Acyclovir-farmak

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

Composition:

Active substance: aciclovir;

1 tablet contains acyclovir, calculated as 100% substance – 200 mg;

Excipients: potato starch, microcrystalline cellulose, sodium croscarmellose, povidone, polyethylene glycol 4000, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets with a flat surface, a score line and beveled edges.

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 exhibits 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, 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. Following 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 may develop, leading to suboptimal response to acyclovir therapy. Most clinical cases of resistance are associated with deficiency of viral thymidine kinase; however, 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 susceptibility of herpes simplex virus strains and clinical response to acyclovir has not been fully established.

Pharmacokinetics.

Acyclovir 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), with a corresponding trough plasma level (C_{ss min}) of 1.8 µmol (0.4 µg/mL). Corresponding C_{ss max} values 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, and the respective C_{ss min} levels are 2.7 µmol (0.6 µg/mL) and 4 µmol (0.9 µg/mL).

In adults, the mean 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 a 1 g dose 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. Acyclovir plasma levels decrease by approximately 60% during dialysis.

The concentration of acyclovir in cerebrospinal fluid is approximately 50% of the corresponding plasma concentration. Plasma protein binding is relatively low (9–33%) and is not altered by concomitant administration of other drugs.

No changes in the pharmacokinetics of acyclovir or zidovudine were observed when the two drugs were coadministered for 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 with a similar elimination mechanism may increase acyclovir plasma concentrations. Probenecid and cimetidine prolong the elimination half-life of acyclovir and increase AUC. When acyclovir is administered concomitantly with immunosuppressants used in transplant patients, such as mycophenolate mofetil, plasma levels of both acyclovir and the inactive metabolite of mycophenolate mofetil are increased. However, due to the wide therapeutic index of acyclovir, dose 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 theophylline plasma concentrations is recommended when acyclovir is administered concomitantly.

Special precautions for use.

Patients with renal impairment and elderly patients

Acyclovir is primarily eliminated from the body via renal clearance; therefore, the dose should be reduced in patients with renal impairment (see section "Dosage and administration"). Elderly patients are also more likely to have impaired renal function, so dose reduction may be required 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 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 compromised immune systems 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.

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.

Post-marketing surveillance data from a pregnancy registry document the outcomes of various pharmaceutical forms of Acyclovir-Farmak used during pregnancy. No increased incidence of congenital malformations has been observed in children whose mothers used this medication during pregnancy compared to the general population. However, Acyclovir-Farmak 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 at concentrations ranging from 0.6 to 4.1 times the level found in plasma. A nursing infant may potentially receive up to 0.3 mg/kg body weight per day of acyclovir. Therefore, acyclovir should be administered to breastfeeding women with caution, taking into account the risk-benefit balance.

Fertility.

There is no information available regarding the effect of acyclovir on female fertility. In a study of 20 male patients with normal sperm counts who received oral doses of up to 1 g daily for six months, no clinically significant effects on sperm count, motility, or morphology were observed.

Ability to affect reaction speed when driving or operating machinery.

When assessing 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. 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 the treatment of infections caused by herpes simplex virus, Acyclovir-Farmak 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 in cases of severe primary infection, it may be prolonged.

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 an intravenous formulation of the drug may be used.

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

For immunocompetent patients, Acyclovir-Farmak tablets are prescribed at a dose of 200 mg four times daily at 6-hour intervals to prevent recurrences of herpes simplex virus infections.

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

Therapy may remain effective even after reducing the dose of Acyclovir-Farmak tablets 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-Farmak 800 mg.

To monitor possible changes in the natural course of the disease, Acyclovir-Farmak 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-Farmak tablets should be taken at a dose of 200 mg four times daily at 6-hour intervals. For patients with significant immunodeficiency (e.g., after bone marrow transplantation) or reduced intestinal absorption, the dose may be doubled to 400 mg or an intravenous formulation may be used.

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

Treatment of varicella and herpes zoster

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

For patients with severe immunodeficiency (e.g., after bone marrow transplantation) or 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 begins immediately after the appearance of rash.

Children

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

For the treatment of chickenpox in children aged 6 years and older, 800 mg of Acyclovir-Farmak is prescribed four times daily. Children aged 2 to 6 years may receive 400 mg of Acyclovir-Farmak four times daily. The duration of treatment 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 total daily dose, divided into four doses).

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

This dosage form 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 "Renal Impairment"). Adequate hydration should be maintained in elderly patients receiving high doses of Acyclovir-Farmak.

Renal Impairment

Acyclovir-Farmak should be prescribed with caution to patients with renal impairment. Adequate hydration should be maintained.

When used for the prevention and treatment of herpes simplex virus infections, the recommended oral doses do not lead to accumulation of acyclovir above the safe levels established for intravenous administration. However, for 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 the treatment of Varicella zoster virus infections (chickenpox and herpes zoster) in patients with significantly reduced immunity, 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-Farmak 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 have been reported without toxic effects. Accidental repeated overdosage 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 carefully examined for signs of intoxication. Since acyclovir is effectively removed from the blood by hemodialysis, hemodialysis should be used in cases of overdose.

Side effects.

The adverse reactions 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).

Blood and lymphatic system disorders

Very rare: anemia, thrombocytopenia, leukopenia.

Immune system disorders

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, thoracic and mediastinal disorders

Rare: dyspnea.

Gastrointestinal disorders

Common: nausea, vomiting, diarrhea, abdominal pain.

Hepatobiliary disorders

Rare: reversible increase in bilirubin and liver enzymes.

Very rare: jaundice, hepatitis.

Skin and subcutaneous tissue disorders

Common: pruritus, rash (including photosensitivity).

Uncommon: urticaria, diffuse alopecia. Since alopecia may be associated with a variety of diseases and medications, a clear association with acyclovir has not been established.

Rare: angioneurotic edema.

Renal and urinary disorders

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.

Do not use the medication after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister. 2 blisters per carton.

Prescription category. Prescription only.

Manufacturer: JSC "Farmak".

Manufacturer's address and location of operations.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.