Zovirax

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOVIRAX (ZOVIRAX)

Composition:

Active substance: acyclovir,

1 tablet contains 200 mg of acyclovir;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, povidone K30, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white, round, biconvex tablets with the imprint GXCL3 on one side.

Pharmacotherapeutic group. Antiviral agents for systemic use.

ATC code J05A B01.

Pharmacological Properties.

Pharmacodynamics.

Acyclovir is a synthetic analogue of purine nucleoside with inhibitory activity in vivo and in vitro against human herpesviruses, including herpes simplex virus types I and II, varicella-zoster virus (chickenpox and shingles), Epstein-Barr virus, and cytomegalovirus. In cell culture, acyclovir demonstrates the greatest activity against herpes simplex virus type I, followed by decreasing activity against herpes simplex virus type II, varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus.

The inhibitory activity of acyclovir against the aforementioned viruses is highly selective. The enzyme thymidine kinase in normal, uninfected cells does not utilize acyclovir as a substrate, thus minimizing toxic effects on host cells. However, the thymidine kinase encoded by herpes simplex viruses, varicella-zoster virus, and Epstein-Barr virus converts acyclovir into acyclovir monophosphate—a nucleoside analogue—which is then sequentially converted into diphosphate and triphosphate forms by cellular enzymes. Once incorporated into viral DNA, acyclovir triphosphate interacts with viral DNA polymerase, resulting in termination of viral DNA chain synthesis.

With prolonged or repeated treatment courses in severely ill patients with compromised immunity, reduced sensitivity of certain viral strains to acyclovir may occur, leading to suboptimal treatment response. Most clinical cases of resistance are associated with deficient viral thymidine kinase activity; however, mutations in viral thymidine kinase and DNA polymerase have also been reported. In vitro, exposure of certain herpes simplex virus strains to acyclovir may lead to the emergence of less sensitive strains. The correlation between in vitro susceptibility of herpes simplex virus strains to acyclovir and clinical treatment outcomes has not been fully established.

Pharmacokinetics.

Acyclovir is only partially absorbed in the gastrointestinal tract. The average peak steady-state plasma concentration (Cssmax) after a 200 mg dose administered at 4-hour intervals is 3.1 µmol (0.7 µg/mL), and the trough plasma level (Cssmin) is 1.8 µmol (0.4 µg/mL). Corresponding Cssmax levels after 400 mg and 800 mg doses at 4-hour intervals are 5.3 µmol (1.2 µg/mL) and 8 µmol (1.8 µg/mL), respectively, with corresponding Cssmin levels of 2.7 µmol (0.6 µg/mL) and 4 µmol (0.9 µg/mL).

In adults, the terminal elimination half-life of acyclovir after intravenous administration is approximately 2.9 hours. Most of the drug is excreted unchanged by the kidneys. Renal clearance of acyclovir is substantially higher than creatinine clearance, indicating that renal elimination occurs not only via glomerular filtration but also through tubular secretion.

9-Carboxymethoxymethylguanine is the only significant metabolite of acyclovir detectable in urine, accounting for approximately 10–15% of the administered dose. When acyclovir is administered one hour after a 1 g dose of probenecid, the terminal elimination half-life and the area under the concentration-time curve increase by 18% and 40%, respectively.

In patients with chronic renal failure, the average terminal elimination half-life is 19.5 hours. The average elimination half-life of acyclovir during hemodialysis is 5.7 hours. Acyclovir plasma levels decrease by approximately 60% during dialysis.

The concentration of acyclovir in cerebrospinal fluid is approximately 50% of the corresponding plasma concentration. Plasma protein binding is relatively low (9–33%) and does not change significantly with concomitant administration of other drugs.

No pharmacokinetic interactions were observed between acyclovir and zidovudine when co-administered in HIV-infected patients.

Clinical characteristics.

Indications.

• Treatment of viral infections of the skin and mucous membranes caused by herpes simplex virus, including primary and recurrent genital herpes.
• Suppression (prevention of recurrences) of infections caused by herpes simplex virus in immunocompetent patients.
• Prevention of infections caused by herpes simplex virus in immunocompromised patients.
• Treatment of infections caused by Varicella zoster virus (chickenpox and shingles).

Contraindications. Hypersensitivity to acyclovir, valacyclovir, or to any other component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

No clinically significant interactions between acyclovir and other medicinal products have been identified.

Acyclovir is primarily excreted unchanged by the kidneys via tubular secretion; therefore, any drugs with a similar elimination mechanism may increase acyclovir plasma concentrations. Probenecid and cimetidine prolong the elimination half-life of acyclovir and increase the area under the concentration-time curve (AUC). When acyclovir is administered concomitantly with immunosuppressants used in transplant patients—such as mycophenolate mofetil—plasma levels of both acyclovir and the inactive metabolite of mycophenolate mofetil increase. However, due to the wide therapeutic index of acyclovir, dose adjustment is not required.

An experimental study in five male subjects indicates that concomitant therapy with acyclovir increases the AUC of intravenously administered theophylline by approximately 50%. Monitoring of plasma concentrations is recommended during concomitant therapy with acyclovir.

Special precautions for use

Patients with renal impairment and elderly patients

Acyclovir is primarily eliminated from the body via renal clearance; therefore, dosage reduction is required in patients with renal impairment (see "Dosage and administration"). Elderly patients are also more likely to have impaired renal function, so dose adjustment may be necessary in this patient group as well. Both of these groups (patients with renal impairment and elderly patients) are at risk of developing neurological adverse reactions and should therefore be closely monitored for such reactions. Available data indicate that these reactions are generally reversible upon discontinuation of acyclovir therapy (see section "Adverse reactions"). Prolonged or repeated courses of acyclovir treatment in individuals with severely compromised immune systems may lead to the emergence of viral strains with reduced sensitivity that may not respond to prolonged acyclovir therapy.

Adequate hydration should be carefully maintained in patients receiving high doses of acyclovir.

The risk of renal damage is increased when acyclovir is used concomitantly with other nephrotoxic agents.

Clinical trial data are insufficient to conclude that acyclovir treatment reduces the incidence of complications associated with varicella in immunocompetent patients.

Use during pregnancy or breastfeeding

There is no information available on the effect of acyclovir on female fertility.
In a study of 20 male patients with normal sperm counts, oral administration of up to 1 g acyclovir daily for six months did not reveal any clinically significant effect on sperm count, motility, or morphology.

Post-marketing surveillance data from a pregnancy registry document outcomes following the use of various pharmaceutical forms of Zovirax during pregnancy. No increased incidence of congenital malformations has been observed in children whose mothers used Zovirax during pregnancy compared to the general population. However, Zovirax tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Following oral administration of 200 mg acyclovir five times daily, acyclovir is present in breast milk at concentrations ranging from 0.6 to 4.1 times the plasma levels. A nursing infant may potentially ingest up to 0.3 mg/kg body weight of acyclovir per day. Therefore, acyclovir should be administered to breastfeeding women with caution, taking into account the risk-benefit ratio.

Ability to influence reaction rate while driving or operating machinery

When assessing the ability to drive a vehicle or operate machinery, the patient’s clinical status and the drug’s adverse reaction profile should be taken into account. Clinical studies specifically evaluating the effect of acyclovir on reaction speed during driving or operating machinery have not been conducted. However, the pharmacological profile of acyclovir does not suggest any expectation of negative effects.

Method of Administration and Dosage

The tablet should be taken whole, with water. When using high doses of acyclovir, adequate hydration should be maintained.

Adults

Treatment of infections caused by herpes simplex virus

For treatment of infections caused by herpes simplex virus, Zovirax tablets should be taken at a dose of 200 mg five times daily at approximately 4-hour intervals, excluding the nighttime period.

Treatment should last for 5 days, but may be prolonged in cases of severe primary infection.

For patients with severe immunodeficiency (e.g., after bone marrow transplantation) or those with impaired intestinal absorption, the dose may be doubled to 400 mg or an appropriate intravenous dose may be administered.

Treatment should be initiated as early as possible after the onset of infection. In recurrent herpes, treatment should ideally begin during the prodromal phase or immediately after the first signs of skin lesions appear.

Prevention of recurrences (suppressive therapy) of infections caused by herpes simplex virus

In immunocompetent patients, to prevent recurrences of herpes simplex virus infections, Zovirax tablets 200 mg should be taken four times daily at approximately 6-hour intervals.

For convenience, most patients may take 400 mg of Zovirax twice daily at approximately 12-hour intervals.

Therapy may remain effective even when the dose of Zovirax tablets is reduced to 200 mg taken three times daily at 8-hour intervals, or even twice daily at 12-hour intervals.

In some patients, significant improvement is observed with a total daily dose of Zovirax 800 mg.

To monitor possible changes in the natural course of the disease, Zovirax therapy should be periodically interrupted at intervals of 6–12 months.

Prevention of infections caused by herpes simplex virus

For prevention of herpes simplex virus infections in immunocompromised patients, Zovirax tablets 200 mg should be taken four times daily at approximately 6-hour intervals. For patients with significant immunodeficiency (e.g., after bone marrow transplantation) or those with impaired intestinal absorption, the dose may be doubled to 400 mg or an appropriate intravenous dose may be administered.

The duration of prophylaxis depends on the duration of the risk period.

Treatment of varicella and herpes zoster

For treatment of infections caused by varicella-zoster virus (chickenpox and herpes zoster), Zovirax tablets should be taken at a dose of 800 mg five times daily at approximately 4-hour intervals, excluding the nighttime period. Treatment should last for 7 days.

For patients with severe immunodeficiency (e.g., after bone marrow transplantation) or those with impaired intestinal absorption, intravenous administration is preferred.

Treatment should be initiated as early as possible after the onset of disease; outcomes are better if treatment is started immediately after the appearance of rash.

Children

For treatment of herpes simplex virus infections and prevention of herpes simplex virus infections in immunocompromised children aged 2 years and older, adult doses may be used. For treatment of chickenpox in children aged 6 years and older, 800 mg of Zovirax should be administered four times daily. Children aged 2 to 6 years may receive 400 mg of Zovirax four times daily. The duration of treatment is 5 days.

The individual dose may be more precisely calculated based on body weight as 20 mg/kg body weight (not exceeding 800 mg) of Zovirax four times daily.

There are no specific data on the use of Zovirax for prevention (recurrence suppression) of herpes simplex virus infections or for treatment of herpes zoster virus infections in immunocompetent children.

For treatment of herpes virus infections in neonates and children under 3 months of age, Zovirax lyophilisate for infusion solution is used.

Elderly patients

Renal function impairment should be considered in elderly patients, and the dose should be adjusted accordingly (see Renal impairment). Adequate hydration should be maintained in elderly patients receiving high doses of Zovirax.

Renal impairment

Zovirax should be administered with caution to patients with renal impairment. Adequate hydration should be maintained.

For prophylaxis and treatment of herpes simplex virus infections in patients with renal impairment, the recommended oral doses do not lead to accumulation of acyclovir above the safe levels established for intravenous administration. However, for patients with severe renal impairment (creatinine clearance less than 10 mL/min), the recommended dose is 200 mg twice daily at approximately 12-hour intervals.

For treatment of Varicella zoster virus infections (chickenpox and herpes zoster) in immunocompromised patients, in cases of severe renal impairment (creatinine clearance less than 10 mL/min), the recommended dose is 800 mg twice daily at approximately 12-hour intervals. For patients with moderate renal impairment (creatinine clearance 10–25 mL/min), the recommended dose is 800 mg three times daily at approximately 8-hour intervals.

Children

Zovirax tablets are indicated for children aged 2 years and older.

Overdose

Symptoms

Acyclovir is only partially absorbed from the gastrointestinal tract. Cases of accidental oral intake of up to 20 g of acyclovir have been reported without toxic effects. Accidental repeated overdose of oral acyclovir over several days may result in gastrointestinal symptoms (such as nausea and vomiting) and neurological symptoms (headache and confusion).

In cases of intravenous acyclovir overdose, serum creatinine and blood urea nitrogen levels increase, leading to renal failure. Neurological manifestations of overdose may include confusion, hallucinations, agitation, seizures, and coma.

Treatment

The patient should be carefully examined to identify symptoms of intoxication. Since acyclovir levels in blood are effectively eliminated by hemodialysis, hemodialysis should be used in cases of overdose.

Side effects

The adverse reactions listed below are classified by organ systems and frequency of occurrence. Frequency categories: very common ≥ 1/10, common ≥ 1/100 and < 1/10, uncommon ≥ 1/1,000 and < 1/100, rare ≥ 1/10,000 and < 1/1,000, very rare < 1/10,000.

Blood and lymphatic system

Very rare: anaemia, thrombocytopenia, leucopenia.

Immune system

Rare: anaphylaxis.

Psychiatric and nervous system disorders

Common: headache, dizziness.

Very rare: excitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, seizures, somnolence, encephalopathy, coma.

The above neurological reactions are generally reversible and usually occur in patients with renal impairment or other risk factors (see section "Special precautions for use").

Respiratory system and thoracic organs

Rare: dyspnoea.

Gastrointestinal system

Common: nausea, vomiting, diarrhoea, abdominal pain.

Hepatobiliary system

Rare: reversible increase in bilirubin and liver enzyme levels.

Very rare: jaundice, hepatitis.

Skin and subcutaneous tissue

Common: pruritus, rash (including photosensitivity).

Uncommon: urticaria, diffuse accelerated hair loss. Since hair loss may be associated with a variety of diseases and medications, a clear link with acyclovir has not been established.

Rare: angioneurotic oedema.

Renal and urinary system

Rare: increased blood urea and creatinine levels.

Very rare: acute renal failure, renal pain.

Renal pain may be associated with renal impairment and crystalluria.

General disorders

Common: fatigue, fever.

Shelf life

5 years.

Storage conditions. Keep out of the reach of children. Store below 25°C in a dry place.

Packaging. 5 tablets in a blister made of polyvinyl chloride, polyvinylidene chloride, paper and aluminium with child-resistant closure; 5 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Glaxo Wellcome S.A. (Spain)/Glaxo Wellcome S. A. (Spain).

Manufacturer's address and place of business. Glaxo Wellcome S.A., Avda. de Extremadura, 3, Pol. Ind. Allendeduero, 09400 Aranda de Duero, Burgos, Spain / Glaxo Wellcome S.A., Avda. de Extremadura, 3, Pol. Ind. Allendeduero, 09400 Aranda de Duero, Burgos, Spain.