Keep out of reach of children.
Read the directions carefully before use.
For prescription only.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredient
Acyclovir ........................ 400 mg
Excipients q.s ……………. 1 tablet
Tablet.
Product description: An oval, pink tablet, plain on one side, a sign , undamaged edges.
Box of 3 blisters x 10 tablets.
Pharmacotherapeutic group: Direct acting antivirals, nucleosides and nucleotides excl. reverse transcriptase inhibitors. ATC code: J05AB01
Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including herpes simplex virus (HSV) types I and II and varicella zoster virus (VZV).
The inhibitory activity of acyclovir for HSV I, HSV II and VZV is highly selective. The enzyme thymidine kinase (TK) of normal, uninfected cells does not use acyclovir effectively as a substrate, hence toxicity of mammalian host cells is low; however, TK encoded by HSV and VZV converts acyclovir to acyclovir monophosphate, a nucleoside analogue which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes. Acyclovir triphosphate interferes with the viral DNA polymerase and inhibits viral DNA replication with resultant chain termination following its incorporation into the viral DNA.
Prolonged or repeated courses of acyclovir in severely immune-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued acyclovir treatment. Most of the clinical isolates with reduced sensitivity have been relatively deficient in viral TK, however, strains with altered viral TK or viral DNA polymerase have also been reported. In vitro exposure of HSV isolates to acyclovir can also lead to the emergence of less sensitive strains. The relationship between the in vitro determined sensitivity of HSV isolates and clinical response to acyclovir therapy is not clear.
Absorption
Acyclovir is only partially absorbed from the gut. The average oral bioavailability varies between 10 and 20%. Under fasting conditions, mean peak concentrations (Cmax) of 0.4 microgram/ml are achieved at approximately 1.6 hours after a 200 mg dose administered as oral suspension or capsule. Mean peak plasma concentrations (Cssmax) increase to 0.7 microgram/ml (3.1 micromolar) at steady state following doses of 200 mg administered every four hours. A less than proportional increase is observed for Cssmax concentration following doses of 400 mg and 800 mg administered four-hourly, with values reaching 1.2 and 1.8 microgram/ml (5.3 and 8 micromolar), respectively.
Distribution
The mean volume of distribution of 26 L indicates that acyclovir is distributed within total body water. Apparent values after oral administration (Vd/F) ranged from 2.3 to 17.8 L/kg. As plasma protein binding is relatively low (9 to 33%), drug interactions involving binding site displacement are not anticipated. Cerebrospinal fluid concentrations are approximately 50% of corresponding plasma concentration at steady-state.
Metabolism
Acyclovir is predominantly excreted unchanged by the kidney. The only significant urinary metabolite is 9-[(carboxymethoxy) methyl] guanine, and accounts for 10 - 15% of the dose excreted in the urine.
Elimination
In adults mean systemic exposure (AUC0-∞) to acyclovir ranges between 1.9 and 2.2 microgram*h/mL after a 200 mg dose. At this dose, the mean terminal plasma half-life after oral administration has been shown to vary between 2.8 and 4.1 hours.
Renal clearance of acyclovir (Clcr = 14.3 L/h) is substantially greater than creatinine clearance, indicating that tubular secretion, in addition to glomerular filtration, contributes to the renal elimination of the drug. The half-life and total clearance of acyclovir are dependent on renal function. Therefore, dosage adjustment is recommended for renally impaired patients.
There are no pharmacokinetic data for the oral formulation in neonates. The only available pharmacokinetic data are for the IV formulation in this age group.
Special patient populations
Elderly
In the elderly patients with normal renal function total clearance falls with increasing age due to decreases in creatinine clearance. However, the possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly.
Paediatric population
In children over 1 year of age similar peak (Cssmax) and trough (Cssmin) levels were observed when a dose of 250 mg/m2 was substituted for 5 mg/kg and a dose of 500 mg/m2 was substituted for 10 mg/kg. In neonates and young infants (0 to 3 months of age) treated with doses of 10 mg/kg administered by infusion over a one-hour period every 8 hours the Cssmax was found to be 61.2 micromolar (13.8 micrograms/ml) and CCssmin to be 10.1 micromolar (2.3 mcg/ml). The terminal plasma half-life in these patients was 3.8 hours. A separate group of neonates treated with 15 mg/kg every 8 hours showed approximate dose proportional increases, with a Cmax of 83.5 micromolar (18.8 mcg/ml) and Cmin of 14.1 micromolar (3.2 mcg/ml). In the elderly, total body clearance falls with increasing age associated with decreases in creatinine clearance although there is little change in the terminal plasma half-life.
Renal impairment
In patients with chronic renal failure the mean terminal half-life was found to be 19.5 hours. The mean acyclovir half-life during haemodialysis was 5.7 hours. Plasma acyclovir levels dropped approximately 60% during dialysis.
There have been no studies to investigate the effect of acyclovir on driving performance or the ability to operate machinery. A detrimental effect on such activities cannot be predicted from the pharmacology of the active substance but the adverse event profile should be borne in mind.
Some side effects such as drowsiness and somnolence may impair a patient’s ability to concentrate and react. Patients should make sure that they are not affected before driving or operating machinery.
Pregnancy
The use of acyclovir should be considered only when the potential benefits outweigh the possibility of unknown risks.
A post-marketing acyclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of acyclovir. The registry findings have not shown an increase in the number of birth defects amongst acyclovir exposed subjects compared with the general population, and any birth defects showed no uniqueness or consistent pattern to suggest a common cause. Systemic administration of acyclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rabbits, rats 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.
Caution should however be exercised by balancing the potential benefits of treatment against any possible hazard.
Breast-feeding
Following oral administration of 200 mg acyclovir five times a day, acyclovir 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 acyclovir dosages of up to 0.3 mg/kg/day. Caution is therefore advised if acyclovir is to be administered to a nursing mother.
Fertility
There is no information on the effect of acyclovir on human female fertility.
In a study of 20 male patients with normal sperm count, oral acyclovir administered at doses of up to 1 g per day for up to six months has been shown to have no clinically significant effect on sperm count, motility or morphology.
Acyclovir is eliminated primarily unchanged in the urine via active renal tubular secretion. Any drugs administered concurrently that compete with this mechanism may increase acyclovir plasma concentrations.
Probenecid and cimetidine increase the AUC of acyclovir by this mechanism and reduce acyclovir renal clearance. Similarly increases in plasma AUCs of acyclovir 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 acyclovir.
An experimental study on five male subjects indicates that concomitant therapy with acyclovir increases AUC of totally administered theophylline by approximately 50%. It is recommended to measure plasma concentrations during concomitant therapy with acyclovir.
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.
An estimate of the frequency of undesirable effects has been included though this is not certain for all adverse effects. 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 the lymphatic system disorders
Very rare: Anaemia, leucopenia and thrombocytopenia.
Immune system disorders
Rare: Anaphylaxis.
Psychiatric and nervous system disorders
Common: Headache, dizziness.
Very rare: Agitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, convulsions, somnolence, encephalopathy, coma. The above events are generally reversible and usually reported in patients with renal impairment or with other predisposing factors.
Respiratory, thoracic and mediastinal disorders
Rare: Dyspnoea.
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: 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 acyclovir 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 and crystalluria.
General disorders
Common: Fatigue, fever.
Please inform your doctor of all undesirable effects upon drug administration.
Symptoms and signs
Acyclovir is only partly absorbed in the gastrointestinal tract.
Patients have ingested overdoses of up to 20 g acyclovir on a single occasion, usually without toxic effects. Accidental, repeated overdoses of oral acyclovir over several days have been associated with gastrointestinal effects (e.g., nausea and vomiting) and neurological effects (headache and confusion).
Management
Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of acyclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.
Store in dry places, not exceeding 30oC, protect from light.
Use in patients with renal impairment and in elderly patients
Acyclovir is eliminated by renal clearance, therefore the dose must be reduced in patients with renal impairment. 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.
Prolonged or repeated courses of acyclovir in severely immune-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued acyclovir treatment.
Hydration status: Care should be taken to maintain adequate hydration in patients receiving high oral doses of acyclovir.
The risk of renal impairment is increased by use with other nephrotoxic drugs.
The data currently available from clinical studies is not sufficient to conclude that treatment with acyclovir reduces the incidence of chickenpox-associated complications in immunocompetent patients.
Excipients
Wheat starch in this medicine contains only very low levels of gluten and is very unlikely to cause problems if you have coeliac disease. If you have wheat allergy, you should not take this medicine.
Lactose monohydrate: Patients with problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Ponceau may cause allergic reactions.
Treatment of herpes simplex virus infections of the skin and mucous membranes including initial and recurrent genital herpes (excluding neonatal HSV and severe HSV infections in immunocompromised children).
Suppression (prevention of recurrences) of recurrent herpes simplex infections in immunocompetent patients.
Prophylaxis of herpes simplex infections in immunocompromised patients.
Treatment of varicella (chickenpox) infections.
Hypersensitivity to acyclovir or valacyclovir, or to any of the excipients listed in the medicinal product.
METHOD OF ADMINISTRATION
For oral administration.
Patients who experience difficulty in swallowing the tablets may disperse them in a minimum of 50 ml water which should be stirred before drinking.
POSOLOGY
Dosage in adults
Treatment of herpes simplex infections: 200 mg acyclovir should be taken five times daily at approximately four hourly intervals omitting the nighttime dose. Treatment should continue for five days, but in severe initial infections this may have to be extended.
In severely immunocompromised patients (e.g., after marrow transplant) or in patients with impaired absorption from the gut the dose can be doubled to 400 mg acyclovir or alternatively intravenous dosing could be considered.
Dosing should begin as early as possible after the start of an infection; for recurrent episodes this should preferably be during the prodromal period or when lesions first appear.
Suppression of herpes simplex infections in immunocompetent patients: 200 mg acyclovir should be taken four times daily at approximately six-hour intervals.
Many patients may be conveniently managed on a regime of 400 mg acyclovir twice daily at approximately twelve-hour intervals.
Dosage titration down to 200 mg acyclovir taken three times daily at approximately eight-hourly intervals or even twice daily at approximately twelve-hourly intervals, may prove effective.
Some patients may experience breakthrough infections on total daily doses of 800 mg acyclovir.
Therapy should be interrupted periodically at intervals of six to twelve months, in order to observe possible changes in the natural history of the disease.
Prophylaxis of herpes simplex infections in immunocompromised patients: 200 mg acyclovir should be taken four times daily at approximately six hourly intervals.
In severely immunocompromised patients (e.g., after marrow transplant) or in patients with impaired absorption from the gut, the dose can be doubled to 400 mg acyclovir or, alternatively, intravenous dosing could be considered.
The duration of prophylactic administration is determined by the duration of the period at risk.
Dosage in the paediatric population
Treatment of herpes simplex infections, and prophylaxis of herpes simplex infections in the immunocompromised: children aged two years and over should be given the adult doses and children below the age of two years should be given half the adult dose. Treatment of varicella infection: children under 2 years should be given 200 mg four times daily. Children aged 2 - 5 years should be given 400 mg four times daily. Children aged 6 years and over should be given 800 mg four times daily. Treatment should continue for 5 days. Dosing may be more accurately calculated as 20 mg/kg body weight (not to exceed 800 mg four times daily). A liquid formulation might be more suitable for small children.
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
The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see Dosage in renal impairment below).
In the elderly, total acyclovir body clearance declines along with creatinine clearance.
Adequate hydration of elderly patients taking high oral doses of acyclovir should be maintained. Special attention should be given to dosage reduction in elderly patients with impaired renal function.
Dosage in renal impairment
Caution is advised when administering acyclovir to patients with impaired renal function. Adequate hydration should be maintained.
In the management of herpes simplex infections in patients with impaired renal function, the recommended oral doses will not lead to accumulation of acyclovir above levels that have been established by intravenous infusion. However, for patients with severe renal impairment (creatinine clearance less than 10 ml/minute) an adjustment of dosage to 200 mg acyclovir twice daily at approximately twelve-hourly intervals is recommended.
In the treatment of herpes zoster infections it is recommended to adjust the dosage to 800 mg acyclovir twice daily at approximately twelve-hourly intervals for patients with severe renal impairment (creatinine clearance less than 10 ml/minute), and to 800 mg acyclovir three times daily at intervals of approximately eight hours for patients with moderate renal impairment (creatinine clearance in the range 10 - 25 ml/minute).
Or as directed by the physician.
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