Zovirax^® (Tablets, Lyophilisate, Ointment, Cream) Instructions for Use

ATC Code

J05AB01 (Aciclovir)

Active Substance

Aciclovir (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; nucleosides and nucleotides, excluding reverse transcriptase inhibitors

Pharmacological Action

Antiviral drug, a synthetic analogue of a purine nucleoside, which has the ability to inhibit in vitro and in vivo the replication of Herpes simplex viruses type 1 and 2, Varicella zoster virus, Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In cell culture, Aciclovir has the most pronounced antiviral activity against Herpes simplex type 1, followed in descending order of activity by: Herpes simplex type 2, Varicella zoster, EBV and CMV.

The action of acyclovir on viruses is highly selective. Aciclovir is not a substrate for the thymidine kinase enzyme of uninfected cells, therefore it is slightly toxic to mammalian cells. Thymidine kinase of cells infected with Herpes simplex viruses type 1 and 2, Varicella zoster, EBV and CMV, converts Aciclovir into acyclovir monophosphate – a nucleoside analogue, which is then sequentially converted into diphosphate and triphosphate under the action of cellular enzymes. The incorporation of acyclovir triphosphate into the viral DNA chain and the subsequent chain termination block further replication of viral DNA.

In patients with severe immunodeficiency, long-term or repeated courses of acyclovir therapy can lead to the formation of resistant strains, and therefore further treatment with acyclovir may be ineffective. Most isolated strains with reduced sensitivity to acyclovir showed relatively low viral thymidine kinase content, impaired viral thymidine kinase or DNA polymerase structure. Exposure of Herpes simplex virus strains to acyclovir in vitro can also lead to the formation of strains less sensitive to it. No correlation has been established between the sensitivity of Herpes simplex virus strains to acyclovir in vitro and the clinical efficacy of the drug.

It has been shown that intravenous administration of Zovirax^® in high doses reduces the incidence and delays the development of cytomegalovirus infection. If, after such infusion therapy, treatment with oral acyclovir in high doses is carried out for 6 months, then mortality and the incidence of viremia are reduced.

Pharmacokinetics

Distribution

In adults, the mean C_max of acyclovir 1 hour after infusion at doses of 2.5 mg/kg, 5 mg/kg, 10 mg/kg and 15 mg/kg was 22.7 µmol (5.1 µg/ml), 43.6 µmol (9.8 µg/ml), 92 µmol (20.7 µg/ml) and 105 µmol (23.6 µg/ml), respectively. The C_min of the drug in plasma 7 hours after infusion was 2.2 µmol (0.5 µg/ml), 3.1 µmol (0.7 µg/ml), 10.2 µmol (2.3 µg/ml) and 8.8 µmol (2.0 µg/ml), respectively.

The concentration of acyclovir in the cerebrospinal fluid is approximately 50% of its plasma concentration.

Aciclovir binds to plasma proteins to a small extent (9-33%).

Elimination

In adults, after intravenous administration of acyclovir, T_1/2 from plasma is about 2.9 hours. Most of the drug is excreted by the kidneys unchanged. The renal clearance of acyclovir significantly exceeds the clearance of creatinine, which indicates the elimination of acyclovir not only by glomerular filtration but also by tubular secretion. The main metabolite of acyclovir is 9-carboxymethoxymethylguanine, which accounts for about 10-15% of the administered dose of the drug in the urine.

When acyclovir was administered 1 hour after taking 1 g of probenecid, the T_1/2 of acyclovir and AUC increased by 18% and 40%, respectively.

Pharmacokinetics in special clinical cases

In children over 1 year of age, the C_max and C_min values corresponding to those in adults were observed when Zovirax^® was administered at a dose of 250 mg/m² instead of 5 mg/kg (adult dose) and at a dose of 500 mg/m² instead of 10 mg/kg (adult dose).

In newborns (from 0 to 3 months) who received Aciclovir as an infusion lasting more than 1 hour every 8 hours, C_max was 61.2 µmol (13.8 µg/ml), and C_min was 10.1 µmol (2.3 µg/ml), and T_1/2 was 3.8 hours.

In elderly individuals, the clearance of acyclovir decreases with age in parallel with the decrease in creatinine clearance, but the T_1/2 of acyclovir changes insignificantly.

In patients with chronic renal failure, the T_1/2 of acyclovir averaged 19.5 hours, and during hemodialysis, the T_1/2 averaged 5.7 hours, and the plasma concentration of acyclovir decreased by approximately 60%.

Indications

• Treatment of infections caused by Herpes simplex virus type 1 and 2;
• Prevention of infections caused by Herpes simplex virus type 1 and 2 in patients with immunodeficiency;
• Treatment of infections caused by Varicella zoster virus;
• Treatment of infections caused by Herpes simplex virus type 1 and 2 in newborns;
• Prevention of cytomegalovirus infection in bone marrow transplant recipients.

ICD codes

Dosage Regimen

Ointment

Adults and children should place a strip of ointment 10 mm long into the lower conjunctival sac. Frequency of application is 5 times/day at intervals of about 4 hours. Therapy should be continued for another 3 days after healing.

Tablets

Adults for treatment of infections caused by Herpes simplex virus type 1 and 2, the recommended dose of Zovirax^® is 200 mg 5 times/day every 4 hours (except during the night’s sleep). The usual course of treatment is 5 days, but may be extended for severe primary infections.

In cases of severe immunodeficiency (e.g., after bone marrow transplantation) or impaired intestinal absorption, the dose of Zovirax^® for oral administration may be increased to 400 mg 5 times/day. Treatment should be started as early as possible after the onset of infection; for recurrences, the drug is recommended to be prescribed already in the prodromal period or when the first elements of the rash appear.

For prevention of recurrences of infections caused by Herpes simplex virus type 1 and 2 in patients with normal immune status, the recommended dose of Zovirax^® is 200 mg 4 times/day (every 6 hours). A more convenient therapy regimen is suitable for many patients: 400 mg 2 times/day (every 12 hours). In some cases, lower doses of Zovirax^® are effective: 200 mg 3 times/day (every 8 hours) or 2 times/day (every 12 hours). Treatment with Zovirax^® should be periodically interrupted for 6-12 months to identify possible changes in the course of the disease.

For prevention of infections caused by Herpes simplex virus type 1 and 2 in patients with immunodeficiency, the recommended dose of Zovirax^® is 200 mg 4 times/day (every 6 hours). In cases of severe immunodeficiency (e.g., after bone marrow transplantation) or impaired intestinal absorption, the dose of Zovirax^® for oral administration may be increased to 400 mg 5 times/day. The duration of the prophylactic course of therapy is determined by the duration of the period of risk of infection.

For treatment of chickenpox and herpes zoster, the recommended dose of Zovirax^® is 800 mg 5 times/day, the drug is taken every 4 hours, except during the night’s sleep. The course of treatment is 7 days.

The drug should be prescribed as early as possible after the onset of infection, as treatment is more effective in this case.

For treatment of patients with severe immunodeficiency, the recommended dose of Zovirax^® is 800 mg 4 times/day (every 6 hours).

Patients who have undergone bone marrow transplantation are usually recommended to undergo a course of intravenous acyclovir therapy for 1 month before prescribing Zovirax^® orally. In clinical studies, the maximum duration of the course of treatment for bone marrow transplant recipients was 6 months (from the 1st to the 7th month after transplantation). In patients with advanced clinical picture of HIV infection, the course of treatment with Zovirax^® was 12 months, but there is reason to believe that longer courses of therapy may be effective in such patients.

Treatment and prevention of infections caused by Herpes simplex viruses in children with immunodeficiency aged 2 years and older – the same doses as for adults; in children under 2 years of age – half the adult dose.

For treatment of chickenpox in children over 6 years of age, the drug is prescribed in a single dose of 800 mg; from 2 to 6 years – 400 mg; under 2 years – 200 mg. Frequency of administration is 4 times/day. A more accurate single dose can be determined at the rate of 20 mg/kg of body weight (but not more than 800 mg). The course of treatment is 5 days.

There are no data on the use of Zovirax^® for prevention of recurrences of infections caused by Herpes simplex viruses and for the treatment of herpes zoster in children with normal immunity.

According to very limited available information, for the treatment of children over 2 years of age with severe immunodeficiency, the same doses of Zovirax^® as for the treatment of adults can be used.

When prescribing Zovirax^® to elderly patients, the possibility of a decrease in acyclovir clearance in parallel with a decrease in creatinine clearance should be taken into account. If there are signs of renal failure, the issue of reducing the dose of Zovirax^® should be decided. Elderly patients should receive sufficient fluids while taking Zovirax^® orally in high doses.

In patients with renal failure, oral administration of acyclovir in recommended doses for the treatment and prevention of infections caused by Herpes simplex viruses does not lead to accumulation of the drug to concentrations exceeding established safe levels. However, in patients with CrCl less than 10 ml/min, the dose of Zovirax^® is recommended to be reduced to 200 mg 2 times/day (every 12 hours). For treatment of chickenpox, herpes zoster, as well as for the treatment of patients with severe immunodeficiency with CrCl less than 10 ml/min, the recommended doses of Zovirax^® are 800 mg 2 times/day every 12 hours; with CrCl 10-25 ml/min 800 mg 3 times/day every 8 hours.

Zovirax^® tablets can be taken with meals, since food intake does not significantly impair its absorption. The tablets should be taken with a full glass of water.

Lyophilisate

The drug is intended for intravenous infusion.

Adults for treatment of infections caused by Herpes simplex viruses (except herpes encephalitis) and Varicella zoster, the drug is prescribed at a dose of 5 mg/kg body weight every 8 hours.

For treatment of infections caused by Varicella zoster virus, and herpes encephalitis in patients with immunodeficiency, intravenous infusions are performed at a dose of 10 mg/kg body weight every 8 hours (with normal renal function).

For prevention of cytomegalovirus infection during bone marrow transplantation, the drug is used at a dose of 500 mg/m² body surface area 3 times/day at 8-hour intervals. The duration of treatment is from 5 days before transplantation and up to 30 days after transplantation.

In obese patients, the same doses are recommended as in patients with normal body weight.

When prescribing intravenous infusions of Zovirax^® to patients with renal failure, the dosage regimen should be adjusted in accordance with the decrease in creatinine clearance.

During hemodialysis: 2.5-5 mg/kg or 250 mg/m² every 24 hours and after dialysis.

Children aged from 3 months to 12 years, doses of Zovirax^® for intravenous infusion are established depending on body surface area.

In newborns, the dosage regimen is established depending on body weight; for infections caused by Herpes simplex virus type 1 and 2, the recommended dose is 10 mg/kg every 8 hours. The duration of treatment for herpes encephalitis and infections caused by Herpes simplex virus in newborns is usually 10 days.

For infections caused by Herpes simplex viruses (except herpes encephalitis) and Varicella zoster, the drug is administered at a dose of 250 mg/m² every 8 hours.

For treatment of herpes encephalitis and infections caused by Varicella zoster virus, in children with immunodeficiency the drug is prescribed at a dose of 500 mg/m² every 8 hours (with normal renal function).

Limited data suggest that for prevention of cytomegalovirus infection in children over 2 years of age who have undergone bone marrow transplantation, Zovirax^® can be administered in doses recommended for adults.

In children with reduced renal function, dose adjustment is required according to the degree of renal failure.

In elderly patients with reduced creatinine clearance, the issue of dose reduction should be considered.

The course of treatment with Zovirax^® as intravenous infusions is usually 5 days, but may vary depending on the patient’s condition and response to therapy.

The duration of prophylactic use of Zovirax^® as intravenous infusions is determined by the duration of the period of risk of infection.

Rules for preparation and administration of the solution

The recommended dose of Zovirax^® should be administered as a slow intravenous infusion over 1 hour.

The following volumes of water for injections or sodium chloride solution for injections (0.9%) are used to prepare a solution of Zovirax^® with a content of 25 mg of acyclovir in 1 ml of the resulting solution.

The recommended volume of diluent must be added to the ampoule with Zovirax^® powder and shaken gently until the contents of the ampoule are completely dissolved.

The resulting Zovirax^® solution after dilution can be administered using a special infusion pump that regulates the rate of drug administration. Another method of administration is possible, in which the prepared Zovirax^® solution is diluted to obtain an acyclovir concentration not exceeding 5 mg/ml (0.5%). To do this, it is necessary to add the prepared solution to the selected infusion solution, which is recommended below, and shake well to completely mix the solutions.

For children and newborns who need to be administered minimal volumes of solutions, it is recommended to add 4 ml of the prepared Zovirax^® solution (100 mg of acyclovir) to 20 ml of solvent.

For adults, it is recommended to use infusion solutions in 100 ml packages, even if this results in an acyclovir concentration significantly below 0.5%. Thus, a 100 ml infusion solution can be used to administer any dose of acyclovir between 250 mg and 500 mg (10 and 20 ml of diluted solution). For doses between 500 mg and 1000 mg of acyclovir, a second infusion solution of this volume must be used.

Zovirax^® for intravenous infusion is compatible with the following infusion solutions and remains stable when diluted with them for 12 hours at room temperature (from 15°C (59°F) to 25°C (77°F)): 0.45% and 0.9% sodium chloride solutions for intravenous infusion; 0.18% sodium chloride and 4% glucose solution for intravenous infusion; 0.45% sodium chloride and 2.5% glucose solution for intravenous infusion; Hartmann’s solution.

Since the solutions do not contain any antibacterial preservative, dissolution and dilution must be carried out completely under aseptic conditions immediately before administration of the drug.

Unused solution should be destroyed.

If the solution becomes cloudy or crystals precipitate, it should be destroyed.

Cream

For external use.

It is important to start treatment as early as possible, preferably at the first signs and symptoms (in the prodromal period or at the stage of redness). Treatment can also be started at later stages (papule or blister).

To prevent worsening of the condition and prevent the spread of infection, it is necessary to wash hands before and after applying the drug, and not to rub or touch the affected areas of skin with a towel.

Adults

The drug is recommended to be applied 5 times a day, approximately every 4 hours, excluding nighttime, to the affected and adjacent areas of skin.

The duration of treatment is at least 4 days. If healing does not occur, treatment may be continued for up to 10 days. If symptoms persist for more than 10 days, you should consult a doctor.

Patients with renal and hepatic insufficiency

Although Aciclovir is mainly excreted by the kidneys, systemic absorption of acyclovir after topical application is insignificant. Accordingly, there is no need to change the dose for patients with renal or hepatic impairment.

Children

The dosage regimen for children does not differ from the dosage regimen for adults.

Adverse Reactions

From the digestive system nausea, vomiting, reversible increase in bilirubin levels and activity of liver enzymes; very rarely – hepatitis, jaundice.

From the hematopoietic system anemia, leukopenia and thrombocytopenia.

From the urinary system rarely – increase in blood urea and creatinine levels, which is associated with the C_max value and the patient’s hydration status. To avoid such phenomena, the drug should be administered as a slow infusion over 1 hour and the patient’s hydration should be maintained. Signs of renal failure that occur during therapy with Zovirax^® are usually quickly relieved by rehydration of patients and/or reduction of the drug dose or its discontinuation. Progression to acute renal failure occurs in exceptional cases.

From the CNS reversible neurological disorders, such as confusion, hallucinations, agitation, tremor, drowsiness, psychosis, seizures, and coma (usually in predisposed patients).

Allergic reactions rash, photosensitivity, urticaria, pruritus, fever; rarely – dyspnea, angioedema, anaphylaxis.

Local reactions severe inflammatory reactions leading to necrosis have been observed when Zovirax^® solution has leaked under the skin.

Contraindications

• Hypersensitivity to aciclovir or valaciclovir.

With caution should be used in cases of dehydration, renal failure, neurological disorders, as well as during the development of reactions to cytotoxic drugs upon their intravenous administration (and with a history of such reactions).

Use in Pregnancy and Lactation

The administration of Zovirax^® during pregnancy and lactation (breastfeeding) requires caution and is possible only after assessing the expected benefit for the mother and the potential risk to the fetus and child.

No increase in the number of birth defects was detected in children whose mothers received Zovirax^® during pregnancy, compared to the general population.

When using Zovirax^® in the form of a lyophilisate during lactation (breastfeeding), it should be taken into account that after oral administration of Zovirax^® at a dose of 200 mg 5 times/day, Aciclovir was detected in breast milk at concentrations ranging from 0.6-4.1% of plasma concentrations. At such concentrations in breast milk, breastfed infants may receive Aciclovir at a dose of up to 0.3 mg/kg/day.

Use in Renal Impairment

When prescribing intravenous infusions of Zovirax^® to patients with renal impairment, the dosage regimen should be adjusted according to the decrease in creatinine clearance.

During hemodialysis: 2.5-5 mg/kg or 250 mg/m² every 24 h and after dialysis.

Pediatric Use

For children aged 3 months to 12 years, the doses of Zovirax^® for intravenous infusion are established based on body surface area.

For newborns, the dosage regimen is established based on body weight; for infections caused by Herpes simplex virus types 1 and 2, the recommended dose is 10 mg/kg every 8 h. The duration of treatment for herpes encephalitis and infections caused by Herpes simplex virus in newborns is usually 10 days.

Geriatric Use

In elderly patients with reduced creatinine clearance, a dose reduction should be considered.

Special Precautions

In patients with herpes encephalitis receiving Zovirax^® in high doses, renal function should be monitored (especially in cases of dehydration or pre-existing renal impairment).

Zovirax^® should be used with caution and under monitoring of renal function when administered concomitantly with drugs that impair renal function (e.g., cyclosporine, tacrolimus).

The prepared Zovirax^® solution has a pH=11, therefore it must not be administered orally.

Overdose

Symptoms increased levels of serum creatinine, blood urea nitrogen, renal failure. Neurological symptoms include confusion, hallucinations, agitation, seizures, and coma.

Treatment symptomatic therapy is performed. Hemodialysis is indicated.

Drug Interactions

No clinically significant interactions of Zovirax^® with other medicinal products have been noted.

Calcium channel blockers and cimetidine increase the AUC of aciclovir and reduce its renal clearance (no adjustment of the Zovirax^® dosage regimen is required).

When Zovirax^® is used concomitantly with drugs eliminated by active tubular secretion, an increase in the plasma concentration of active substances or their metabolites is possible (caution is advised when prescribing such combinations).

Concomitant use of aciclovir and mycophenolate mofetil, an immunosuppressant used in organ transplantation, leads to an increase in the AUC of aciclovir and the inactive metabolite of mycophenolate mofetil.

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 5 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.