 1/10,000).

Blood and lymphatic system disorders.

Very rare: anaemia, leucopenia, thrombocytopenia.

Immune system disorders.

Rare: anaphylaxis.

Psychiatric and nervous system disorders.

Common: headache, dizziness, confusion, hallucinations, somnolence, convulsions. Very rare: agitation, tremor, ataxia, dysarthria, psychotic symptoms, encephalopathy, coma.
The above events are reversible and usually reported in patients with renal impairment in whom the dosage was in excess of that recommended, or with other predisposing factors.

Respiratory, thoracic and mediastinal disorders.

Rare: dyspnoea.

Gastrointestinal disorders.

Common: nausea, vomiting, diarrhoea, abdominal pains.

Hepatobiliary disorders.

Rare: reversible rises in bilirubin and liver related enzymes. Very rare: hepatitis, jaundice.

Skin and subcutaneous tissue disorders.

Common: pruritus, rashes (including photosensitivity). Uncommon: urticaria, accelerated diffuse hair loss. Accelerated diffuse hair loss has been associated with a wide variety of disease processes and medicines; the relationship of the event to aciclovir therapy is uncertain. Rare: angioedema.

Renal and urinary disorders.

Rare: increases in blood urea and creatinine. Very rare: acute renal failure, renal pain. Renal pain may be associated with renal failure.

General disorders and administration site conditions.

Common: fatigue, fever.

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 http://www.tga.gov.au/reporting-problems or contact Apotex Medical Information enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

Treatment of initial genital herpes.

One 200 mg tablet every four (4) hours, while awake, for a total of 5 tablets daily for 10 days (total 50 tablets).

Chronic suppressive therapy for recurrent genital herpes.

One 200 mg tablet 3 times daily for up to 6 months. Many patients will, however, respond satisfactorily to one 200 mg tablet twice daily. Occasional breakthroughs have been reported in patients receiving 2, 3, 4 or 5 tablets daily. Suppressive therapy is not indicated for all patients with recurrent genital herpes (see Section 4.1 Therapeutic Indications). Therapy should be discontinued at the end of 6 months to ascertain whether any change has occurred in the natural course of the disease in the particular patient.

Intermittent therapy for recurrent genital herpes in certain patients (see Section 4.1 Therapeutic Indications).

One 200 mg tablet every 4 hours, while awake, for a total of 5 tablets daily for 5 days (total 25 tablets). Therapy should be initiated at the earliest sign or symptom (prodrome) of recurrence.

Treatment of herpes zoster in adults.

800 mg 5 times daily at approximately 4 hourly intervals, omitting the night time dose. Therapy should commence as early as possible after the onset of rash but definitely within 72 hours of the appearance of the rash. Treatment should be continued for 7 days. For herpes zoster ophthalmicus, the recommended duration of therapy is 7 to 10 days. Attention should be given to maintaining adequate hydration in elderly patients.

Management of patients with advanced symptomatic HIV disease.

800 mg four times daily at approximately six hourly intervals. The duration of treatment in the controlled trials was 12 months. Oral aciclovir was given in conjunction with oral zidovudine in most studies, at a range of doses. In a high percentage of the patients in the controlled trials, an initial zidovudine dose of 2 g daily, followed after 4 weeks by 1 g daily, was used. These doses are above the currently recommended dose of 600 mg daily. The safety and effectiveness of oral aciclovir taken in conjunction with other antiretroviral therapies could not be assessed.

Patients with acute or chronic renal impairment.

No data are currently available on the kinetics of oral aciclovir in patients with impaired renal function. However, based on studies with intravenous aciclovir infusion and theoretical considerations, the following dosage adjustments are recommended.

Genital herpes.

For patients with creatinine clearance < 10 mL/min/1.73 m2, a 200 mg dose every 12 hours is recommended.

Herpes zoster and in the management of patients with advanced symptomatic HIV disease.

For patients with creatinine clearance in the range 10-25 mL/min/1.73 m2, it is recommended to adjust the dosage to 800 mg three times daily (approximately every 8 hours). For patients with creatinine clearance < 10 mL/min/1.73 m2, 800 mg twice daily (approximately every 12 hours).

Dosage in the elderly.

The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see above). Adequate hydration of elderly patients taking high oral doses of aciclovir should be maintained.

4.7 Effects on Ability to Drive and Use Machines

The clinical status of the patient and the adverse event profile of aciclovir should be borne in mind when considering the patient's ability to drive or operate machinery. There have been no studies to investigate the effect of aciclovir on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the active substance.

4.9 Overdose

Symptoms.

Aciclovir is only partly absorbed in the gastrointestinal tract. Patients have ingested overdoses of up to 20 g aciclovir on a single occasion, usually without toxic effects. Accidental, repeated overdoses of oral aciclovir over several days have been associated with gastrointestinal effects (such as nausea and vomiting) and neurological effects (headache and confusion).
Overdosage of intravenous aciclovir has resulted in elevations of serum creatinine, blood urea nitrogen and subsequent renal failure. Neurological effects including confusion, hallucinations, agitation, seizures and coma have been described in association with intravenous overdosage.

Treatment.

Patients should be observed closely for signs of toxicity. Adequate hydration is essential to reduce the possibility of crystal formation in urine. Haemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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.

6.5 Nature and Contents of Container

200 mg tablets.

Blister pack (clear PVC/PVDC/aluminium silver foil) of 25 or 50 or 90 tablets (AUST R 71816).

800 mg tablets.

Blister pack (clear PVC/PVDC/aluminium silver foil) of 35 tablets (AUST R 71817).
Not all strengths, pack sizes and/or pack types may be available.

6.6 Special Precautions for Disposal

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

Summary Table of Changes