Uses and Administration of Zovirax/Univir in Kenya
Aciclovir is a synthetic purine nucleoside analogue structurally related to guanine. It is used mainly for the treatment of viral infections due to herpes simplex virus (types 1 and 2) and varicella-zoster virus (herpes zoster and chickenpox).
Herpes simplex infections, including herpes keratitis, herpes labialis, and genital herpes, respond to aciclovir by the intravenous, oral, or topical route, given as soon as possible after symptoms appear. Both initial and recurrent infections can be successfully treated. Prolonged treatment can reduce the incidence of recurrence which is particularly important in immunocompromised patients. However, when prolonged treatment is withdrawn, infections may recur.
Aciclovir also improves the healing of herpes zoster lesions and reduces acute pain when given intravenously or by mouth; use to prevent postherpetic neuralgia is controversial. Beneficial effects may be more marked in immunocompromised patients.
administration and dosage. Aciclovir/Herperax in Kenya is administered by intravenous infusion as the sodium salt over 1 hour. Doses are expressed in terms of the base. Aciclovir sodium 1.1 g is approximately equivalent to 1 g of aciclovir. Solutions for infusion are usually prepared to give a concentration of 25 or 50 mg of aciclovir per mL; this must then be further diluted in a suitable infusion fluid such as water for injections or sodium chloride 0.9% to a final concentration not greater than about 5 mg/mL (0.5%). Alternatively, a solution containing 25 mg/mL may be given by injection using a controlled-rate infusion pump, over 1 hour.
For herpes simplex infections in the immunocompromised, and for severe initial genital herpes, or varicella-zoster infections in immunocompetent patients, the dose by the intravenous route is 5 mg/kg given every 8 hours, and recommended periods of treatment range from 5 to 7 days. A similar dose may be used for prophylaxis of herpes simplex infections in immunocompromised patients. A higher dose of 10 mg/kg every 8 hours is given in the treatment of herpes simplex encephalitis. This higher dose is also given in varicella-zoster infections in immunocompromised patients. Herpes simplex encephalitis usually requires treatment for 10 days.
Oral doses of aciclovir vary according to indication. For treatment of primary herpes simplex infectionsin Kenya, including genital herpes, the usual oral dose is 200 mg five times daily (usually every 4 hours while awake) for 5 to 10 days. Severely immunocompromised patients or those with impaired absorption may be given 400 mg five times daily for 5 days. For suppression of recurrent herpes simplex in immunocompetent patients, the oral dose is 800 mg daily in two to four divided doses; dosage reduction to 400 to 600 mg daily can be tried. Higher doses of 1 g daily have also been used. Therapy should be interrupted every 6 to 12 months for reassessment of the condition. For prophylaxis of herpes simplex in immunocompromised patients, the dose is 200 to 400 mg four times daily. Chronic suppressive treatment is not suitable for mild or infrequent recurrences of herpes simplex. In such cases episodic treatment of recurrences may be more beneficial; a dose of 200 mg five times daily for 5 days has been recommended, preferably initiated during the prodromal period. The usual oral dose of aciclovir for treatment of chickenpox is 800 mg four or five times daily for 5 to 7 days; for herpes zoster 800 mg five times daily may be given for 7 to 10 days.
In herpes simplex infections of the skin in Kenya, including genital herpes and herpes labialis, topical treatment with an ointment or cream containing aciclovir 5% may be applied 5 or 6 times daily for periods of 5 to 10 days. In herpes simplex keratitis a 3% eye ointment may be applied 5 times daily until 3 days after healing.
Doses should be reduced in renal impairment.?
Children’s doses. In children, the 8-hourly intravenous dose is best calculated by body-surface using 250 mg/m2 for herpes simplex and varicella-zoster infections in immunocompetent patients and 500 mg/m2 for herpes simplex encephalitis and varicella-zoster infection in the immunocompromised. A suggested 8-hourly dose for infants and neonates is 10 mg/kg; treatment for neonatal herpes usually continues for 10 days. In the treatment of herpes simplex infections, and in the prophylaxis of herpes simplex infections in the immunocompromised, oral doses of aciclovir for children aged 2 years and over are as for adults. Children aged under 2 years are given half the adult dose. In the treatment of chickenpox, children over 2 years of age may be given 20 mg/kg, up to a maximum of 800 mg, four times daily for 5 days. Alternatively, children aged 6 years and over may be given 800 mg four times daily, those aged 2 to 5 years may be given 400 mg four times daily, and those aged under 2 years may be given 200 mg four times daily.
Administration in renal impairment.
Doses of aciclovir should be reduced in renal impairment according to creatinine clearance (CC) and the manufacturers have given the following guidance:
CC between 25 and 50 mL/minute: the interval between infusions may be increased to 12 hours
CC 10 to 25 mL/minute: the interval between infusions may be increased to 24 hours
CC less than 10 mL/minute: patients on peritoneal dialysis should receive half the usual appropriate dose given once every 24 hours; patients on haemodialysis should receive half the usual dose every 24 hours plus an extra half-dose following haemodialysis
CC less than 10 mL/minute: herpes simplex infections: 200 mg every 12 hours; varicella-zoster infections: 800 mg every 12 hours
CC between 10 and 25 mL/minute: varicella-zoster infections: 800 mg three times daily every 8 hours
Resistance towards Acyclovir
Herpes simplex virus develops resistance to aciclovir in vitro and in vivo by selection of mutants deficient in thymidine kinase. Other mechanisms of resistance include altered substrate specificity of thymidine kinase and reduced sensitivity of viral DNA polymerase. Resistance has also been reported with varicella-zoster virus, probably by similar mechanisms.
Although occasional treatment failures have been reported, resistance has not yet emerged as a major problem in treating herpes simplex infections. However, resistant viruses are more likely to be a problem in patients with a suppressed immune response; AIDS patients may be particularly prone to aciclovir-resistant mucocutaneous herpes simplex virus infections.
Viruses resistant to aciclovir because of absence of thymidine kinase may be cross-resistant to other antivirals phosphorylated by this enzyme, such as brivudine, idoxuridine, and ganciclovir. Viruses resistant because of altered substrate specificity of thymidine kinase may display cross-resistance to brivudine; those with altered DNA polymerase sensitivity may be resistant to brivudine and vidarabine. However, those viruses with altered enzyme specificity or sensitivity tend to have variable cross-resistance patterns and may be relatively susceptible to the aforementioned antivirals.
Adverse Effects of Acyclovir in Kenya
Aciclovir is generally well tolerated. When administered intravenously as aciclovir sodium it may cause local reactions at the injection site with inflammation and phlebitis; these reactions may be associated with extravasation that leads rarely to ulceration.
Renal impairment may be associated with systemic use of aciclovir in some patients; it is usually reversible and is reported to respond to hydration and/or dosage reduction or withdrawal, but may progress to acute renal failure. The risk of renal toxicity is increased by conditions favouring deposition of aciclovir crystals in the tubules such as when the patient is poorly hydrated, has existing renal impairment, or when the drug is given at a high dosage or by rapid or bolus injection. Some patients receiving systemic aciclovir may experience transient increases in blood concentrations of urea and creatinine although this is more acute with intravenous administration.
Occasional adverse effects following systemic administration include increased serum bilirubin and liver enzymes, haematological changes, skin rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), fever, headache, dizziness, and gastrointestinal effects such as nausea, vomiting, and diarrhoea. Anaphylaxis has been reported. Hepatitis and jaundice have been reported rarely. Neurological effects including lethargy, somnolence, confusion, hallucinations, agitation, tremors, psychosis, convulsions, and coma have been reported in a small number of patients, particularly in those receiving intravenous aciclovir and with predisposing factors such as renal impairment; these effects may be more marked in older patients. Thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome, sometimes resulting in death, have occurred in immunocompromised patients receiving high parenteral doses of aciclovir. Accelerated diffuse hair loss has also been reported.
Topical application of aciclovir, especially to genital lesions, may sometimes produce transient stinging, burning, itching, or erythema. Eye ointments may occasionally produce transient stinging, superficial punctate keratopathy, blepharitis, or conjunctivitis.