Zovirax

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

Composition:

Active substance: acyclovir,

1 vial contains acyclovir 250 mg;

Excipient: sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties: white or almost white powder; when reconstituted with water for injections, rapidly forms a particle-free solution.

Pharmacotherapeutic group. Antiviral agents for systemic use.

ATC code J05A B01.

Pharmacological Properties.

Pharmacodynamics.

Acyclovir is a synthetic purine nucleoside analogue with high activity in vitro and in vivo against herpesviruses, including herpes simplex virus types I and II, Varicella zoster virus, Epstein-Barr virus, and cytomegalovirus. In cell culture, acyclovir exhibits the highest 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 herpes simplex virus type I, herpes simplex virus type II, Varicella zoster virus, and Epstein-Barr virus is highly selective. The enzyme thymidine kinase in normal, uninfected cells does not utilize acyclovir as a substrate; therefore, it has very low toxicity toward human cells. However, the thymidine kinase encoded by the aforementioned viruses converts acyclovir into acyclovir monophosphate, a nucleoside analogue, which is further converted into the diphosphate and then into the triphosphate form. Acyclovir triphosphate interacts with viral DNA polymerase and inhibits viral DNA replication.

During prolonged or repeated treatment courses in severely ill immunocompromised patients, cases of reduced sensitivity of certain viral strains may occur, which may not respond to acyclovir therapy. Most clinical cases of resistance are associated with a deficiency of viral thymidine kinase; however, there are reports of mutations affecting both thymidine kinase and DNA polymerase. In vitro, interaction of certain herpes simplex virus strains with acyclovir may also lead to the emergence of less sensitive strains. The correlation between in vitro susceptibility of individual herpes simplex virus strains and clinical outcomes of acyclovir treatment has not been fully established.

Pharmacokinetics.

In neonates and infants under 3 months of age treated with intravenous administration of 10 mg/kg over 1 hour at 8-hour intervals, the Cssmax was 61.2 µmol (13.8 µg/mL) and the Cssmin was 10.1 µmol (2.3 µg/mL). In another group of neonates and infants under 3 months of age treated with 15 mg/kg every 8 hours, approximately dose-proportional increases were observed, with Cmax of 83.5 µmol (18.8 µg/mL) and Cmin of 14.1 µmol (3.2 µg/mL).

Absorption

Acyclovir is only partially absorbed in the gastrointestinal tract. The average bioavailability after oral administration ranges from 10–20%. The mean peak concentration (Cmax) of acyclovir of 0.4 µg/mL is achieved approximately 1.6 hours after fasting oral administration of a 200 mg dose. An increase in the mean peak steady-state plasma concentration (Cssmax) to 0.7 µg/mL (3.1 µmol) occurs after administration of 200 mg every four hours. After administration of 400 mg and 800 mg doses every four hours, Cssmax values reach 1.2 and 1.8 µg/mL (5.3 and 8 µmol), respectively.

Distribution

The mean volume of distribution of acyclovir is 26 L, indicating its distribution into body fluids. Values after oral administration (Vd/F) range from 2.3 to 17.8 L/kg. Plasma protein binding is relatively low (9–33%) and does not change with concomitant administration of other drugs. Drug concentration in cerebrospinal fluid is approximately 50% of the plasma concentration.

Biotransformation

Acyclovir is primarily excreted unchanged by the kidneys. 9-Carboxymethoxymethylguanine is the only major metabolite of acyclovir, accounting for approximately 10–15% of the administered dose.

Elimination

Mean systemic exposure (AUC0–∞) of acyclovir is 1.9–2.2 µg*h/mL after administration of a 200 mg dose. In adults, the terminal elimination half-life after oral administration of acyclovir ranges from 2.8 to 4.1 hours. In adults, the terminal elimination half-life of acyclovir after intravenous administration of Zovirax is 2.9 hours. Renal clearance of acyclovir (CLr = 14.3 L/h) is significantly higher than creatinine clearance, indicating that the drug is eliminated by the kidneys through both glomerular filtration and tubular secretion. The elimination half-life and total clearance of acyclovir depend on renal function; therefore, dose adjustment is recommended in patients with impaired renal function.

In neonates and infants under 3 months of age receiving intravenous acyclovir at 10 mg/kg over 1 hour at 8-hour intervals, the terminal elimination half-life was 3.8 hours.

Special patient groups

Elderly patients

In elderly patients, total clearance decreases with age, resulting from reduced creatinine clearance and minor changes in terminal elimination half-life. Impaired renal function may be present in elderly patients; therefore, the dose of the drug should be adjusted accordingly.

Renal impairment

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

Excess body weight

In a clinical study, obese female patients (n=7) received intravenous acyclovir at doses calculated based on their actual body weight. Plasma concentrations were approximately twice as high as those in patients (n=5) with normal body weight, consistent with the difference in body weight between the two patient groups.

Clinical characteristics.

Indications.

Treatment of infections caused by herpes simplex virus in patients with immunodeficiency and severe genital herpes in patients without immunodeficiency.

Prevention of infections caused by herpes simplex virus in patients with immunodeficiency.

Treatment of infections caused by Varicella zoster virus.

Treatment of herpes encephalitis.

Treatment of infections caused by herpes simplex virus in neonates and infants under 3 months of age.

Contraindications.

Hypersensitivity to acyclovir, valacyclovir, or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Clinically significant interactions of acyclovir with other medicinal products have not 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; however, due to the wide therapeutic index of acyclovir, dose adjustment is not required.

In patients receiving Zovirax for intravenous administration concomitantly with other agents that have a similar elimination mechanism, there may be a potential increase in plasma concentrations of one or both agents or their metabolites. When acyclovir is administered concomitantly with an immunosuppressant used in transplant patients—mycophenolate mofetil—plasma levels of both acyclovir and the inactive metabolite of mycophenolate mofetil are also increased.

When lithium is administered concomitantly with high-dose intravenous acyclovir, serum lithium concentrations should be closely monitored due to the risk of lithium toxicity.
Caution (with monitoring of renal function) is also required when administering Zovirax for intravenous infusion with agents affecting renal function (such as cyclosporine, tacrolimus).

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

Special precautions for use

An adequate level of hydration must be maintained in patients receiving intravenous acyclovir or high oral doses of acyclovir.

Intravenous doses should be administered by infusion over one hour to avoid acyclovir precipitation in the kidneys. Rapid or bolus injection must be avoided.

The risk of renal damage increases when other nephrotoxic drugs are used concomitantly. Caution is required when administering intravenous acyclovir together with other nephrotoxic agents.

Patients with renal impairment and elderly patients

Acyclovir is primarily eliminated from the body by renal clearance; therefore, dosage reduction is necessary 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 required 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 must therefore be closely monitored. Available data indicate that such 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.

In patients receiving high intravenous doses of the drug, for example for the treatment of herpes encephalitis, renal function parameters should be taken into account, especially in cases of dehydration or existing renal impairment.

Diluted Zovirax for intravenous infusion has a pH of approximately 11.0 and must not be administered orally. The product contains sodium (26 mg, approximately 1.13 mmol). This should be taken into consideration in patients on a sodium-restricted diet.

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, no clinically significant effect on sperm count, motility, or morphology was observed after oral administration of up to 1 g daily for six months.

Post-marketing surveillance data from a pregnancy registry document the outcomes of various Zovirax formulations used 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, intravenous Zovirax should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

After oral administration of 200 mg acyclovir five times daily, acyclovir passes into breast milk at concentrations of 0.6–4.1 times the plasma acyclovir levels. A breastfed infant may potentially ingest acyclovir at a dose of up to 0.3 mg/kg body weight per day. Acyclovir should be administered with caution to breastfeeding women, taking into account the risk-benefit ratio for the infant.

Ability to affect the speed of reactions when driving or operating machinery

Intravenous Zovirax is primarily used for the treatment of hospitalized patients; therefore, information on its effect on the ability to drive or operate machinery is generally not required. No studies have been conducted to evaluate the effect of Zovirax on the ability to drive or operate machinery.

Method of Administration and Dosage

Administered by slow intravenous infusion over a period of not less than 1 hour.

The usual course of treatment with Zovirax for intravenous administration lasts 5 days, but it may be adjusted depending on the patient's condition and response to therapy. Treatment of herpes encephalitis usually lasts 10 days. Treatment of herpes simplex virus infections in newborns lasts usually 14 days when skin and mucous membranes are affected, and 21 days when there is dissemination or central nervous system involvement.

The duration of prophylactic use of Zovirax for intravenous administration is determined by the length of the infection risk period.

For the treatment of infections caused by herpes simplex virus (excluding herpes encephalitis) or Varicella zoster virus, Zovirax for intravenous administration should be given at a dose of 5 mg/kg body weight every 8 hours, assuming normal renal function.

For the treatment of Varicella zoster virus infections in immunocompromised patients or in patients with herpes encephalitis, Zovirax for intravenous administration should be given at a dose of 10 mg/kg body weight every 8 hours, assuming normal renal function.

For obese patients, the dose should be calculated based on ideal body weight rather than actual body weight.

Children

Dosages for children aged 3 months to 12 years are calculated per unit of body surface area.

For the treatment of infections caused by herpes simplex virus (excluding herpes encephalitis) or Varicella zoster virus, Zovirax for intravenous administration should be given at a dose of 250 mg/m² body surface area every 8 hours, assuming normal renal function.

For the treatment of Varicella zoster virus infections in immunocompromised children or children with herpes encephalitis, Zovirax for intravenous administration should be given at a dose of 500 mg/m² body surface area every 8 hours, assuming normal renal function.

The dose of Zovirax for intravenous administration in newborns and infants under 3 months of age is calculated based on the child's body weight.

The recommended treatment regimen for newborns and infants under 3 months of age with herpes simplex virus infection is 20 mg/kg body weight every 8 hours for 21 days in disseminated disease or central nervous system involvement, or for 14 days in cases limited to skin and mucous membranes.

Dosage in children and infants with impaired renal function should be adjusted according to the degree of impairment (see Patients with Renal Impairment).

Elderly Patients

Renal function impairment should be considered in elderly patients, and the dose should be adjusted accordingly (see Patients with Renal Impairment). Adequate hydration should be maintained.

Patients with Renal Impairment

Zovirax for intravenous administration should be used with caution in patients with renal impairment. Adequate hydration should be maintained.

The dosage adjustments listed below should be made according to creatinine clearance values.

Adults:

Creatinine clearance	Recommended dosage
25 – 50 mL/min	5-10 mg/kg body weight every 12 hours
10 – 25 mL/min	5-10 mg/kg body weight every 24 hours
0 (anuria) – 10 mL/min	For patients undergoing long-term ambulatory peritoneal dialysis or hemodialysis, 2.5-5 mg/kg every 24 hours and after hemodialysis session

Children:

Creatinine clearance	Recommended dosage
25 – 50 mL/min/1.73 m²	250-500 mg/kg/m² body surface area or 20 mg/kg body weight every 12 hours
10 – 25 mL/min/1.73 m²	250-500 mg/kg/m² body surface area or 20 mg/kg body weight every 24 hours
0 (anuria) – 10 mL/min/1.73 m²	For patients on long-term ambulatory peritoneal dialysis or hemodialysis, 125-250 mg/kg/m² body surface area or 10 mg/kg body weight every 24 hours and after a hemodialysis session

Route of administration

The required dose of Zovirax is administered by slow intravenous infusion over a period of not less than 1 hour, regardless of the dose administered.

First, the contents of the Zovirax vial for intravenous administration must be dissolved in an appropriate volume of Water for Injections or 0.9% Sodium Chloride Solution for Injections. To obtain a solution containing 25 mg of acyclovir per 1 ml, 250 mg of the drug should be dissolved in 10 ml of solvent.

After adding the liquid, gently shake the vial until the contents are completely dissolved.

To prepare the solution for intravenous infusion, the solution prepared as described above should be further diluted to achieve a concentration of not more than 5 mg/ml (0.5%): the solution obtained after dissolving 250 mg of acyclovir in 10 ml of Water for Injections (or 0.9% Sodium Chloride Solution) is added to the chosen infusion fluid as specified below.

For children and infants, when it is necessary to minimize the volume of infused liquid, it is recommended that 4 ml of the diluted solution (100 mg of acyclovir) be added to 20 ml of infusion fluid.

For adults, the recommended volume of infusion fluid should be at least 100 ml, even if the acyclovir concentration is lower than 0.5%. Therefore, 100 ml of infusion fluid should be used for administering Zovirax at doses of 250 mg and 500 mg (10 or 20 ml of the diluted solution). If higher doses of the drug are required (500–1000 mg of acyclovir), the volume of infusion fluid should be increased to 200 ml.

After reconstitution as recommended above, Zovirax for intravenous administration is compatible with the following infusion fluids and remains stable for 12 hours at room temperature (15°C–25°C):

• 0.45% or 0.9% Sodium Chloride Solution;
• 0.18% Sodium Chloride and 4% Glucose Solution;
• 0.45% Sodium Chloride and 2.5% Glucose Solution;
• Hartmann’s Solution.

When preparing intravenous infusion solutions as described above, the resulting concentration of acyclovir does not exceed 0.5%.

Since Zovirax for intravenous administration does not contain any antimicrobial preservatives, reconstitution and dilution of the drug must be performed under aseptic conditions immediately before use, and any unused portions of the solution must be discarded.

If cloudiness or crystallization occurs, such solutions are unsuitable for use and must be destroyed.

Children. Can be used from birth.

Overdose.

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

Acyclovir is effectively eliminated from the blood by hemodialysis; therefore, this method can be successfully used in the treatment of drug overdose.

Adverse Reactions

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

Uncommon: decreased hematological parameters (anemia, thrombocytopenia, leukopenia).

Immune System

Very rare: anaphylaxis.

Psychiatric and Nervous System Disorders

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

The above neurological reactions are generally reversible and usually occur during treatment of patients with renal impairment and other risk factors (see section "Special Warnings and Precautions for Use").

Cardiovascular System

Common: phlebitis.

Respiratory System and Thoracic Organs

Very rare: dyspnea.

Gastrointestinal System

Common: nausea, vomiting.

Very rare: diarrhea, abdominal pain.

Hepatobiliary System

Common: reversible increase in liver enzyme levels.

Very rare: reversible increase in bilirubin levels, jaundice, hepatitis.

Skin and Subcutaneous Tissues

Common: pruritus, urticaria, rash (including photosensitivity).

Uncommon: diffuse, accelerated hair loss. Since hair loss may be associated with a wide range of diseases and medications, a definite association with acyclovir has not been established.

Very rare: angioneurotic edema.

Renal and Urinary System

Common: increased blood urea and creatinine levels.

This may be related to disturbances in water and electrolyte balance. To avoid this effect, the drug must not be administered as an intravenous bolus, but only by slow infusion over at least 1 hour.

Very rare: renal dysfunction, acute renal failure, renal pain.

Adequate hydration should be maintained in these patients. Renal function abnormalities are usually rapidly reversible following rehydration therapy and/or dose reduction or complete discontinuation of the drug. However, development of acute renal failure may occur in exceptional cases.

Renal pain may be associated with renal impairment and crystalluria.

General Disorders

Very rare: fatigue, fever, local inflammatory reactions.

Severe local inflammatory reactions, sometimes leading to skin damage, may occur following intravenous administration of Zovirax when the drug inadvertently leaks into surrounding tissues.

Incompatibilities. No data available.

Shelf Life.

5 years.

Storage Conditions.

Store at temperatures not exceeding 25 °C. Keep out of the reach of children. Do not freeze the reconstituted solution.

Packaging. Lyophilisate in glass vials. 5 vials in a blister pack, contained in a cardboard box.

Prescription Category. Prescription only.

Manufacturer. GlaxoSmithKline Manufacturing S.p.A. (Italy)

GlaxoSmithKline Manufacturing S.p.A. (Italy)

Manufacturer's Name and Address.

GlaxoSmithKline Manufacturing S.p.A.,

Strada Provinciale Asolana 90, (loc. San Polo) – 43056 Torrile (Parma), Italy.

GlaxoSmithKline Manufacturing S.p.A.,

Strada Provinciale Asolana 90, (loc. San Polo) – 43056 Torrile (Parma), Italy.