ACICLOVIR TABLETS BP 800mg

Each tablet contains 800mg Aciclovir PhEur.

White uncoated tablets.

1) Treatment of varicella (chickenpox) and herpes zoster (shingles) infections.

Adults: Treatment of herpes zoster infections: 800mg aciclovir should be taken five times daily at approximately four-hourly intervals, omitting the night time dose. Treatment should continue for seven days.

In severely immunocompromised patients (eg after marrow transplant) or in patients with impaired absorption from the gut, consideration should be given to intravenous dosing.

Dosing should begin as early as possible after the start of an infection. Treatment of herpes zoster yields better results if initiated as soon as possible after the onset of the rash.

Dosage in children: Treatment of varicella infection: Children aged 6 years and over should be given 800mg four times daily. Treatment should continue for 5 days. Dosing may be more accurately calculated as 20mg/kg bodyweight (not to exceed 800mg four times daily).

No specific data are available on the suppression of herpes simplex infections or the treatment of herpes zoster infections in immunocompetent children. When treatment of herpes zoster infections is required in immunocompromised children, intravenous dosing should be considered.

Dosage in the elderly: In the elderly, total aciclovir body clearance declines along with creatinine clearance. Adequate hydration of elderly patients taking high oral doses of aciclovir should be maintained. Special attention should be given to dosage reduction in elderly patients with impaired renal function.

Dosage in renal impairment: In the treatment of herpes zoster infections it is recommended to adjust the dosage to 800mg aciclovir twice daily at approximately twelve-hourly intervals for patients with renal impairment (creatinine clearance less than 10ml/minute), and to 800mg aciclovir three times daily at intervals of approximately six to eight hours for patients with moderate renal impairment (creatinine clearance in the range 10-25ml/minute).

In the treatment of herpes zoster infections it is recommended to adjust the dosage to 800mg aciclovir twice daily at approximately twelve-hourly intervals for patients with renal impairment (creatinine clearance less than 10ml/minute), and to 800mg aciclovir three times daily at intervals of approximately six to eight hours for patients with moderate renal impairment (creatinine clearance in the range 10-25ml/minute).

Method of Administration

Administration: Patients who experience difficulty in swallowing the tablets may disperse them in a minimum of 50ml water which should be stirred before drinking.

For oral administration.

Known hypersensitivity to aciclovir, any other ingredients in the product or to valaciclovir.

The data currently available from clinical studies is not sufficient to conclude that treatment with aciclovir reduces the incidence of chickenpox-associated complications in immunocompetent patients.

Hydration status: Care should be taken to maintain adequate hydration in patients receiving higher dose oral regimens, e.g. for the treatment of herpes zoster infection (4g daily), in order to avoid the risk of possible renal toxicity.

• Ciclosporin: There has been a small number of transplant patients with increased serum levels of ciclosporin and signs of nephrotoxicity when aciclovir is given concurrently. Renal function should be monitored closely in patients taking both drugs.

• Cimetidine and probenecid: Cimetidine and probenecid increase the bioavailability of aciclovir by competing for active secretion by the renal tubules. Dosage adjustment is usually not necessary because of the wide therapeutic index of aciclovir.

• Mycophenolate mofetil: Increases in plasma AUCs of aciclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant agent used in transplant patients, have been shown when the drugs are coadministered. However, no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.

• Theophylline: Serum levels of theophylline may be increased by concurrent administration of aciclovir and it may be necessary to reduce the dosage of theophylline if aciclovir is added to the established treatment.

• Zidovudine: Although co-administration of zidovudine and aciclovir is not usually associated with toxicity, there is a single case report of overwhelming fatigue developing in a patient when given the two drugs together. This did not occur when zidovudine and aciclovir were given alone.

Pregnancy

Experience in humans is limited so the use of aciclovir should be considered only when the potential benefits outweigh the possibility of unknown risks. Herpes simplex encephalitis and varicella pneumonia constitute a significant risk for mother and foetus and primary genital herpes may retard intrauterine growth and increase the risk of premature birth and neonatal herpes infection. (See section 5.3 Preclinical Safety Data). Aciclovir readily crosses the placenta and levels in cord blood are higher than in maternal serum. Prospective studies have shown that congenital malformations do occur in infants exposed to aciclovir during pregnancy but the incidence is no higher than in the general population and they do not appear to be related to the drug. There is no experience of the effect of aciclovir on human female fertility.

Lactation

Following oral administration of 200mg aciclovir five times a day, aciclovir has been detected in breast milk at concentrations ranging from 0.6-4.1 times the corresponding plasma levels. These levels would potentially expose nursing infants to aciclovir dosages of up to 0.3mg/kg/day. Caution is therefore advised if aciclovir is to be administered to a nursing mother.

As aciclovir administration is occasionally associated with drowsiness and somnolence (usually in patients receiving high doses or with impaired renal function), patients should make sure that they are not affected before driving or using machinery.

An estimate of the frequency of undesirable effects has been included though this is not certain for all adverse effects. The frequencies are: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000, very rare (<1/10000).

Blood and the lymphatic system disorders

Very rare: Anaemia, leucopenia and thrombocytopenia.

Immune system disorders

Rare: Dyspnoea, angioedema and anaphylaxis.

Nervous system disorders

Common: Dizziness and headache.

Rare: Reversible neurological reactions including drowsiness, confusional states, hallucinations, somnolence, convulsions, coma and malaise. These effects were usually reported in patients receiving high doses of aciclovir (usually given intravenously) or with renal impairment. Aciclovir should be used with caution in patients with underlying neurological abnormalities.

Gastrointestinal disorders

Common: Nausea, vomiting, diarrhoea and abdominal pain.

Hepato-biliary disorders

Rare: Reversible rises in bilirubin and liver related enzymes.

Very rare: Hepatitis and jaundice.

Skin and sub-cutaneous tissue disorders

Common: Skin rashes, pruritus and urticaria.

Uncommon: Photosensitivity.

Rare: Erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis, accelerated diffuse hair loss. This type of hair loss has been associated with a wide variety of disease processes and medicines, the relationship of the event to aciclovir therapy is uncertain.

Renal and urinary disorders

Rare: Increases in blood urea and creatinine; renal impairment, usually during intravenous therapy, which is usually reversible and responds to hydration and/or dosage reduction but may progress to acute renal failure in patients with predisposing factors.

General disorders

Common: Fatigue.

Uncommon: Fever.

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 (eg nausea and vomiting) and neurological effects (eg confusion). Patients should be observed closely for signs of toxicity. The removal of aciclovir from the blood is significantly enhanced by haemodialysis in patients with symptomatic overdose.

ATC code: J05A B

Aciclovir is an antiviral agent which is highly active in vitro against herpes simplex virus (HSV) types I and II and varicella zoster virus. Toxicity to mammalian host cells is low.

Aciclovir is phosphorylated after entry into herpes infected cells to the active compound aciclovir triphosphate. The first step in this process is dependant on the presence of the HSV-coded thymidine kinase. Aciclovir triphosphate acts as an inhibitor of, and substrate for, the herpes-specified DNA polymerase, preventing further viral DNA synthesis without affecting the normal cellular processes.

Herpes simplex virus develops resistance to aciclovir by selection of mutants deficient in thymidine kinase which are usually of diminished virulence with reduced infectivity and latency. Resistance is rare in immunocompetent patients on short courses of oral therapy but it is more prevalent in immunocompromised patients who have often received prolonged courses of treatment. Herpes zoster resistance develops by a similar mechanism and has been reported in immunocompromised patients undergoing prolonged therapy with aciclovir.

Absorption

Aciclovir is slowly and incompletely absorbed from the gastrointestinal tract. The peak plasma concentration occurs about 2 hours following ingestion.

Distribution

There is a wide distribution to various tissues, including the CSF where concentrations achieved are about 50% of those achieved in plasma. Protein binding is reported to range from 9-33%. Aciclovir crosses the placenta and is excreted in breast milk in concentrations approximately 3 times higher than those in maternal serum.

Metabolism and Elimination

Renal excretion is the major route of elimination by both glomerular filtration and tubular secretion. The terminal or beta-phase half-life is reported to be about 2-3 hours for adults without renal impairment. As aciclovir persists in the plasma of patients with renal insufficiency, in chronic renal failure this value is increased and may be up to 19.5 hours in anuric patients. As renal function decreases, a greater percentage of the drug is eliminated by metabolic conversion to carboxymethoxymethyl guanine. During haemodialysis the half-life is reduced to 5.7 hours, with 60% of a dose of aciclovir being removed in 6 hours. Faecal excretion may account for about 2% of a dose.

Systemic administration of aciclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rats, rabbits or mice. In a non-standard test in rats, foetal abnormalities were observed, but only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.

Two generation studies in mice do not reveal any effect of aciclovir on fertility.

The results of a wide range of mutagenicity tests in vitro and in vivo indicate that aciclovir does not pose a genetic risk to man. Aciclovir was not found to be carcinogenic in long term studies in the rat and the mouse. Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of aciclovir greatly in excess of those employed therapeutically. Aciclovir has been shown to have no definite effect upon sperm count, morphology or motility in man.

Also contains: colloidal anhydrous silica, magnesium stearate, polyvidone, sodium starch glycollate, E460

None known.

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

Store below 25°C in a dry place.

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps and polyfoam wad or cotton wool.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

The product may be contained in blister packs which enhances security of the pack increasing resistance to deliberate contamination, pilfering, etc.

Pack sizes: 25s, 28s, 30s, 35s, 56s, 60s, 84s.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

Not applicable.

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon, EX32 8NS.

PL 0142/0403

26 February 1997

Renewed 14.6.02

March 2007