Domina

Composition:

Each film coated tablet contains 200 or 400 mg Acyclovir.

Mechanism of action:

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 (VSV)

Pharmacokinetic properties:

Absorption:

Acyclovir is only partially absorbed from the gut. Mean steady state peak plasma concentrations (CSSmax) following doses of 200mg acyclovir administered four-hourly were 3.1 microMol (0.7 microgram/ml) and the equivalent trough plasma levels (CSSmin) were 1.8 microMol (0.4 microgram/ml). Corresponding steady-state plasma concentrations following doses of 400mg and 800mg acyclovir administered four-hourly were 5.3 microMol (1.2 microgram/ml) and 8 microMol (1.8 microgram/ml) respectively, and equivalent trough plasma levels were 2.7 microMol (0.6 microgram/ml) and 4 microMol (0.9 microgram/ml)

Most of the drug is excreted unchanged by the kidney. Renal clearance of acyclovir is substantially greater than creatinine clearance, indicating that tubular secretion, in addition to glomerular filtration, contributes to the renal elimination of the drug.

9-carboxymethoxymethylguanine is the only significant metabolite of acyclovir, and accounts for 10-15% of the dose excreted in the urine.

Elimination:

In children over 1 year of age The terminal plasma half-life in these patients was 3.8 hours

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.

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.

Distribution:

Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels. Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not anticipated.

Indications:

For the 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)
For the suppression (prevention of recurrences) of recurrent herpes simplex infections in immunocompetent patients.
For the prophylaxis of herpes simplex infections in immunocompromised patients.
For the treatment of varicella (chickenpox) and herpes zoster (shingles) infections.

Contraindications:

Hypersensitivity to acyclovir or valacyclovir, or to any of the excipients

Warnings and precautions:

Acyclovir is eliminated by renal clearance, therefore the dose must be adjusted in patients with renal impairment.
Elderly patients are likely to have reduced renal function and therefore the need for dose adjustment 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.
Thrombotic , thrombocytopenic purpurahemolytic uremic syndrome (TTPHUS) which has resulted in death , has occurred in immunocompromised patients receiving acyclovir therapy.
Hydration status: Care should be taken to maintain adequate hydration in patients receiving high oral doses of acyclovir.
This risk of renal impairment is increased by use with other nephrotoxic drugs.

Interaction with other medicinal products:

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.

Concomitant therapy with acyclovir increases AUC of totally administered theophylline with approximately 50%. It is recommended to measure plasma concentrations during concomitant therapy with acyclovir.

Pregnancy:

Category B, Caution should however be exercised by balancing the potential benefits of treatment against any possible hazard.

Breast-feeding:

Following oral administration of 200mg acyclovir five times a day, acyclovir 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 acyclovir dosages of up to 0.3mg/kg/day. Caution is therefore advised if Virax is to be administered to a nursing woman.

Undesirable effects:

Blood and lymphatic system disorders: very rare such as Anaemia, leukopenia, thrombocytopenia,vasculitis, leucopenia, lymphadenopathy
Immune system disorders: Rare such as Anaphylaxis
Psychiatric and nervous system disorders: Common such as Headache, dizziness, and very rare such as Agitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, convulsions, somnolence, encephalopathy, coma.
Respiratory, thoracic and mediastinal disorders: Rare such as Dyspnoea
Gastrointestinal disorders: Common such as Nausea, vomiting, diarrhea, abdominal pains
Hepato-biliary disorders: Rare such as Reversible rises in bilirubin and liver related enzymes, and very rare such as Hepatitis, jaundice
Skin and subcutaneous tissue disorders: Common:Pruritus, rashes (including photosensitivity), uncommon: urticaria, accelerated diffuse hair loss, Stevens Johnson syndrome , necrolysis, and the rare is angioedema
Renal and urinary disorders: Rare:Increases in blood urea and creatinine, and very rare:Acute renal failure, renal pain.. Renal pain may be associated with renal failure and crystalluria.
Effects on special senses such as visual abnormalities, Musculoskeletal: myalgia, and general disorders and administration site conditions such as Fatigue, fever

Dosage:

Adults

Treatment of herpes simplex infections: 200mg 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 immunocompromised patients (e.g. after marrow transplant) or in patients with impaired absorption from the gut the dose can be doubled to 400mg or alternatively intravenous dosing could be considered.

Dosing should begin as early as possible after the start of an infection

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

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

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: 200mg 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 or, alternatively, intravenous dosing could be considered.

Treatment of varicella and herpes zoster infections: 800mg 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 within 24 hours after onset of the rash.

Treatment of initial genital herpes: 200 mg every 4 hours , 5 times daily for 10 days

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.

For treatment of neonatal herpes virus infections, intravenous acyclovir is recommended.

Treatment of varicella infections:

6 years and over: 800mg four times daily.

2 to 5 years: 400mg four times daily.

Under 2 years: 200mg four times daily.

Treatment should continue for five days.

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

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)

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

Dosage in Renal Impairment:

Caution is advised when administering acyclovir to patients with impaired renal function

Adequate hydration should be maintained.

Creatinine clearance	Adjusted dosage regimen
Mlmin1,73 m2	Dose (mg)	Dosing interval
>10	200	Every 4 h
		5 x daily
0-10	200	Every 12 h
>10	400	Every 12 h
0-10	200	Every 12 h
>25	800	Every 4 h
		5 x daily
10-25	800	Every 8 h
0-10	800	Every 12 h

Overdose:

Symptoms & signs: Aciclovir 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)

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.