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ALPHA ACICLOVIR 400mg tablets are white, oval biconvex tablets identified ACY400 on one side. Each tablet contains 400mg aciclovir and typically weighs 525mg.
ALPHA ACICLOVIR 800mg tablets are white, oval biconvex tablets identified ACY800 on one side and a breakline on the other. Each tablet contains 800mg aciclovir and typically weighs 1050mg.
Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, varicella-zoster virus, Epstein-Barr virus and to a lesser extent cytomegalovirus.
Aciclovir has an antiviral effect on herpes simplex viruses and varicella zoster virus resulting from its interference with DNA synthesis leading to inhibition of virus replication. The exact mechanism of aciclovir action in other susceptible viruses has not been fully elucidated.
Aciclovir triphosphate is the pharmacologically active metabolite of the drug. The initial phosphorylation of aciclovir to aciclovir monophosphate is catalysed by virus-induced thymidine kinase. Thus selective activation of the drug is achieved principally in infected cells. Further phosphorylation to aciclovir diphosphate is catalysed via cellular guanylate kinase and then phosphorylation to aciclovir triphosphate is catalysed via other intracellular enzymes (phosphoglycerate kinase, pyruvate kinase, phosphoenolpyruvate carboxykinase). The extent of formation of aciclovir monophosphate, diphosphate and triphosphate is directly related to the concentration of aciclovir in the cellular culture medium. In vitro studies indicate that aciclovir tri-phosphate is produced in low concentrations via unidentified cellular phosphorylating enzymes in cells infected with Epstein-Barr virus and cytomegalovirus.
Aciclovir triphosphate inhibits DNA synthesis by competing with deoxyguanosine triphosphate for viral DNA polymerase. Viral DNA polymerase exhibits a 10- to 30-fold greater affinity for aciclovir triphosphate than does cellular α-DNA polymerase. Following incorporation of aciclovir triphosphate into the growing viral DNA chain, DNA synthesis is terminated. Cytomegalovirus does not produce thymidine kinase and so the antiviral activity of aciclovir in cytomegalovirus-induced infections is poor. The selective action of aciclovir on the infected cells is due to poor uptake of aciclovir into uninfected cells, minimal phosphorylation of aciclovir to aciclovir monophosphate in uninfected cells and low cellular DNA polymerase affinity for aciclovir triphosphate.
Following oral administration absorption of aciclovir is slow, variable and incomplete. The bioavailability of oral aciclovir is low (15% to 30% of an oral dose is absorbed) and decreases with increasing dosage. Peak plasma concentrations occur within 1.5 and 2.5 hours after oral administration.
In an uncontrolled study of 35 immunocompromised patients with herpes simplex or varicella-zoster infection, aciclovir capsules were administered in doses of 200mg to 1000mg every 4 hours, 6 times daily for 5 days, and steady-state plasma levels were reached by the second day of dosing. Mean steady-state peak and trough concentrations following the final 200mg dose were 0.49 mcg/mL (0.47 - 0.54 mcg/mL) and 0.31 mcg/mL (0.18 - 0.41 mcg/mL) respectively, and following the final 800mg dose were 2.8mcg/mL (2.3 - 3.1mcg/mL) and 1.8mcg/mL (1.3 - 2.5mcg/mL) respectively. In another uncontrolled study of 20 younger immunocompetent patients with recurrent genital herpes simplex infections, aciclovir capsules were administered in doses of 800mg every 6 hours, 4 times daily for 5 days; the mean steady-state peak and trough concentrations were 1.4 mcg/mL (0.66 - 1.8 mcg/mL) and 0.55 mcg/mL (0.14 - 1.1 mcg/mL) respectively.
In general, the pharmacokinetics of aciclovir in children is similar to adults. Mean half-life after oral doses of 300mg/m2 and 600mg/m2 in children aged 7 months to 7 years was 2.6 hours (range 1.59 - 3.74 hours).
Some data suggest that the absorption of aciclovir is a saturable process. In a multiple-dose cross-over study where 23 volunteers received aciclovir as one 200mg capsule, one 400mg tablet and one 800mg tablet 6 times daily, absorption decreased with increasing dose and the estimated bioavailabilities of aciclovir were 20%, 15% and 10% respectively. The decrease in bioavailability is believed to be a function of the dose and not the dosage form. It was demonstrated that aciclovir is not dose proportional over the dosing range 200mg to 800mg. In this study steady state peak and trough concentrations of aciclovir were 0.83 and 0.46 mcg/mL, 1.21 and 0.63 mcg/mL, and 1.61 and 0.83 mcg/mL for the 200mg, 400mg and 800mg dosage regimens respectively.
Absorption is not markedly affected by food.
Aciclovir is widely distributed into body tissues and fluids, including principally the kidney, brain, liver, muscle, spleen, uterus, saliva, vaginal mucosa and secretions, cerebrospinal fluid and hepatic vesicular fluid. The apparent volume of distribution of aciclovir is 32.4L to 61.8L per 1.73m2 in adults.
Aciclovir is approximately 9% to 33% bound to plasma proteins at plasma concentrations of 0.41 to 5.2 mcg/mL.
The plasma concentrations of aciclovir appear to decline in a biphasic manner. In adult patients with normal renal function, the elimination half-life of aciclovir in the initial phase is 0.34 hours and in the terminal phase 2.1 to 3.5 hours. In neonates up to 3 months of age the elimination half-life appears to be slightly prolonged (1.5 to 4.0 hours) with the total body clearance being much less.
Aciclovir is excreted mainly through the kidneys by glomerular filtration and tubular secretion with 8.5 -14% of the dose being oxidised to 9-carboxymethoxymethylguanine. Less than 2% of an administered dose is excreted in the faeces.
Up to 80% of a dose may be excreted unchanged in the urine. In anuric patients the elimination half-life may be extended to 19.5 hours.
The clearance of aciclovir depends on renal function. Total body clearance of aciclovir is reported as 327, 248, 190 or 29mL/min per 1.73m2 in patients with creatinine clearance greater than 80, 50-80, 15-50 or 0 mL/min per 1.73m2 respectively.
Aciclovir is removed by haemodialysis and peritoneal dialysis. A single 6-hour course of haemodialysis reduced aciclovir concentrations by 50% - 60%.
Alpha-Aciclovir tablets are indicated for the treatment of herpes simplex infections including initial episodes and the management of recurrent episodes of genital herpes, suppression of herpes simplex infections in immune-compromised patients and for the acute treatment of herpes zoster (shingles).
The promptness of initiation of therapy and/or the patient's prior exposure to herpes simplex virus may influence the degree of benefit from therapy. Patients with mild disease may derive less benefit than those with more severe disease.
In patients with frequent recurrences (6 or more episodes per year) chronic suppressive therapy may be appropriate, if in the judgement of the physician the benefits of such a regimen outweigh known or potential adverse effects. After 1 year of therapy the need for aciclovir should be reassessed. Re-evaluation will usually require a trial off aciclovir to assess the need for reinstitution of suppressive therapy.
Limited studies have shown that there are certain patients for whom intermittent short-term treatment of recurrent episodes is effective. This approach may be more appropriate than a suppressive regimen in patients with infrequent recurrences.
Aciclovir is indicated for acute treatment, for reduction of the duration and severity of acute symptoms and rash, for reduction of zoster-associated pain and for reduction of the incidence and duration of post-herperic neuralgia.
Aciclovir is indicated for the management of patients with severe AIDS who have a CD4 count of less than 50/microL. Studies have shown that oral aciclovir given in conjunction with anti-retroviral therapy reduced mortality in patients with advanced HIV disease.
Aciclovir tablets, preceded by one month's treatment with intravenous aciclovir, are indicated for patients undergoing allogenic bone marrow transplantation who are at risk of developing CMV infection while immunosuppressed. Studies have shown that oral aciclovir reduced mortality in allogenic bone marrow transplant recipients and provided effective prophylaxis for herpes virus disease.
For adults and children over 2 years, 200mg 5 times daily (approximately every 4 hours) for 5 days although this may need to be extended in severe initial infections. For children under 2 years, half the adult dose. In severely immune-compromised patients or in patients with impaired absorption from the gut, the dose can be doubled to 400mg or intravenous dosing can be considered. Dosage should be as soon as possible after the start of the infection. For recurrent episodes this should preferably be in the prodromal period or when lesions first appear.
In immune-competent patients 200mg 4 times daily (approximately every 6 hours). Many patients may be managed on 400mg doses taken twice daily at approximately 12 hourly intervals. Dosage titration down to either 200mg 3 times daily or twice daily may be effective. The patients condition should be reassessed every 6 - 12 months.
In immune-compromised patients 200mg every 4 times daily (approximately every 6 hours) although in severely immune-compromised patients or in patients with impaired absorption from the gut the dose may be increased to 400mg or intravenous dosing could be considered. The duration of prophylactic administration is determined by the duration of the period at risk.
800mg 5 times daily (approximately every 4 hours) for 7 days. Dosing should begin as soon as possible after the onset of infection. Best results are obtained if treatment begins within 48 hours of the onset of the rash.
For adults and children over 2 years of age, 800mg every 6 hours 4 times daily. In patients with advanced HIV disease, 12 months treatment has been studied but it is likely that these patients would continue to benefit from a longer duration of treatment.
800mg every 6 hours 4 times daily. This would normally be preceded by up to one month's therapy with intravenous aciclovir. The duration of treatment studied was 6 months (from 1 to 7 months post-transplant).
In the elderly, total aciclovir body clearance declines in parallel with creatinine clearance. Adequate hydration of elderly patients taking high oral doses of aciclovir should be maintained. Special attention should be given to dosage reduction in elderly patients with impaired renal function.
The following dosage adjustments are recommended for genital herpes and herpes zoster indications:
| Normal Dosage Regimen |
Creatinine Clearance (ml/min/1.73m2) |
Adjusted Dosage Regimen |
|---|---|---|
| 200mg every 4 hours | >10 0 - 10 |
200mg every 4 hours, 5x daily 200mg every 12 hours |
| 400mg every 12 hours | >10 0 - 10 |
400mg every 12 hours 200mg every 12 hours |
| 800mg every 4 hours | >25 10 - 25 0 - 10 |
800mg every 4 hours, 5x daily 800mg every 8 hours 800mg every 12 hours |
The mean plasma half-life of aciclovir during haemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentration following a 6 hour dialysis period. Therefore, the patient's dosing schedule should be adjusted so that an additional dose is administered after each dialysis.
No supplemental dose appears to be necessary after adjustment of the dosing interval.
Aciclovir is contraindicated in patients with a hypersensitivity to this drug.
Aciclovir should be used with caution in patients with impaired renal function to prevent accumulation of the drug and to decrease the risk of nephrotoxicity and neurotoxicity.
Both the dose and the dosing interval should be carefully adjusted in patients undergoing haemodialysis to maintain adequate plasma concentrations of aciclovir.
Aciclovir should be used with caution in patients with underlying neurologic abnormalities, in patients with nutritional and metabolic disorders (dehydration, electrolyte abnormalities) and in patients with impaired kidney and liver function.
The recommended dosage should not be exceeded.
The possibility of the appearance of less sensitive viruses in humans must be considered when treating patients. Because of the possibility that less sensitive viruses may be selected in patients who are receiving aciclovir, all patients should be advised to take particular care to avoid potential transmission of virus if active lesions are present while they are on therapy.
Category B3.
There are no adequate and well-controlled studies in pregnant women. Aciclovir
should not be used during pregnancy unless the potential benefit justifies the
potential risk to the foetus. Although aciclovir is not teratogenic in standard
animal studies, the drug's potential for causing chromosomal breaks at high
concentrations should be taken into consideration in making this determination.
Aciclovir concentrations have been documented in breast milk in a lactating woman was more than 3 times the simultaneous plasma concentration. Caution should be exercised when aciclovir is administered to a nursing woman.
Aciclovir is generally well tolerated and adverse events are uncommon. Reported adverse events are: -
Fever, headache, pain, peripheral oedema, and rarely anaphylaxis
Confusion, dizziness, hallucinations, paraesthesia, somnolence
Diarrhoea, elevated liver function tests, gastrointestinal distress, nausea and vomiting
Leukopenia, lymphadenopathy
Myalgia
Alopecia, pruritis, rash, urticaria
Visual abnormalities
Elevated creatinine
Probenicid - co-administration of probonecid with intravenous aciclovir increases the terminal half-life of aciclovir by 18% and the area under the concentration-time curve by 40% as a result of decreased tubular secretion of aciclovir. Urinary excretion and renal clearance are reduced by 13% and 32% respectively.
Studies have shown no apparent changes in the pharmacokinetic behaviour of aciclovir or zidovudine when both are administered simultaneously to HIV-infected patients.
Patients have ingested intentional overdoses of up to 20g of aciclovir with no unexpected adverse effects. Precipitation of aciclovir in renal tubules may occur when the solubility (2.5mg/mL) in the intratubular fluid is exceeded. Ingestion of doses of aciclovir in excess of 5g warrants close observation of the patient.
A 6-hour haemodialysis results in a 60% decrease in plasma aciclovir concentration. Data concerning peritoneal dialysis are incomplete but indicate that this method may be significantly less efficient in removing aciclovir from the blood. In the event of acute renal failure and anuria, the patient may benefit from haemodialysis until renal function is restored.
Store below 25°C.
Protect from heat, light and moisture
Prescription Only Medicine
ALPHA-ACICLOVIR 400mg:
Calendar blister packs of 56 tablets
Bottle packs of 50, 56, 100, 250 and 500 tablets
ALPHA-ACICLOVIR 800mg:
Calendar blister packs of 35 tablets
Bottle packs of 35, 50, 100, 250 and 500 tablets
Tablets contain cornstarch
ALPHA PHARMACEUTICALS LTD
Melville House
159 Broadway Avenue
PO Box 705
Palmerston North
Tel: (06) 355-1066
Fax: (06) 356-6293
28 April 1999