Acyclovir

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT aciclovir

Composition:

Active substance: aciclovir;

1 tablet contains 200 mg of aciclovir (0.2 g);

Excipients: lactose monohydrate, maize starch, magnesium stearate, sodium croscarmellose.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or almost white tablets.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Aciclovir. ATC code J05A B01.

Pharmacological Properties.

Pharmacodynamics.

Acyclovir is a synthetic analogue of 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 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 transformed into diphosphate and triphosphate forms by cellular enzymes. Once incorporated 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, cases of reduced sensitivity of certain viral strains may occur, which do not always respond to acyclovir therapy. Most clinical cases of resistance are associated with deficiencies in viral thymidine kinase; however, there are reports of mutations affecting both viral thymidine kinase and DNA. In vitro, exposure of certain herpes simplex virus strains 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 treatment has not been fully established.

Pharmacokinetics.

Acyclovir is only partially absorbed in the gastrointestinal tract. The average peak steady-state plasma concentration (C_{ss max}) following a 200 mg dose administered every 4 hours is 3.1 µmol (0.7 µg/mL), with the corresponding trough plasma level (C_{ss min}) being 1.8 µmol (0.4 µg/mL). Corresponding C_{ss max} levels following 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, with equivalent C_{ss min} levels of 2.7 µmol (0.6 µg/mL) and 4 µmol (0.9 µg/mL).

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

9-Carboxymethoxymethylguanine is the only significant metabolite of acyclovir, accounting for approximately 10–15% of the administered dose and detectable in urine. When acyclovir is administered one 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 failure, the mean terminal half-life is 19.5 hours. The mean half-life of acyclovir during hemodialysis is 5.7 hours. Acyclovir plasma levels 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 (ranging from 9% to 33%) and remains unchanged during interactions with other medicinal agents.

No alterations in the pharmacokinetics of either drug were observed when acyclovir and zidovudine were coadministered for 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 shingles).

Contraindications.

Hypersensitivity to acyclovir, valacyclovir, or to any other component of the drug.

Interaction with other medicinal products and other forms of interaction.

Clinically significant interactions between acyclovir and 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 plasma concentration-time curve of acyclovir. When administered concomitantly with immunosuppressants in transplant patients, plasma levels of both acyclovir and the inactive metabolite of the immunosuppressive drug are increased; however, due to the wide therapeutic index of acyclovir, dose adjustment is not required.

Special precautions for use.

Acyclovir is eliminated from the body primarily 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 adjustment 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 the occurrence of such reactions. 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 forms of 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 compared to the general population. However, acyclovir tablets should be used only when the potential benefit to the mother outweighs the possible 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 affect reaction speed when driving or operating machinery.

When assessing the ability to drive 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. However, 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 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, 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 for 5 days, but may be prolonged in cases of severe primary infection.

For some immunocompromised patients (e.g., after bone marrow transplantation) or patients with reduced intestinal absorption, the dose may be doubled to 400 mg or the appropriate 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 upon the appearance of the first skin lesions.

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

In patients with normal immunity, to prevent recurrences of herpes simplex virus infections, acyclovir 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 of acyclovir twice daily at 12-hour intervals.

Therapy may remain effective even when the dose of oral acyclovir is reduced to 200 mg 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 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 6-hour intervals. In patients with severe immunodeficiency (e.g., after bone marrow transplantation) or with reduced intestinal absorption, the dose may be doubled to 400 mg or the appropriate intravenous dose may be administered.

The duration of prophylactic treatment is determined by the duration of the risk period.

Treatment of varicella and herpes zoster.

For treatment of infections caused by varicella and herpes zoster viruses, acyclovir 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.

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

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

Children.

For treatment and prevention of herpes simplex virus infections in immunocompromised children aged 2 years and older, the same doses as for adults may be used.

For treatment of varicella, children aged 6 years and older should be given 800 mg of acyclovir four times daily. Children aged 2 to 6 years may be given 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 body weight per day (not exceeding 800 mg) of acyclovir, 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 children with normal immunity.

This dosage form of the drug should not be used in children under 2 years of age.

Elderly patients.

Renal function impairment should be considered in elderly patients, and the drug dosage should be adjusted accordingly (see 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 levels established for intravenous administration. However, in patients with severe renal impairment (creatinine clearance less than 10 mL/min), a dose 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 dose of 800 mg twice daily at approximately 12-hour intervals is recommended. For patients with moderate renal impairment (creatinine clearance 10–25 mL/min), a dose of 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. Cases of accidental oral intake of up to 20 g of acyclovir in patients have been reported without toxic effects. Accidental repeated overdose of oral acyclovir over several days may cause gastrointestinal symptoms (such as nausea and vomiting) and neurological symptoms (headache and confusion).

Overdose of intravenous acyclovir leads to elevated serum creatinine and blood urea nitrogen levels, resulting in renal failure. Neurological manifestations of overdose may include confusion, hallucinations, agitation, seizures, and coma.

Treatment: The patient should be carefully examined for signs of intoxication. Gastric lavage and symptomatic treatment are recommended. Since acyclovir levels in blood are effectively eliminated by hemodialysis, hemodialysis should be used in cases of overdose.

Adverse Reactions

The adverse reactions listed below are classified as follows:

Blood and lymphatic system disorders.

Anaemia, thrombocytopenia, leukopenia.

Immune system disorders.

Anaphylaxis.

Psychiatric and nervous system disorders.

Headache, dizziness, excitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, seizures, somnolence, encephalopathy, coma.

The above-mentioned neurological reactions are generally reversible and usually occur during treatment of patients with renal impairment or other risk factors.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Gastrointestinal disorders.

Nausea, vomiting, diarrhoea, abdominal pain.

Hepatobiliary disorders.

Reversible increases in bilirubin and liver enzymes, jaundice, hepatitis.

Skin and subcutaneous tissue disorders.

Pruritus, rash (including photosensitivity), urticaria, diffuse alopecia. Since hair loss may be associated with a variety of diseases and medications used by the patient, a clear association with acyclovir has not been established. Angioneurotic oedema.

Renal and urinary disorders.

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.

3 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.

Private Joint-Stock Company "Lekhym-Kharkiv".

PJSC "Tekhnolohiya".

Manufacturer's address and place of business.

36 Severina Pototskoho Street, Kharkiv, Kharkiv region, 61115, Ukraine.

8 Stara Prorizna Street, Uman, Cherkasy region, 20300, Ukraine.