Acyclovir-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACYCLOVIR-DARNITSA (ACICLOVIR-DARNITSA)

Composition:

Active substance: aciclovir;

1 tablet contains aciclovir 200 mg;

Excipients: potato starch, povidone, sodium croscarmellose, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or almost white tablets with a bevel and a score line.

Pharmacotherapeutic group. Antiviral agents for systemic use.

ATC code J05A B01.

Pharmacological properties.

Pharmacodynamics.

Acyclovir is a synthetic analogue of a purine nucleoside with inhibitory activity in vivo and in vitro against human herpesviruses, including herpes simplex virus types I and II, varicella-zoster virus (chickenpox and shingles), Epstein-Barr virus, and cytomegalovirus. In cell culture, acyclovir demonstrates 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 the aforementioned viruses is highly selective. The enzyme thymidine kinase in normal, uninfected cells does not use acyclovir as a substrate, so its toxic effect on host cells is minimal. However, 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.

With 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 deficiency of viral thymidine kinase, although there are reports of mutations affecting both viral thymidine kinase and DNA polymerase. In vitro, exposure of certain herpes simplex virus strains to acyclovir may also lead to emergence of less sensitive strains. The correlation between in vitro sensitivity of individual 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 (approximately 20% of the administered dose). Concomitant food intake does not reduce absorption. Maximum plasma concentrations are reached within 1.5–2 hours.

The extent of plasma protein binding is relatively low (ranging from 9% to 33%) and remains unchanged during interactions with other medicinal agents.

Acyclovir crosses the placental barrier, enters cerebrospinal fluid (reaching concentrations of about 50% of those in plasma), and is excreted in breast milk.

The majority of the drug (85–90%) is excreted unchanged by the kidneys, while only a small portion (10–15%) is eliminated as a metabolite (9-carboxymethoxymethylguanine). Renal clearance of acyclovir is substantially higher than creatinine clearance, indicating that the drug is eliminated by the kidneys not only via glomerular filtration but also through tubular secretion.

The terminal elimination half-life of acyclovir after intravenous administration is approximately 2.9 hours, 19.5 hours in patients with chronic renal failure, and 5.7 hours during hemodialysis. Acyclovir plasma levels decrease by approximately 60% during dialysis.

Clinical characteristics.

Indications.

• Treatment of skin and mucous membrane infections caused by Herpes simplex virus, including primary and recurrent genital herpes.
• Prevention of recurrences of infections caused by Herpes simplex virus in immunocompetent patients.
• Prevention of infections caused by Herpes simplex virus in immunocompromised patients.
• Treatment of infections caused by Varicella zoster virus (chickenpox, herpes zoster).

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.

Acyclovir is primarily excreted unchanged by the kidneys via tubular secretion; therefore, any medicinal products with a similar elimination mechanism may increase acyclovir plasma concentrations.

Concomitant administration of the medicinal product with other medicinal products may result in:

with probenecid, cimetidine – prolonged elimination half-life of acyclovir and area under the plasma concentration-time curve;

with immunosuppressive agents in organ transplant recipients – increased plasma levels of acyclovir and of the inactive metabolite of the immunosuppressive medicinal product (mycophenolate mofetil); however, due to the wide therapeutic index of acyclovir, dosage adjustment is not required.

An experimental study in 5 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.

No clinically significant interactions of acyclovir with other medicinal products have been identified.

Special precautions for use.

When high doses of the medicinal product are used, adequate hydration should be maintained.

ACYCLOVIR-DARNITSA should be used with caution in patients with impaired renal function, as acyclovir is primarily eliminated from the body via renal clearance. Dose adjustment should be performed (see section "Dosage and administration").

ACYCLOVIR-DARNITSA should be used with caution in elderly patients, as this patient group has a higher probability of impaired renal function. Dose adjustment should be considered if necessary (see section "Dosage and administration").

Both of these groups (patients with impaired renal function and elderly patients) are at risk for developing neurological disorders and therefore require close monitoring for detection of these adverse reactions. According to available data, such reactions are generally reversible upon discontinuation of the medicinal product (see section "Adverse reactions").

The risk of renal damage increases when used concomitantly with other nephrotoxic medicinal products.

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.

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

Use during pregnancy or breastfeeding.

In a post-marketing surveillance registry of pregnant women, outcomes following 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.

After oral administration of acyclovir at a dose of 200 mg five times daily, acyclovir is excreted into breast milk at concentrations ranging from 0.6% to 4.1% of the corresponding plasma acyclovir levels. A nursing infant may potentially ingest up to 0.3 mg/kg body weight per day of acyclovir.

During pregnancy or breastfeeding, the medicinal product should be used only when its potential benefit to the mother outweighs the possible risk to the fetus.

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 daily for 6 months did not reveal any clinically significant effect on sperm count, motility, or morphology.

Ability to affect reaction speed when driving or operating machinery.

Clinical studies on the effect of acyclovir on the ability to drive or operate machinery have not been conducted. The pharmacological profile of acyclovir does not suggest any expected negative impact. When assessing the ability to drive or operate machinery, the patient's clinical status and the adverse reaction profile of the medicinal product should be taken into account.

Dosage and Administration.

The tablet should be taken whole, with water. When using high doses of the medicinal product, adequate hydration of the body should be maintained.

Adults.

Treatment of infections caused by Herpes simplex virus.

ACYCLOVIR-DARNYTSIA should be administered at a dose of 200 mg five times daily at approximately 4-hour intervals, excluding the nighttime period. The duration of treatment is 5 days, but may be extended in cases of severe primary infection.

If necessary, in patients with severe immunodeficiency (e.g., after bone marrow transplantation) or reduced intestinal absorption, the single 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 recurrent Herpes simplex virus infections in patients with normal immunity.

ACYCLOVIR-DARNYTSIA should be administered at a dose of 200 mg four times daily at 6-hour intervals (or, for convenience, 400 mg twice daily at 12-hour intervals).

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

In some cases, significant improvement is observed with a daily dose of 800 mg.

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

Prevention of Herpes simplex virus infections in immunocompromised patients.

ACYCLOVIR-DARNYTSIA should be administered at a dose of 200 mg four times daily at 6-hour intervals.

If necessary, in patients with severe immunodeficiency or reduced intestinal absorption, the single 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 infections caused by Varicella zoster virus.

ACYCLOVIR-DARNYTSIA should be administered at a dose of 800 mg five times daily at approximately 4-hour intervals, excluding the nighttime period. The duration of treatment is 7 days.

Treatment should be initiated as early as possible after the onset of disease; better outcomes are achieved when therapy is started immediately after the appearance of rash.

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

Children aged 2 years and older.

Treatment and prevention of Herpes simplex virus infections in immunocompromised children.

ACYCLOVIR-DARNYTSIA should be administered at the same doses as for adults.

Treatment of varicella (chickenpox).

ACYCLOVIR-DARNYTSIA should be administered at the following doses: children aged 2 to 6 years – 400 mg four times daily; children aged 6 years and older – 800 mg four times daily.

Alternatively, the dose may be calculated more precisely based on the child's body weight – 20 mg/kg/day, divided into four doses. The maximum daily dose is 800 mg. The duration of treatment is 5 days.

There are no specific data on the use of acyclovir for prophylaxis of Herpes simplex virus infections or for treatment of Varicella zoster virus infections in children with normal immunity.

Patients with renal impairment.

ACYCLOVIR-DARNYTSIA should be administered with caution. Adequate hydration of the body should be maintained.

For prophylaxis and treatment of Herpes simplex virus infections in patients with renal insufficiency, 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), ACYCLOVIR-DARNYTSIA is recommended at a dose of 200 mg twice daily at approximately 12-hour intervals.

For treatment of Varicella zoster virus infections in patients with significantly impaired immunity, ACYCLOVIR-DARNYTSIA is recommended at the following doses: in severe renal impairment (creatinine clearance less than 10 mL/min) – 800 mg twice daily at approximately 12-hour intervals; in moderate renal impairment (creatinine clearance 10–25 mL/min) – 800 mg three times daily at approximately 8-hour intervals.

Elderly patients.

ACYCLOVIR-DARNYTSIA should be administered with caution. Adequate hydration of the body should be maintained.

Renal function impairment should be considered in elderly patients, and the dose of the medicinal product should be adjusted accordingly.

Children.

ACYCLOVIR-DARNYTSIA is indicated for children aged 2 years and older.

Overdose.

Symptoms. Acyclovir is only partially absorbed from the gastrointestinal tract. Accidental ingestion of up to 20 g of acyclovir has been reported without toxic effects.

In cases of accidental oral acyclovir overdose over several days, the following symptoms may occur: gastrointestinal (nausea, vomiting) and neurological (headache, confusion).

In cases of intravenous acyclovir overdose, serum creatinine levels increase, leading to renal failure. Neurological manifestations of overdose may include confusion, hallucinations, agitation, seizures, and coma.

Treatment: Patients should be examined for signs of intoxication and receive symptomatic therapy. In severe cases, hemodialysis should be performed.

Adverse reactions.

The adverse effects listed below are classified by system organ class 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.

Respiratory, thoracic and mediastinal disorders: rare – dyspnoea.

Gastrointestinal disorders: rare – nausea, vomiting, diarrhoea, abdominal pain, decreased appetite, gastritis, dysphagia.

Hepatobiliary disorders: rare – transient increase in liver enzyme activity and bilirubin levels; very rare – jaundice, hepatitis.

Renal and urinary disorders: rare – increased blood urea and creatinine concentrations; very rare – acute renal failure, renal pain.

Renal pain may be associated with renal impairment and crystalluria.

Nervous system disorders: common – headache, dizziness; very rare – psychomotor agitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, seizures, somnolence, encephalopathy, coma.

The above-mentioned symptoms are in most cases reversible and are mainly observed in patients with renal impairment or other predisposing factors (see section "Special precautions").

Cardiac disorders: rare – palpitations, chest pain.

Blood and lymphatic system disorders: very rare – anaemia, leucopenia, thrombocytopenia.

Immune system disorders: rare – hypersensitivity reactions, including angioneurotic oedema, anaphylactic reactions.

Skin and subcutaneous tissue disorders: common – rash, pruritus, photosensitivity; uncommon – hyperaemia, urticaria, alopecia.

Since hair loss may be associated with a wide variety of diseases and use of medicinal products, a clear link with acyclovir administration has not been established.

General disorders and administration site conditions: common – fatigue, fever.

Shelf life.

3 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 tablets in a blister pack; 2 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13, Boryspylska Street, Kyiv, 02093, Ukraine.