Zovirax Tablet

Zovirax Tablet

aciclovir

Manufacturer:

GlaxoSmithKline Indonesia
Full Prescribing Info
Contents
Aciclovir.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including herpes simplex virus (HSV) types 1 and 2, varicella zoster virus (VZV), Epstein-Barr Virus (EBV) and cytomegaloviruses (CMV). In cell culture, aciclovir has the greatest antiviral activity against HSV-1, followed (in decreasing order of potency) by HSV-2, VZV, EBV and CMV.
The inhibitory activity of aciclovir for HSV-1, HSV-2, VZV, EBV and CMV is highly selective. The enzyme thymidine kinase (TK) of normal, noninfected cells does not use aciclovir effectively as substrate, hence toxicity to mammalian host cells is low; however, TK encoded by HSV, VZV and EBV converts aciclovir to aciclovir monophosphate, a nucleoside analogue, which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes.
Aciclovir triphosphate interferes with the viral DNA polymerase and inhibits viral DNA replication with resultant chain termination following its incorporation into the viral DNA.
Pharmacodynamic Effects: Prolonged or repeated courses of aciclovir in severely immunocompromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued aciclovir treatment.
Most of the clinical isolates with reduced sensitivity have been relatively deficient in viral TK; however, strains with altered viral TK or DNA polymerase have also been reported. In vitro exposure of HSV isolates to aciclovir can also lead to the emergence of less sensitive strains. The relationship between the in vitro determined sensitivity of HSV isolates and clinical response therapy is not clear.
All patients should be cautioned to ensure they avoid the potential of virus transmission, particularly when active lesions are present.
Clinical Studies: There is no information on the effect of Zovirax oral formulations on human female fertility. In a study of 20 male patients with normal sperm count, oral aciclovir administered at doses of up to 1 g/day for up to 6 months has been shown to have no clinically significant effect on sperm count, motility or morphology.
Pharmacokinetics: Absorption: Aciclovir is only partially absorbed from the gut. Mean steady state peak plasma concentrations (Cssmax) following doses of 200 mg administered 4 hrly were 3.1 micromoles (0.7 mcg/mL) and the equivalent trough plasma levels (Cssmin) were 1.8 micromoles (0.4 mcg/mL). Corresponding Cssmax levels following doses of 400 mg and 800 mg administered 4-hrly were 5.3 micromoles (1.2 mcg/mL) and 8 micromoles (1.8 mcg/mL) respectively, and equivalent Cssmin levels were 2.7 micromoles (0.6 mcg/mL) and 4 micromoles (0.9 mcg/mL).
In adults, mean steady state peak plasma concentrations (Cssmax) following a 1-hr infusion of 2.5 mg/kg, 5 mg/kg, 10 mg/kg and 15 mg/kg were 22.7 micromoles (5.1 mcg/mL), 43.6 micromoles (9.8 mcg/mL), 92 micromoles (20.7 mcg/mL) and 105 micromoles (23.6 mcg/mL), respectively. The corresponding trough levels (Cssmin) 7 hrs later were 2.2 micromoles (0.5 mcg/mL), 3.1 micromoles (0.7 mcg/mL), 10.2 micromoles (2.3 mcg/mL) and 8.8 micromoles (2 mcg/mL), respectively. In children >1 year similar mean 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.
Distribution: Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels. Plasma protein-binding is relatively low (9-33%) and drug interactions involving binding site displacement is not anticipated.
Elimination: In adults the terminal plasma half-life (t½) of aciclovir after administration of IV aciclovir is about 2.9 hrs. Most of the drug is excreted unchanged by the kidney. Renal clearance of aciclovir is substantially greater than creatinine clearance indicating that tubular secretion in addition to glomerular filtration contributes to the renal elimination of the drug. 9-carboxymethoxy- methylguanine is the only significant metabolite of aciclovir and accounts for approximately 10-15% of the dose excreted in the urine. When aciclovir is given 1 hr after 1 g of probenecid the terminal t½ and the area under the plasma concentration time curve is extended by 18% and 40%, respectively.
Special Patient Populations: In patients with chronic renal failure the mean terminal t½ was found to be 19.5 hrs. The mean aciclovir t½ during haemodialysis was 5.7 hrs. Plasma aciclovir levels dropped approximately 60% during dialysis.
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 t½.
Toxicology: Preclinical Safety Data: The results of a wide range of mutagenicity tests in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man.
Aciclovir was not 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. Two-generation studies in mice did not reveal any effect of orally administered aciclovir on fertility.
Systemic administration of aciclovir 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 SC doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.
Indications/Uses
Treatment of herpes simplex virus infections of the skin and mucous membranes, including initial and recurrent genital herpes; suppression (prevention of recurrences) of recurrent herpes simplex infections in immunocompetent patients; prophylaxis of herpes simplex infections in immunocompromised patients; treatment of varicella (chickenpox) and herpes zoster (shingles) infections.
Dosage/Direction for Use
Adults: Treatment of Herpes Simplex: 200 mg 5 times daily at approximately 4-hrly intervals omitting the nighttime dose. Treatment should continue for 5 days, but in severe infections, may have to be extended.
Severely Immunocompromised Patients (eg, after marrow transplant) or In Patients with Impaired Absorption from the Gut: Dose can be doubled to 400 mg or alternatively, IV 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 appeared.
Suppression of Herpes Simplex in Immunocompetent Adults:
200 mg 4 times daily at approximately 6-hrly intervals.
Many patients may be conveniently managed on a regimen of 400 mg twice daily at approximately 12-hrly intervals.
Dosage titration down to 200 mg 3 times daily at approximately 8-hrly intervals or even twice daily at approximately 12-hrly intervals, may prove effective.
Some patients may experience breakthrough infections on total daily doses of 800 mg.
Therapy should be interrupted periodically at intervals of 6-12 months in order to observe possible changes in the natural history of the disease.
Prophylaxis of Herpes Simplex in Immunocompromised Adults: 200 mg 4 times daily at approximately 6-hrly intervals.
Severe Immunocompromised Patients (eg, after marrow transplant) or In Patients with Impaired Absorption from the Gut: Dose can be doubled to 400 mg or alternatively, IV dosing could be considered.
The duration of prophylactic administration is determined by the duration of the period at risk.
Treatment of Varicella and Herpes Zoster in Adults: 800 mg 5 times daily at approximately 4-hrly intervals, omitting the nighttime dose. Treatment should continue for 7 days.
In severe immunocompromised patients (eg, after marrow transplant) or in patients with impaired absorption from the gut,consideration should be given to IV dosing.
Dosing should begin as early as possible after the start of an infection; treatment yields better results if initiated as soon as possible after onset of the rash.
Children: Treatment of Herpes Simplex Infections and Prophylaxis of Herpes Simplex Infections in Immunocompromised: ≥2 years: Same as adult dose, <2 years: ½ the adult dose should be given.
Treatment of Varicella Infection: Children >6 years: 800 mg 4 times daily, 2-6 years: 400 mg 4 times daily, <2 years: 200 mg 4 times daily. Dosing may be more accurately calculated as 20 mg/kg bodyweight not exceeding 800 mg 4 times daily.
Treatment should continue for 5 days.
No specific data are available on the suppression of herpes simplex infections or the treatment of herpes zoster infection in immunocompetent children.
Elderly: The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly (see Renal Impairment as follows). Adequate hydration of elderly patients taking high oral doses of aciclovir should be maintained.
Renal Impairment: Caution is advised when administering Zovirax oral formulations to patients with impaired renal function. Adequate hydration should be maintained.
In the treatment and prophylaxis of herpes simplex infections in patients with impaired renal function, the recommended oral doses will not lead to accumulation of aciclovir above levels that have been established safe by IV infusion. However, for patients with severe renal impairment (creatinine clearance <10 mL/min), an adjustment of dosage to 200 mg twice daily at approximately 12-hrly intervals is recommended.
In the treatment of varicella and herpes zoster infections, it is recommended to adjust the dosage to 800 mg twice daily at approximately 12-hrly intervals for patients with severe renal impairment (creatinine clearance <10 mL/min) and to 800 mg 3 times daily at intervals of approximately 8 hrs for patients with moderate renal impairment (creatinine clearance in the range of 10-25 mL/min).
Overdosage
Symptoms: Aciclovir is only partly absorbed in the gastrointestinal tract. Patients have ingested overdoses of up to aciclovir 20 g 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 (headache and confusion).
Overdosage of aciclovir IV 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 IV overdosage.
Treatment: Patients should be observed closely for signs of toxicity. Haemodialysis significantly enhances the removal of aciclovir from the blood and may therefore be considered a management option in the event of symptomatic overdose.
Contraindications
Known hypersensitivity to aciclovir or valaciclovir.
Special Precautions
Patients with Renal Impairment and in Elderly Patients: Aciclovir is eliminated by renal clearance; therefore the dose must be reduced in patients with renal impairment (see Dosage & 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 Adverse Reactions).
Hydration Status: Care should be taken to maintain adequate hydration in patients receiving high oral doses of aciclovir.
Effects on the Ability to Drive or Operate Machinery: The clinical status of the patient and the adverse event profile of Zovirax 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.
Use in pregnancy: A post-marketing aciclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of Zovirax. The birth defects described amongst Zovirax exposed subjects have not shown any uniqueness or consistent pattern to suggest a common cause.
The use of aciclovir should be considered only when the potential benefits outweigh the possibility of unknown risks.
Use in lactation: Following oral administration of aciclovir 200 mg 5 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 0.3 mg/kg/day. Caution is therefore advised if Zovirax is to be administered to a nursing woman.
Use In Pregnancy & Lactation
Use in pregnancy: A post-marketing aciclovir pregnancy registry has documented pregnancy outcomes in women exposed to any formulation of Zovirax. The birth defects described amongst Zovirax exposed subjects have not shown any uniqueness or consistent pattern to suggest a common cause.
The use of aciclovir should be considered only when the potential benefits outweigh the possibility of unknown risks.
Use in lactation: Following oral administration of aciclovir 200 mg 5 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 0.3 mg/kg/day. Caution is therefore advised if Zovirax is to be administered to a nursing woman.
Adverse Reactions
The frequency categories associated with the adverse events as follows 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 adverse effects in terms of frequency: Very common ≥1/10, common ≥1/100 and <1/10, uncommon ≥1/1000 and <1/100, rare ≥1/10,000 and <1/1000, very rare <1/10,000.
Blood and Lymphatic System Disorders: Very Rare: Anaemia, leukopenia, 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, and coma.
The previously mentioned events are generally reversible and usually reported in patients with renal impairment, or with other predisposing factors (see Precautions).
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 are 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.
Drug Interactions
No clinically significant interactions have been identified.
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. Similarly 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.
Storage
Store below 25°C. Keep dry.
MIMS Class
ATC Classification
J05AB01 - aciclovir ; Belongs to the class of nucleosides and nucleotides excluding reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
Presentation/Packing
Tab 200 mg (white, round, biconvex tablet which are branded with "GXCL3" on one side and plain on the other) x 5 x 5's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in