Herpervir

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT HERPEVIR® (HERPEVIR®)

Composition:

Active substance: acyclovir;

1 vial contains acyclovir – 250 mg;

Excipient: sodium hydroxide.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: lyophilized powder of white or almost white color.

Pharmacotherapeutic group. Antiviral agents for systemic use.

ATC code J05A B01.

Pharmacological properties.

Pharmacodynamics.

Acyclovir is a synthetic analogue of a purine nucleoside 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, thus 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 diphosphate and then into triphosphate. Acyclovir triphosphate interacts with viral DNA polymerase and inhibits viral DNA replication.

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

Pharmacokinetics.

In neonates and infants up to 3 months of age treated with intravenous administration of 10 mg/kg over 1 hour every 8 hours, the steady-state maximum concentration (Cssmax) was 61.2 µmol (13.8 µg/mL), and the steady-state minimum concentration (Cssmin) was 10.1 µmol (2.3 µg/mL). In another group of neonates and infants up to 3 months of age treated with 15 mg/kg every 8 hours, 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 from the gastrointestinal tract. The average bioavailability after oral administration ranges between 10–20%. The mean peak concentration (Cmax) of acyclovir is approximately 0.4 µg/mL, reached about 1.6 hours after fasting oral administration of a 200 mg dose. The average peak steady-state plasma concentration (Cssmax) increases to 0.7 µg/mL (3.1 µmol) 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 significantly with concomitant medication use. The concentration of the drug 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

The 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 half-life after oral administration of acyclovir ranges from 2.8 to 4.1 hours. The terminal half-life of acyclovir after intravenous administration in adults 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 up to 3 months of age receiving intravenous acyclovir at 10 mg/kg over 1 hour every 8 hours, the terminal half-life was 3.8 hours.

Special patient groups

Elderly patients

In elderly patients, total clearance is reduced according to age, as a result of decreased creatinine clearance and minor changes in terminal half-life. Impaired renal function may occur in elderly patients; therefore, the dose of the drug should be adjusted accordingly.

Renal impairment

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

Increased body weight

In a clinical study, female patients (n=7) with obesity received intravenous acyclovir dosed 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.

Prophylaxis 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 newborns and infants up to 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.

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; however, due to the wide therapeutic index of acyclovir, dose adjustment is not required.

In patients receiving intravenous acyclovir concomitantly with other medicinal products that have a similar elimination pathway, there may be a potential increase in plasma concentrations of one or both drugs or their metabolites. When acyclovir is administered concomitantly with an immunosuppressant used in the treatment of organ transplant patients—mycophenolate mofetil—plasma levels of both acyclovir and the inactive metabolite of mycophenolate mofetil are 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 Herpevir® intravenously with medicinal products that affect renal function (such as cyclosporine, tacrolimus).

An experimental study in five male subjects indicates that concomitant therapy with acyclovir increases the AUC of orally administered theophylline by approximately 50%. Monitoring 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 one-hour infusion to avoid acyclovir precipitation in the kidneys. Rapid or bolus injection must be avoided.

The risk of renal damage increases when other nephrotoxic medicinal products are used. Caution is necessary when administering intravenous acyclovir concomitantly with other nephrotoxic medicinal products.

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 section "Dosage and administration"). Elderly patients are also more likely to have impaired renal function, and thus dose adjustment may be necessary in this patient group. 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. Available data indicate that such reactions are generally reversible upon discontinuation of the drug (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, e.g. for the treatment of herpes encephalitis, renal function parameters should be taken into account, especially in cases of dehydration or existing renal impairment.

Diluted Herpevir® for intravenous infusion has a pH of approximately 10.7 to 11.7 and must not be administered orally.

The medicinal product contains sodium – 24.4 mg. This should be taken into consideration if the patient is on a sodium-controlled 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 count, no clinically significant effect on sperm count, motility, or morphology was observed following oral administration of up to 1 g per day for six months.

A post-marketing pregnancy registry has documented outcomes of various pharmaceutical forms of acyclovir used during pregnancy. No increased incidence of congenital malformations has been observed in children whose mothers used acyclovir during pregnancy compared to the general population. However, intravenous acyclovir should be used during pregnancy only if the potential benefit to the mother outweighs the possible risk to the fetus.

Following oral administration of 200 mg acyclovir five times daily, acyclovir is excreted into breast milk at concentrations of 0.6–4.1 times the plasma level of acyclovir. A breastfed infant may potentially absorb 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 reaction speed when driving or operating machinery.

Herpevir® for intravenous administration 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. Studies specifically investigating the effect of the medicinal product on the ability to drive or operate machinery have not been conducted.

Administration and Dosage

Administer by slow intravenous infusion over a period of at least 1 hour.

The treatment course with the medicinal product Herpevir® for intravenous administration usually lasts 5 days, but the duration may be adjusted depending on the patient's condition and response to therapy. Treatment of herpes encephalitis typically lasts 10 days. Treatment of herpes simplex virus infections in newborns usually lasts 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 Herpevir® 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, Herpevir® for intravenous administration should be administered 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 patients with herpes encephalitis, Herpevir® for intravenous administration should be administered at a dose of 10 mg/kg body weight every 8 hours, assuming normal renal function.

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

Children

Doses 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, Herpevir® for intravenous administration should be administered 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, Herpevir® for intravenous administration should be administered at a dose of 500 mg/m² body surface area every 8 hours, assuming normal renal function.

The dosage of Herpevir® for intravenous administration in newborns and infants under 3 months of age is based on 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 cases of disseminated disease or central nervous system involvement, or 14 days for disease limited to skin and mucous membranes.

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

Geriatric Patients

Renal function impairment should be considered in geriatric patients, and the dosage of the medicinal product should be adjusted accordingly (see "Patients with Renal Impairment" below). Adequate hydration should be maintained.

Patients with Renal Impairment

Herpevir® should be used with caution when administered intravenously for the treatment of 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/m² body surface area or 20 mg/kg body weight every 12 hours
10–25 mL/min/1.73 m²	250–500 mg/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/m² body surface area or 10 mg/kg body weight every 24 hours and after hemodialysis session

Administration method

The required dose of Herpevir® should be administered by slow intravenous infusion over a period of not less than 1 hour, regardless of the dose administered.

First, the contents of the Herpevir® 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, dissolve 250 mg of the drug in 10 ml of solvent.

After adding the solvent, 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) should be 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 to add 4 ml of the diluted solution (100 mg of acyclovir) 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 Herpevir® 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, Herpevir® for intravenous administration is compatible with the following infusion fluids and remains stable for 12 hours at room temperature (15–25 °C):

• 0.45% or 0.9% sodium chloride solution;
• 0.18% sodium chloride solution and 4% glucose solution;
• 0.45% sodium chloride solution and 2.5% glucose solution;
• Hartmann’s solution.

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

Since Herpevir® 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 symptoms of overdose may include confusion, hallucinations, agitation, seizures, and coma.

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

Side effects

The adverse reactions listed below are classified by system organ class and frequency of occurrence. Frequency categories are: 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 disorders

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

Immune system disorders

Very rare: anaphylaxis.

Psychiatric and nervous system disorders

Very rare: headache, dizziness, excitation, 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 precautions for use").

Cardiovascular system disorders

Common: phlebitis.

Respiratory, thoracic and mediastinal disorders

Very rare: dyspnea.

Gastrointestinal disorders

Common: nausea, vomiting.

Very rare: diarrhea, abdominal pain.

Hepatobiliary disorders

Common: reversible increase in liver enzyme levels.

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

Skin and subcutaneous tissue disorders

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 clear association with acyclovir has not been established.

Very rare: angioneurotic edema.

Renal and urinary disorders

Common: increased blood urea and creatinine levels.

This may be related to fluid and electrolyte imbalance. To avoid this effect, the medicinal product should not be administered as an intravenous bolus, but only by slow infusion over a period of not less than 1 hour.

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

Adequate hydration of these patients should be maintained. Renal dysfunction is usually rapidly reversible after rehydration therapy and/or dose reduction or complete discontinuation of the medicinal product. 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 acyclovir when the drug inadvertently leaks into surrounding tissues.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

1 year.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibilities

The medicinal product should not be mixed with other solutions except those specified in the section "Dosage and administration".

Packaging

10 vials with powder in a blister pack, contained in a cardboard box.

Prescription status

Prescription only.

Manufacturer

JSC "Kyivmedpreparat".

Manufacturer's address and place of business

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.