Herpervir

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GHERPEVIR® (HERPEVIR)

Composition:

Active substance: aciclovir;

1 vial contains sterile sodium aciclovir equivalent to aciclovir – 250 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white powder.

Pharmacotherapeutic group. Antiviral agents for systemic use.

ATC code J05A B01.

Pharmacological Properties.

Pharmacodynamics.

Aciclovir is a synthetic analogue of 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, aciclovir 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 aciclovir against herpes simplex virus types I and II, Varicella zoster virus, and Epstein-Barr virus is highly selective. The enzyme thymidine kinase in normal uninfected cells does not use aciclovir as a substrate, thus it has very low toxicity towards human cells. However, thymidine kinase encoded by the aforementioned viruses converts aciclovir into aciclovir monophosphate, a nucleoside analogue, which is further transformed into diphosphate and then into triphosphate. Aciclovir triphosphate interacts with viral DNA polymerase and inhibits viral DNA replication.

With prolonged or repeated treatment courses in severely ill patients with impaired immunity, cases of reduced sensitivity of individual viral strains may occur, which may not respond to aciclovir treatment. 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 exposure of certain herpes simplex virus strains to aciclovir may also lead to the emergence of less sensitive strains. The correlation between in vitro sensitivity of individual herpes simplex virus strains and clinical response to aciclovir treatment has not been fully established.

Pharmacokinetics.

In adults, the terminal half-life after intravenous administration of aciclovir is approximately 2.9 hours. The majority of the drug is excreted unchanged by the kidneys. Renal clearance of aciclovir is significantly higher than creatinine clearance, indicating that the drug is eliminated by the kidneys through both glomerular filtration and tubular secretion.

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

In adults, mean peak plasma concentrations at steady state (Cssmax) after a 1-hour infusion of 2.5 mg/kg, 5 mg/kg, 10 mg/kg, and 15 mg/kg are 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. Corresponding minimum plasma concentrations at steady state (Cssmin) measured 7 hours later were 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). In children aged 1 year and older, similar Cssmax and Cssmin levels were observed when the dose of 250 mg/m² was replaced with 5 mg/kg and the dose of 500 mg/m² was replaced with 10 mg/kg.

In neonates and infants up to 3 months of age treated with a 1-hour intravenous infusion of 10 mg/kg every 8 hours, Cssmax was 61.2 µmol (13.8 µg/mL) and Cssmin was 10.1 µmol (2.3 µg/mL). The terminal half-life in these patients was 3.8 hours. In a separate group of neonates and infants up to 3 months of age treated with 15 mg/kg every 8 hours, approximately dose-proportional increases were observed, with Cmax at 83.5 µmol (18.8 µg/mL) and Cmin at 14.1 µmol (3.2 µg/mL).

In elderly individuals, total clearance decreases with age, a consequence of reduced creatinine clearance as well as minor changes in terminal half-life.

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

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

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 neonates and infants under 3 months of age.

Contraindications.
Hypersensitivity to acyclovir, valacyclovir.

Interaction with other medicinal products and other forms of interactions.

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 Herpevir concomitantly with other drugs eliminated via a similar mechanism, increased plasma concentrations of one or both drugs or their metabolites may occur. When acyclovir is used concomitantly with an immunosuppressant used in transplant patients—mycophenolate mofetil—plasma levels of both acyclovir and the inactive metabolite of mycophenolate mofetil may increase.

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 intravenous Herpevir with drugs affecting renal function (such as cyclosporine, tacrolimus).

An experimental study involving five male subjects revealed 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 should 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 should be avoided.

The risk of renal impairment increases when other nephrotoxic agents are used. Caution should be exercised when administering intravenous acyclovir concomitantly with other nephrotoxic drugs.

Patients with renal impairment and elderly patients

Acyclovir is primarily eliminated via the kidneys; therefore, dosage adjustment is required in patients with renal impairment (see section "Dosage and administration"). Elderly individuals are also more likely to have impaired renal function, so dose reduction may be necessary in this patient group as well. Both of these groups (patients with renal impairment and elderly patients) are at increased risk of neurological adverse reactions and should be closely monitored. 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 immunity may lead to the emergence of viral strains with reduced sensitivity, which may not respond to prolonged acyclovir therapy.

If a patient is 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 Herpevir® for intravenous infusion has a pH of approximately 10.7 to 11.7 and must not be administered orally. The 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 involving 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.

In a post-marketing pregnancy registry, outcomes of various acyclovir formulations used during pregnancy were documented. No increased incidence of congenital malformations was observed in children born to mothers who used acyclovir during pregnancy compared to the general population. However, intravenous acyclovir should only be used during pregnancy 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 is excreted into breast milk at concentrations of 0.6–4.1 times the plasma level. A nursing infant may potentially receive up to 0.3 mg acyclovir per kg body weight daily. Acyclovir should be used with caution in breastfeeding women, taking into account the risk-benefit ratio.

Ability to affect the speed of reactions 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. No studies have been conducted to evaluate the effect of this medicinal product on the ability to drive or operate machinery.

Method of administration and dosage.

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

The usual duration of treatment with Herpevir for intravenous administration is 5 days, but may be adjusted depending on the patient's condition and response to therapy. Treatment of herpes encephalitis usually lasts 10 days. Treatment of neonatal infections caused by herpes simplex virus typically lasts 14 days when involving skin and mucous membranes, and 21 days when disseminated disease or central nervous system involvement is present.

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 (except 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 infections caused by Varicella zoster virus in immunocompromised patients or in 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.

For 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 (except 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 infections caused by Varicella zoster virus 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 dose of Herpevir for intravenous administration in neonates and infants under 3 months of age is calculated based on body weight.

The recommended treatment regimen for neonates 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 impairment (see "Patients with renal impairment" below).

Elderly patients

Renal function impairment should be considered in elderly patients, and dosage should be adjusted accordingly (see "Patients with renal impairment" below). Adequate hydration should be maintained.

Patients with renal impairment

Herpevir® 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 based on creatinine clearance values.

Adults:

Children:

Route of administration

The required dose of Gerpevir is administered by slow intravenous infusion over a period of at least 1 hour, regardless of the dose administered.

First, the contents of the Gerpevir 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 liquid.

After adding the liquid, gently shake the vial until its 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 no 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 to administer Gerpevir at doses of 250 mg and 500 mg (10 or 20 ml of 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, Gerpevir® 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, a concentration of acyclovir of not more than 0.5% is obtained.

Since Gerpevir® for intravenous administration does not contain any antimicrobial preservatives, reconstitution and dilution 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.

May be used from birth.

Overdose.

In cases 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 efficiently removed from the blood by hemodialysis; therefore, this method can be successfully used in the treatment of drug overdose.

Adverse Reactions

The adverse effects listed below are classified by organ systems and frequency of occurrence. Frequency categories: very common ≥ 1/10, common ≥ 1/100 and < 1/10, uncommon ≥ 1/1000 and < 1/100, rare ≥ 1/10000 and < 1/1000, very rare < 1/10000.

Blood and lymphatic system.

Uncommon: hematological parameter reductions (anemia, thrombocytopenia, leukopenia).

Immune system.

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.

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 hair loss. Since hair loss may be associated with a large number of diseases and medications, a definite link 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-electrolyte balance. 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 function impairment, acute renal failure, renal pain.

Adequate hydration of these patients should be maintained. Renal function disturbances are usually rapidly reversible after rehydration therapy and/or dose reduction or complete discontinuation of the medicinal product. However, development of acute renal failure may exceptionally occur.

Renal pain may be associated with renal impairment and crystalluria.

General disorders.

Very rare: fatigue, fever, local inflammatory reactions.

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

Shelf life. 5 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

250 mg in vials; 10 vials in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of its business activity.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.