Instructions for use Herpevir powder for solution for injection 250 mg vial No. 10
Composition
active ingredient: aciclovir;
1 vial contains sterile acyclovir sodium salt equivalent to acyclovir – 250 mg.
Dosage form
Powder for solution for injection.
Main physicochemical properties: white powder.
Pharmacotherapeutic group
Antiviral agents for systemic use. ATX code J05A B01.
Pharmacological properties
Pharmacodynamics
Acyclovir is a synthetic purine nucleoside analogue with high in vitro and in vivo activity against herpes viruses, including herpes simplex virus types I and II, Varicella zoster virus, Epstein-Barr virus, and cytomegalovirus. In cell culture, acyclovir has the greatest activity against herpes simplex virus type I, followed, in decreasing order of activity, by 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 a normal uninfected cell does not use acyclovir as a substrate, so it has very low toxicity to human cells. However, the thymidine kinase encoded in the above viruses converts acyclovir to acyclovir monophosphate, a nucleoside analogue, which is further converted to a diphosphate, then to a triphosphate. Acyclovir triphosphate interacts with viral DNA polymerase and inhibits viral DNA replication.
With prolonged or repeated courses of treatment of seriously ill patients with reduced immunity, cases of reduced sensitivity of individual virus strains may occur, which may not respond to treatment with acyclovir. Most clinical cases of insensitivity are associated with a deficiency of viral thymidine kinase, but there are reports of damage to thymidine kinase and DNA polymerase. In vitro interaction of individual herpes simplex viruses with acyclovir may also lead to the formation of less sensitive strains. The relationship between the sensitivity of individual herpes simplex viruses in vitro and the clinical results of treatment with acyclovir has not been fully elucidated.
Pharmacokinetics
In adults, the terminal half-life of intravenous acyclovir is approximately 2.9 hours. Most of the drug is excreted unchanged by the kidneys. Renal clearance of acyclovir is significantly higher than creatinine clearance, which indicates that the drug is excreted by the kidneys not only by glomerular filtration, but also by tubular secretion.
9-Carboxymethoxymethylguanine is the only major metabolite of acyclovir and accounts for approximately 10–15% of the amount excreted in the urine. When acyclovir is administered one hour after 1 gram of probenecid, the terminal half-life and area under the concentration-time curve increase by 18% and 40%, respectively.
In adults, the mean steady-state maximum plasma concentrations of acyclovir (Cssmax) after a 1-hour infusion of 2.5 mg/kg, 5 mg/kg, 10 mg/kg and 15 mg/kg were 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 corresponding steady-state minimum plasma concentrations of acyclovir (Cssmin) after 7 hours 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 µg/ml). In children aged 1 year and older, similar Cssmax and Cssmin levels were observed when the 250 mg/m2 dose was changed to 5 mg/kg and the 500 mg/m2 dose was changed to 10 mg/kg.
In neonates and infants up to 3 months of age treated with 10 mg/kg intravenously over 1 hour 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 of 83.5 μmol (18.8 μg/ml) and Cmin of 14.1 μmol (3.2 μg/ml).
In the elderly, total clearance decreased with age, resulting from decreased creatinine clearance and small changes in terminal half-life.
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 are reduced by approximately 60% during dialysis.
The concentration of the drug in the cerebrospinal fluid is approximately 50% of the corresponding concentration in plasma. The level of binding to plasma proteins is relatively low (9–33%) and does not change when interacting with other drugs.
Indication
Treatment of herpes simplex virus infections in immunocompromised patients and severe genital herpes in non-immunocompromised patients. Prevention of herpes simplex virus infections in immunocompromised patients. Treatment of Varicella zoster virus infections. Treatment of herpetic encephalitis. Treatment of herpes simplex virus infections in neonates and infants up to 3 months of age.
Contraindication
Hypersensitivity to acyclovir, valacyclovir.
Interaction with other medicinal products and other types of interactions
No clinically significant interactions of acyclovir with other drugs have been identified.
Acyclovir is mainly excreted unchanged by the kidneys by tubular secretion, therefore any drugs with a similar mechanism of excretion may increase the plasma concentration of acyclovir.
Probenecid and cimetidine prolong the half-life of acyclovir and increase the area under the concentration-time curve, but given the wide therapeutic index of acyclovir, dose adjustment is not necessary.
In patients who are simultaneously treated with Herpevir for intravenous administration and other drugs with a similar mechanism of excretion, an increase in the plasma concentration of one or both drugs or their metabolites is possible. With simultaneous use of acyclovir with an immunosuppressant used in the treatment of patients after organ transplantation - mycophenolate mofetil - the plasma level of acyclovir and the inactive metabolite of mycophenolate mofetil also increases.
When lithium is used concomitantly with high-dose intravenous acyclovir, serum lithium concentrations should be carefully monitored due to the risk of lithium toxicity.
Caution (with monitoring of renal function) is also required when prescribing Herpevir for intravenous administration with drugs that affect renal function (such as cyclosporine, tacrolimus).
In a pilot study in five men, concomitant acyclovir therapy was shown to increase the AUC of fully administered theophylline by approximately 50%. It is recommended that plasma concentrations be measured during concomitant acyclovir therapy.
Application features
Adequate hydration levels should be maintained in patients receiving intravenous acyclovir or high doses of oral acyclovir.
Intravenous doses should be administered by infusion over one hour to avoid renal deposition of acyclovir. Rapid or bolus injection should be avoided.
The risk of renal damage is increased by the use of other nephrotoxic drugs. Caution should be exercised when administering intravenous acyclovir with other nephrotoxic drugs.
Patients with renal insufficiency and elderly patients
Acyclovir is excreted mainly by the kidneys, so the dose should be reduced in patients with renal insufficiency (see section "Method of administration and dosage"). Elderly patients are also more likely to have impaired renal function, so the dose may also be reduced in this group of patients. Both these groups (patients with renal insufficiency and elderly patients) are at risk of developing neurological adverse reactions and should therefore be closely monitored. Such reactions are generally reversible upon discontinuation of treatment with the drug (see section "Adverse reactions").
Prolonged or repeated courses of acyclovir treatment in severely immunocompromised individuals may result in the isolation of viral strains with reduced susceptibility that may not respond to prolonged acyclovir treatment.
If the patient receives high doses of the drug intravenously, for example for the treatment of herpetic encephalitis, renal function indicators should be taken into account, especially in cases of dehydration or the presence of renal failure.
Diluted Herpevir® for intravenous infusion has a pH of approximately 10.7 to 11.7 and should not be administered orally. The product contains 24.4 mg of sodium. This should be taken into account if the patient is on a controlled sodium diet.
Ability to influence reaction speed when driving vehicles or other mechanisms
Herpevir® for intravenous administration is mainly used for the treatment of patients who are inpatients, therefore information on the effect on the ability to drive and use machines is usually not necessary. Studies on the effect of the drug on the ability to drive and use machines have not been conducted.
Use during pregnancy or breastfeeding
There is no information 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 per day for six months showed no clinically significant effects on sperm count, motility, or morphology.
A post-marketing surveillance registry has documented the use of various pharmaceutical formulations of acyclovir in pregnant women. There has been no increase in the number of birth defects in children whose mothers used acyclovir during pregnancy compared with the general population. However, acyclovir for infusion should be used only in cases where the potential benefit to the mother outweighs the potential risk to the fetus.
When 200 mg of acyclovir is administered orally 5 times a day, acyclovir is excreted in breast milk at concentrations that are 0.6–4.1 times the plasma acyclovir level. A child fed this milk could potentially absorb up to 0.3 mg/kg of body weight per day of acyclovir. Caution should be exercised when prescribing acyclovir to breastfeeding women, taking into account the risk/benefit ratio.
Method of administration and doses
Administer by slow intravenous infusion over at least 1 hour.
The course of treatment with Herpevir for intravenous administration usually lasts 5 days, but the duration can be changed depending on the patient's condition and the respective response to therapy. Treatment of herpetic encephalitis usually lasts 10 days. Treatment of infections in newborns caused by the herpes simplex virus usually lasts 14 days for skin and mucous membrane lesions and 21 days for dissemination and central nervous system lesions.
The duration of prophylactic use of Herpevir for intravenous administration is determined by the duration of the period of risk of infection.
For the treatment of infections caused by the herpes simplex virus (except for herpetic encephalitis) or Varicella zoster virus, Herpevir® for intravenous administration should be administered at a dose of 5 mg/kg body weight every 8 hours, provided that renal function is normal.
For the treatment of infections caused by the Varicella zoster virus in immunocompromised patients or patients with herpetic encephalitis, Herpevir® for intravenous administration should be administered at a dose of 10 mg/kg body weight every 8 hours, provided that renal function is normal.
Obese patients should be dosed based on ideal, not 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 the herpes simplex virus (except for herpetic encephalitis) or Varicella zoster virus, Herpevir® for intravenous administration should be administered at a dose of 250 mg/m2 of body surface area every 8 hours, provided that renal function is normal.
For the treatment of infections caused by the Varicella zoster virus in children with immunodeficiency or with herpetic encephalitis, Herpevir® for intravenous administration is prescribed at a dose of 500 mg/m2 of body surface area every 8 hours, provided that kidney function is normal.
The dose of Gerpevir for intravenous administration to 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 up to 3 months of age with infection caused by the herpes simplex virus is 20 mg/kg/body weight every 8 hours for 21 days for disseminated form and central nervous system involvement or 14 days for disease limited to the skin and mucous membranes.
In children and infants with impaired renal function, the dose should be modified according to the degree of impairment of this function (see “Patients with renal insufficiency” below).
Elderly patients
The possibility of decreased renal function in elderly patients should be considered and the dose should be adjusted accordingly (see “Patients with renal impairment” below). Adequate hydration should be maintained.
Patients with renal failure
Intravenous Herpevir® should be used with caution in patients with renal insufficiency. Adequate hydration should be maintained.
The following dosage adjustments should be made based on creatinine clearance.
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 on long-term ambulatory peritoneal dialysis or hemodialysis, 2.5–5 mg/kg every 24 hours and after hemodialysis sessions |
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 sessions |
Method of administration
The required dose of Herpevir is administered by slow intravenous infusion over a period of at least 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 injection or 0.9% sodium chloride solution for injection. To obtain a solution containing 25 mg of acyclovir per ml, 250 mg of the drug is dissolved in 10 ml of liquid.
After adding the liquid, shake the bottle lightly until its contents are completely dissolved.
To obtain a solution for intravenous administration, the solution prepared as described above is further diluted to a concentration of not more than 5 mg/ml (0.5%): the solution formed after dissolving 250 mg of acyclovir in 10 ml of water for injection (or 0.9% sodium chloride solution) is added to the selected infusion solution, as described below.
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 the administration of Gerpevir in doses of 250 mg and 500 mg (10 or 20 ml of diluted solution). If it is necessary to use higher doses of the drug (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 fluids for the preparation of infusion solutions 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 solutions for intravenous infusions, as indicated above, an acyclovir concentration of no more than 0.5% is formed.
Due to the fact that Herpevir® for intravenous administration does not contain any antimicrobial preservatives, dissolution and dilution of the drug should be carried out under aseptic conditions immediately before use, and unused solution residues should be disposed of.
If turbidity or crystallization appears, such solutions are unsuitable for use and must be destroyed.
Children
Apply from birth.
Overdose
Overdose of acyclovir by intravenous administration increases serum creatinine, blood urea nitrogen and, thus, renal failure occurs. Neurological manifestations of overdose may include confusion, hallucinations, agitation, convulsions and coma.
Acyclovir is very well eliminated from the blood by hemodialysis, so this method can be successfully used in the treatment of drug overdose.
Adverse reactions
The adverse reactions listed below are classified by system organ class and by frequency. The frequency categories are: 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: decreased hematological parameters (anemia, thrombocytopenia, leukopenia).
Immune system.
Very rare: anaphylaxis.
Mental and nervous system disorders.
Very rare: headache, dizziness, agitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, convulsions, drowsiness, encephalopathy, coma.
The above neurological reactions are generally reversible and are usually observed in patients with renal insufficiency and other risk factors (see section "Special warnings and precautions for use").
Cardiovascular system.
Common: phlebitis.
Respiratory system and chest organs.
Very rare: shortness of breath.
Gastroenterological system.
Common: nausea, vomiting.
Very rare: diarrhea, abdominal pain.
Hepatobiliary system.
Common: reversible elevations in liver enzymes.
Very rare: reversible increase in bilirubin levels, jaundice, hepatitis.
Skin and subcutaneous tissues.
Common: itching, urticaria, rash (including photosensitivity).
Uncommon: accelerated diffuse hair loss. Since hair loss can be associated with a large number of diseases and drugs, no clear association with acyclovir has been identified.
Very rare: angioedema.
Kidneys and urinary system.
Common: increased blood urea and creatinine levels.
This may be due to a violation of water and electrolyte metabolism. In order to avoid this effect, the drug should not be administered by intravenous bolus, but only by slow infusion lasting at least 1 hour.
Very rare: renal dysfunction, acute renal failure, kidney pain.
Adequate hydration should be maintained in these patients. Impaired renal function usually resolves rapidly after rehydration therapy and/or dose reduction or complete discontinuation of the drug. However, the development of acute renal failure may occur in exceptional cases.
Kidney pain may be associated with renal failure and crystalluria.
General disorders.
Very rare: fatigue, fever, local inflammatory reactions.
Severe local inflammatory reactions, sometimes leading to skin damage, have been observed with intravenous administration of acyclovir when it inadvertently enters the perivascular tissues.
Expiration date
5 years.
Storage conditions
In the original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Packaging
250 mg per vial; 10 vials per pack.
Vacation category
According to the recipe.
Producer
PJSC "Kyivmedpreparat".
Location of the manufacturer and its business address
Ukraine, 01032, Kyiv, Saksaganskoho St., 139.
