Acyclovir-astrafarm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT aciclovir-ASTRAPHARM (aciclovir-ASTRAPHARM)

Composition:

Active substance: aciclovir;

1 tablet contains 200 mg of aciclovir;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (type A); povidone; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets, round in shape, biconvex with a score line on one side.

Pharmacotherapeutic group.

Antiviral agents for systemic use. Direct-acting antiviral agents. Aciclovir. ATC code J05AB01.

Pharmacological properties.

Pharmacodynamics.

Aciclovir 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, Epstein-Barr virus, and cytomegalovirus. In cell culture, aciclovir 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 aciclovir against the aforementioned viruses is highly selective. The enzyme thymidine kinase in normal, uninfected cells does not utilize aciclovir as a substrate, thus minimizing toxic effects on host cells. However, thymidine kinase encoded by herpes simplex viruses, varicella-zoster virus, and Epstein-Barr virus converts aciclovir into aciclovir monophosphate—a nucleoside analogue—which is then sequentially converted into diphosphate and triphosphate forms by cellular enzymes. Subsequently, aciclovir triphosphate incorporates into viral DNA and 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, cases of reduced sensitivity of certain viral strains may occur, which do not always respond to aciclovir therapy. Most clinical cases of resistance are associated with deficiency of viral thymidine kinase; however, reports exist of mutations affecting both viral thymidine kinase and DNA. 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 herpes simplex virus strains and clinical outcomes of aciclovir treatment has not been fully established.

Concurrent use of aciclovir with antiretroviral agents reduces mortality in patients with advanced HIV infection. Additionally, when intravenous aciclovir has been administered for 1 month prior, it reduces mortality following bone marrow transplantation.

Pharmacokinetics.

Aciclovir is only partially absorbed in the gastrointestinal tract. The mean 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), and the trough plasma level (C_{ss min}) is 1.8 µmol (0.4 µg/mL). Corresponding C_{ss max} levels after 400 mg and 800 mg doses given every 4 hours are 5.3 µmol (1.2 µg/mL) and 8 µmol (1.8 µg/mL), respectively, while the corresponding C_{ss min} levels are 2.7 µmol (0.6 µg/mL) and 4 µmol (0.9 µg/mL).

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

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

In patients with chronic renal impairment, 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 concentrations in cerebrospinal fluid are approximately 50% of the corresponding plasma concentrations. Plasma protein binding is relatively low (from 9 to 33%) and does not change significantly upon coadministration with other medicinal products.

When aciclovir and zidovudine are used concomitantly in the treatment of HIV-infected patients, no changes in the pharmacokinetics of either drug have been observed.

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.

Clinically significant interactions of acyclovir with other medicinal products have not been identified.

Acyclovir is primarily excreted unchanged by the kidneys via tubular secretion; therefore, any medicinal products with a similar excretion mechanism may increase acyclovir plasma concentrations. Probenecid and cimetidine prolong the elimination half-life and the area under the concentration-time curve of acyclovir. When used concomitantly with immunosuppressants in organ transplant patients, plasma levels of both acyclovir and the inactive metabolite of mycophenolate mofetil are increased; however, due to the wide therapeutic index of acyclovir, dosage adjustment is not required.

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 "Dosage and administration"). Elderly patients 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 developing neurological adverse reactions and should therefore be closely monitored for such events. Available data indicate that such reactions are generally reversible upon discontinuation of acyclovir therapy.

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

The drug contains lactose and therefore should not be administered to patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

No increased incidence of congenital malformations has been observed in children whose mothers used acyclovir during pregnancy. However, acyclovir tablets should be used during pregnancy only when the potential benefit justifies the potential risk to the fetus.

After oral administration of 200 mg acyclovir five times daily, acyclovir is excreted into breast milk. Therefore, acyclovir should be administered to breastfeeding women with caution, taking into account the risk-benefit ratio.

Ability to affect reaction speed while driving or operating machinery

When assessing the ability to drive or operate machinery, the patient's clinical status and the drug's adverse effect 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 swallowed whole with water. When using high doses of acyclovir, adequate hydration should be maintained.

Adults

Treatment of infections caused by herpes simplex virus

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

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

For patients with severe immunodeficiency (e.g., after bone marrow transplantation) or with impaired intestinal absorption, the dose may be doubled to 400 mg or an appropriate intravenous dose may be used.

Treatment should be initiated as early as possible after the onset of infection. In recurrent herpes, treatment should be started at the earliest sign, preferably during the prodromal phase or immediately after the first 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-Astrafarm tablets at a dose of 200 mg should be taken four times daily at 6-hour intervals.

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

Therapy remains effective even when the dose of Acyclovir-Astrafarm tablets is reduced to 200 mg 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 daily dose of Acyclovir-Astrafarm 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-Astrafarm tablets at a dose of 200 mg should be taken four times daily at 6-hour intervals. For patients with significant immunodeficiency (e.g., after bone marrow transplantation) or with impaired intestinal absorption, the dose may be doubled to 400 mg or an appropriate intravenous dose may be used.

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-Astrafarm tablets should be taken at a dose of 800 mg five times daily at 4-hour intervals, excluding the nighttime period. Treatment should last for 7 days.

For patients with severe immunodeficiency (e.g., after bone marrow transplantation) or with impaired 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 skin eruptions.

Children

For treatment and prevention of herpes simplex virus infections, children aged 2 years and older with immunodeficiency may receive adult doses.

For treatment of chickenpox in children aged 6 years and older, the dose is 800 mg of acyclovir four times daily. Children aged 2 to 6 years may receive 400 mg of acyclovir four times daily. Treatment duration is 5 days.

The dose may be more precisely calculated based on body weight: 20 mg/kg/day (not exceeding 800 mg), divided into four doses.

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.

This pharmaceutical form of the drug is not recommended for children under 2 years of age.

Elderly patients

Renal function impairment should be considered in elderly patients, and the dose should be adjusted accordingly (see section Renal Impairment). Adequate hydration should be maintained.

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 level established for intravenous administration. However, for patients with severe renal impairment (creatinine clearance < 10 mL/min), the recommended dose is 200 mg twice daily at approximately 12-hour intervals.

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

Children

This pharmaceutical form of the drug is not used in children under 2 years of age.

Overdose.

Symptoms: accidental repeated overdosage of oral acyclovir over several days may result in gastrointestinal symptoms (such as nausea and vomiting) and neurological symptoms (headache and confusion).

Neurological manifestations of overdose may include confusion, hallucinations, agitation, seizures, and coma.

Treatment: the patient should be thoroughly examined to identify symptoms of intoxication. Gastric lavage and symptomatic treatment are recommended. Since acyclovir levels in blood are effectively removed by hemodialysis, hemodialysis should be employed in cases of overdose.

Side effects.

Blood system: anemia, thrombocytopenia, leukopenia.

Immune system: anaphylaxis.

Central nervous system: headache, dizziness, excitability, 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.

Respiratory system: dyspnea.

Gastrointestinal tract: nausea, vomiting, diarrhea, abdominal pain.

Hepatobiliary system: reversible increases in bilirubin and liver enzymes, jaundice, hepatitis.

Skin: pruritus, rash (including photosensitivity), urticaria, diffuse hair loss (since hair loss may be associated with a variety of diseases and medications used by the patient, a clear link with acyclovir has not been established); angioneurotic edema.

Urinary system: increased blood urea and creatinine levels, acute renal failure, renal pain.

Renal pain may be associated with renal impairment and crystalluria.

General disorders: increased 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.

10 tablets in a blister; 1 or 2 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

ASTRAFARM LLC.

Manufacturer's address and place of business.

6 Kyivska Street, Vyshneve, Kyiv-Sviatoshyn District, Kyiv Oblast, 08132, Ukraine.