CYCLOVIR TABLETS (ACICLOVIR BP 200mg)

CYCLOVIR TABLETS (ACICLOVIR BP 200mg)

CYCLOVIR TABLETS (ACICLOVIR BP 200mg)

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 I and II and varicella zoster virus (VZV)

The inhibitory activity of aciclovir for HSSV I, HSV II and VZV is highly selective. The enzyme thymidine kinase (TK) of normal uninfected cells does not use aciclovir effectively as a substrate, hence toxicity of mammalian host cells is low; however, TK encoded by HSV and VZV 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.

Prolonged or repeated courses of aciclovir in severely immune-compromised 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 viral DNA polymerase have also been reported. In vitro exposure of HSV isolates to aciclovir can also lead to the emergency of less sensitive strains. The relationship between the in vitro determined sensitivity of HSV isolates and clinical response to aciclovir therapy is not clear.

Therapeutic indications

Aciclovir tablets are indicated for the treatment of herpes simplex virus infection of the skin and mucous membranes including initial and recurrent genital herpes (excluding neonates HSV and severe HSV infections in immunocompromised children).

Aciclovir tablets are indicated for the suppression (prevention of recurrences) of recurrent herpes simplex infections in immunocompetent patients.

Aciclovir tablets are indicated for the prophylaxis of herpes simplex infections in immunocompromised patients.

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Aciclovir tablets are indicated for the treatment of varicella (chickenpox) and herpes zoster (shingles) infections.

Route of administration: oral

Posology and method of administration

Aciclovir tablets may be dispersed in a minimum of 50ml of water or swallowed whole with a little water. Ensure that patients on high doses of aciclovir are adequately hydrated.

Dosage in adults

Treatment of herpes simplex infections: 200mg aciclovir should be taken five times daily at approximately four hourly intervals omitting the night time dose. Treatment should continue for 5 days, but in severe initial infections this may have to be extended.

In severely immunocpmpromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut tha dose can be doubled to 400mg aciclovir or alternatively intravenous dosing could be considered.

Dosing should begin as early as possible after the start of an infection; for recurrent episode this should preferably be during the prodromal period or when lesions first appear.

Suppression of herpes simplex infections in immunocompetent patients: 200mg aciclovir should be taken four times daily at approximately six-hourly intervals.

Many patients may be conveniently managed on a regimen of 400mg aciclovir twice daily at approximately twelve-hourly intervals.

Dosage titration down to 200mg aciclovir taken thrice daily at approximately eight-hourly intervals or even twice daily at approximately twelve-hourly intervals may prove effective.

Some patients may experience break-through infection on total daily doses of 800mg aciclovir.

Prophylaxis of herpes simplex infections in immunocompromised patients: 200mg aciclovir 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 400mg aciclovir, or alternatively intravenous 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 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 (e.g. 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. Treatment of chickenpox in immunocompetent patients should begin with 24 hours after the onset of the rash.

Dosage in children

Treatment of herpes simplex infections and prophylaxis of herpes simplex infections in the immunocompromised: Children aged two years and over should be given adult dosages and children below the age of two years should be given half the adult dose.

Treatment of varicella infection

6 years and over:800mg aciclovir four times daily
2-5 years400mg aciclovir four times daily
Under 2 years200mg aciclovir four times daily

Treatment should continue for five days.

Dosing may be more accurately calculated as 20mg/kg body weight (not to exceed 800mg) aciclovir 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.

Dosage in elderly:

The possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly.

Adequate hydration of elderly patients taking high oral doses of aciclovir should be maintained.

Contraindications

Aciclovir tablets are contra-indicated in patients known to be hypersensitive to aciclovir or valaciclovir or to any of the excipients.

Interactions with other medicinal products and other forms of interaction

Aciclovir is eliminated primarily unchanged in the urine viia active renal tubular secretion. Any drugs administered concurrently that compete with the mechanism may increase aciclovir plasma concentrations. Probenecid and cimetidine increase the AUC of aciclovir by this mechanism, and reduce aciclovir renal clearance. Similarly increase 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 drug s are coadministered. However no dosage adjustment is necessary because of the wide therapeutic index of aciclovir.

An experimental study on five male subjects indicates that concomitant therapy with aciclovir increases AUC of totally administered theophylline with approximately 50%. It is recommended to measure plasma concentrations during concomitant therapy with aciclovir.

Fertility, pregnancy and breast-feeding

Pregnancy: The use of aciclovir should be considered only when the potential benefits outweigh the possibility of unknown risks.

Breast-feeding: Following oral administration of 200mg aciclovir five times a day, aciclovir has been detected in breast milk at concentrations ranging from 0.6 to 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 woman.

Fertility

There is no information on the effect of aciclovir on human female fertility.

Effects on ability to drive and use machines

There have been no studies to investigate the effects of aciclovir on driving performance or the ability to operate machinery. A detrimental effect on such activities cannot be predicted from the pharmacology of the active substances, but the adverse event profile should be borne in mind.

Undesirable effects

The frequency categories associated with the adverse events below are estimates. In addition, adverse events may vary in their incidence depending on the indication

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Blood and lymphatic system disorders: anemia, leucopenia, thrombocytopenia

Immune system disorders: anaphylaxis

Psychiatric and nervous system disorders: headache, dizziness

Respiratory, thoracic and mediastinal disorders: dyspnoea

Gastrointestinal disorders: nausea, vomiting, diarrhea, abdominal pains

Skin and subcutaneous tissue disorders: pruritus, rashes (including photosensitivity)

Overdose

Acicloviir is only partly absorbed in the gastrointestinal tract. Patients have ingested overdoses of up to 20g 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 elevation 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.

Management: 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.

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