Herpevir

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

Composition:

Active ingredient: 1 tablet contains acyclovir calculated as 100% substance 200 mg
or 400 mg;

Excipients: potato starch, povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

200 mg tablets: white or almost white, round-shaped tablets with flat surface, bevelled edges and a score line;

400 mg tablets: white or almost white, round-shaped tablets with flat surface, bevelled edges, a score line and a groove;

Pharmacotherapeutic group. Antiviral agents for systemic use.

ATC code J05A B01.

Pharmacological Properties

Pharmacodynamics

Acyclovir is a synthetic purine nucleoside analogue with inhibitory activity in vivo and in vitro against human herpesviruses, including herpes simplex virus types I and II, varicella-zoster virus (chickenpox and herpes zoster), Epstein-Barr virus, and cytomegalovirus. In cell culture, acyclovir demonstrates the greatest 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 the aforementioned viruses is highly selective. The enzyme thymidine kinase in normal, uninfected cells does not utilize acyclovir as a substrate, thus minimizing toxic effects on host cells. However, the thymidine kinase encoded by herpes simplex viruses, varicella-zoster virus, and Epstein-Barr virus converts acyclovir into acyclovir monophosphate, a nucleoside analogue, which is then sequentially converted into diphosphate and triphosphate forms by cellular enzymes. After incorporation into viral DNA, acyclovir triphosphate interacts with viral DNA polymerase, resulting in termination of viral DNA chain synthesis.

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

Pharmacokinetics

Acyclovir is only partially absorbed from the gastrointestinal tract. The average peak steady-state plasma concentration (C_{ss max}) after a 200 mg dose administered every 4 hours is 3.1 µmol (0.7 µg/mL), with a corresponding trough plasma level (C_{ss min}) of 1.8 µmol (0.4 µg/mL). Corresponding C_{ss max} levels after 400 mg and 800 mg doses administered every 4 hours are 5.3 µmol (1.2 µg/mL) and 8 µmol (1.8 µg/mL), respectively, with corresponding C_{ss min} levels of 2.7 µmol (0.6 µg/mL) and 4 µmol (0.9 µg/mL).

In adults, the terminal elimination half-life following intravenous administration of acyclovir is approximately 2.9 hours. The majority of the drug is excreted unchanged by the kidneys. Renal clearance of acyclovir is substantially higher than creatinine clearance, indicating that renal elimination involves not only glomerular filtration but also tubular secretion.

9-Carboxymethoxymethylguanine is the only significant metabolite of acyclovir detectable in urine, accounting for approximately 10–15% of the administered dose. When acyclovir is administered one hour after 1 g of probenecid, the terminal elimination half-life and the area under the concentration-time curve (AUC) increase by 18% and 40%, respectively.

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.

Drug concentrations in cerebrospinal fluid are approximately 50% of the corresponding plasma concentrations. Plasma protein binding is relatively low (9–33%) and remains unchanged during co-administration with other drugs.

No pharmacokinetic interactions were observed between acyclovir and zidovudine when used concomitantly in the treatment of HIV-infected patients.

Clinical characteristics.

Indications.

• Treatment of viral infections of the skin and mucous membranes caused by herpes simplex virus, including primary and recurrent genital herpes.
• Suppression (prevention of recurrences) of infections caused by herpes simplex virus in patients with normal immunity.
• Prevention of infections caused by herpes simplex virus in immunocompromised patients.
• Treatment of infections caused by Varicella zoster virus (chickenpox and herpes zoster).

Contraindications. Hypersensitivity to acyclovir, valacyclovir, or to any other component 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 that have a similar elimination mechanism may increase acyclovir plasma concentrations. Probenecid and cimetidine prolong the elimination half-life and the area under the plasma concentration-time curve (AUC) of acyclovir. 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 increase. However, due to the wide therapeutic index of acyclovir, dose adjustment is not required.

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

Special precautions for use

Acyclovir is primarily eliminated from the body via renal clearance; therefore, the dose should be reduced in patients with renal impairment (see "Administration and dosage"). Elderly patients are also more likely to have reduced renal function, and thus may require dose adjustment. Patients with renal impairment and elderly patients are at risk groups for the development of neurological adverse reactions and should therefore be closely monitored for such reactions. Available data indicate that these reactions are generally reversible upon discontinuation of acyclovir therapy (see section "Adverse reactions"). Prolonged or repeated courses of acyclovir treatment in individuals with severely impaired immunity may lead to the emergence of viral strains with reduced susceptibility, which may not respond to prolonged acyclovir therapy.

Particular attention should be paid to maintaining adequate hydration in patients receiving high doses of acyclovir.

The risk of renal damage is increased when acyclovir is used concomitantly with other nephrotoxic agents.

Available clinical trial data are insufficient to conclude that acyclovir treatment reduces the incidence of complications associated with varicella in immunocompetent patients.

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, oral administration of acyclovir at doses up to 1 g per day for six months did not reveal any clinically significant effect on sperm count, motility, or morphology.

In a post-marketing surveillance registry of pregnant women, outcomes of exposure to various pharmaceutical forms of acyclovir during pregnancy have been documented.

No increased incidence of congenital malformations has been observed in children whose mothers used acyclovir during pregnancy compared to the general population. However, Herpevir tablets should be used during pregnancy only when 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% of the corresponding plasma acyclovir levels. A nursing infant may potentially ingest up to 0.3 mg acyclovir per kg body weight per day. Therefore, acyclovir should be administered to breastfeeding women with caution, taking into account the risk-benefit ratio.

Ability to influence reaction rate while driving or operating machinery

When considering the ability to drive a vehicle or operate machinery, the patient's clinical status and the drug's adverse reaction profile should be taken into account. Clinical studies on the effect of acyclovir on reaction speed during driving or operating machinery have not been conducted. Furthermore, the pharmacological profile of acyclovir does not suggest any expected negative impact.

Method of Administration and Dosage

The tablet should be taken whole, with water. When high doses of acyclovir are used, adequate hydration should be maintained.

Adults

Treatment of infections caused by herpes simplex virus

For treatment of infections caused by herpes simplex virus, acyclovir tablets should be taken at a dose of 200 mg five times daily at approximately 4-hour intervals, excluding the nighttime period.

Treatment should last 5 days, but may be prolonged in cases of severe primary infection.

For patients with severe immunodeficiency (e.g., after bone marrow transplantation) or those with reduced intestinal absorption, the dose may be doubled to 400 mg or the corresponding intravenous dose may be administered.

Treatment should be initiated as early as possible after the onset of infection. In recurrent herpes, treatment should ideally begin during the prodromal phase or immediately after the first signs of skin lesions appear.

Prevention of recurrences (suppressive therapy) of infections caused by herpes simplex virus

In immunocompetent patients, to prevent recurrences of herpes simplex virus infections, acyclovir tablets at a dose of 200 mg should be taken four times daily at approximately 6-hour intervals.

For convenience, most patients may take 400 mg of acyclovir twice daily at approximately 12-hour intervals.

Therapy may remain effective even when the dose is reduced to 200 mg of acyclovir taken three times daily at 8-hour intervals, or even twice daily at 12-hour intervals.

In some patients, significant improvement is observed with a total daily dose of acyclovir of 800 mg.

To monitor possible changes in the natural course of the disease, acyclovir therapy should be periodically interrupted at intervals of 6–12 months.

Prevention of infections caused by herpes simplex virus

For prevention of herpes simplex virus infections in immunocompromised patients, acyclovir tablets at a dose of 200 mg should be taken four times daily at approximately 6-hour intervals. For patients with significant immunodeficiency (e.g., after bone marrow transplantation) or those with reduced intestinal absorption, the dose may be doubled to 400 mg or the corresponding intravenous dose may be administered.

The duration of prophylaxis depends on the duration of the risk period.

Treatment of varicella and herpes zoster

For treatment of infections caused by varicella-zoster virus (chickenpox and herpes zoster), acyclovir tablets should be taken at a dose of 800 mg five times daily at approximately 4-hour intervals, excluding the nighttime period. Treatment should last 7 days.

For patients with severe immunodeficiency (e.g., after bone marrow transplantation) or those with reduced intestinal absorption, intravenous administration is preferred.

Treatment should be initiated as early as possible after the onset of disease. The outcome is better if treatment is started immediately after the appearance of rash.

Children

For treatment of herpes simplex virus infections and prevention of herpes simplex virus infections in immunocompromised children aged 2 years and older, adult doses may be used. For treatment of chickenpox in children aged 6 years and older, 800 mg of acyclovir should be administered four times daily. Children aged 2 to 6 years may receive 400 mg of acyclovir four times daily. The duration of treatment is 5 days.

The individual dose may be more precisely calculated based on body weight as 20 mg/kg (not exceeding 800 mg) of acyclovir four times daily.

There are no specific data on the use of acyclovir for prophylaxis (prevention of recurrences) of herpes simplex virus infections or for treatment of herpes zoster virus infections in immunocompetent children.

For treatment of herpesvirus infections in neonates and children under 3 months of age, Herpevir, powder for solution for injection, should be used.

Elderly patients

Renal function impairment should be considered in elderly patients, and dosage should be adjusted accordingly (see section «Renal Impairment» below). Adequate hydration should be maintained in elderly patients receiving high doses of acyclovir.

Renal Impairment

Acyclovir should be administered with caution in patients with renal impairment. Adequate hydration should be maintained.

For prophylaxis and treatment of herpes simplex virus infections in patients with renal impairment, the recommended oral doses do not lead to accumulation of acyclovir above the safe levels established for intravenous administration. However, in patients with severe renal impairment (creatinine clearance less than 10 mL/min), a dosage of 200 mg twice daily at approximately 12-hour intervals is recommended.

For treatment of Varicella zoster virus infections (chickenpox and herpes zoster) in immunocompromised patients, in cases of severe renal impairment (creatinine clearance less than 10 mL/min), a dosage of 800 mg twice daily at approximately 12-hour intervals is recommended; for patients with moderate renal impairment (creatinine clearance 10–25 mL/min), 800 mg three times daily at approximately 8-hour intervals is recommended.

Children

Acyclovir tablets are indicated for children aged 2 years and older.

Overdose.

Symptoms. Acyclovir is only partially absorbed from the gastrointestinal tract. Accidental oral intake of up to 20 g of acyclovir by patients has not resulted in toxic effects. However, accidental repeated overdose of oral acyclovir over several days may cause gastrointestinal symptoms (such as nausea and vomiting) and neurological symptoms (headache and confusion). In cases of intravenous acyclovir overdose, serum creatinine and blood urea nitrogen levels increase, leading to renal failure. Neurological manifestations of overdose may include confusion, hallucinations, agitation, seizures, and coma.

Treatment. The patient should be thoroughly examined to identify symptoms of intoxication. Since acyclovir is effectively removed by hemodialysis, hemodialysis should be employed in cases of overdose.

Adverse Reactions

Adverse reactions 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 — ≥ 1/10,000 and < 1/1000, very rare — < 1/10,000.

Blood and lymphatic system

Very rare: anemia, thrombocytopenia, leukopenia.

Immune system

Rare: anaphylaxis.

Psychiatric and nervous system disorders

Common: headache, dizziness.

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

The above neurological reactions are generally reversible and usually occur in patients with renal impairment or other risk factors (see section "Special precautions").

Respiratory system and thoracic organs

Rare: dyspnea.

Gastrointestinal system

Common: nausea, vomiting, diarrhea, abdominal pain.

Hepatobiliary system

Rare: reversible increase in bilirubin and liver enzyme levels.

Very rare: jaundice, hepatitis.

Skin and subcutaneous tissue

Common: pruritus, rash (including photosensitivity).

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

Rare: angioneurotic edema.

Renal and urinary system

Rare: increased blood urea and creatinine levels.

Very rare: acute renal failure, renal pain.

Renal pain may be associated with renal impairment and crystalluria.

General disorders

Common: fatigue, fever.

Shelf life. 5 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

200 mg tablets, 10 in a blister, 2 blisters in a carton.

400 mg tablets, 10 in a blister, 1 blister in a carton.

Prescription category. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address.

139 Saksahanskoho Street, Kyiv, 01032, Ukraine.