Acik

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACIC® (ACIC®)

Composition:

Active substance: acyclovir;

1 tablet contains 200 mg of acyclovir;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), copovidone (copolyvidone)*, magnesium stearate;

1 tablet contains 400 mg of acyclovir;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), copovidone (copolyvidone)*, magnesium stearate.

*Copovidone and copolyvidone are synonyms.

Pharmaceutical form. Tablets.

Main physicochemical properties:
200 mg tablets: white, round tablets with a break line on one side;
400 mg tablets: white, biconvex, round tablets with a break line on one side.

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

Pharmacological Properties

Pharmacodynamics

Acyclovir is active against herpes simplex virus types I and II (Herpes simplex), varicella-zoster virus (Varicella zoster), Epstein-Barr virus, and cytomegalovirus.

The antiviral activity of the drug is highly selective and results from its competitive interaction with the viral enzyme thymidine kinase. Under the influence of thymidine kinase, acyclovir is converted into acyclovir monophosphate, then diphosphate, and finally triphosphate. The triphosphate form is incorporated into the DNA being synthesized for new viruses. As a result, viral DNA is formed with structural defects, leading to inhibition of replication of new virus generations.

During prolonged or repeated treatment courses in severely ill patients with impaired immunity, cases of reduced sensitivity of certain viral strains, which do not always respond to acyclovir treatment, may occur. Most clinical cases of resistance are associated with deficiency of viral thymidine kinase; however, there have been reports of mutations in viral thymidine kinase and DNA polymerase. In vitro, interaction of certain herpes simplex viruses with acyclovir may also lead to the emergence of less sensitive strains. The correlation between in vitro sensitivity of individual herpes simplex viruses and clinical outcomes of acyclovir treatment has not been fully established.

Pharmacokinetics

Acyclovir is only partially absorbed in the gastrointestinal tract. Peak plasma concentrations, measured at steady state after repeated oral doses of 200 mg and 400 mg of acyclovir administered every 4 hours for 5 doses per day, averaged 3.02 ± 0.5 μmol/L and 5.21 ± 1.32 μmol/L, respectively. Acyclovir is no longer detectable in the body 24 hours after administration. In adults, the volume of distribution at steady state is 50 ± 8.7 L/m².

Protein binding ranges from 9% to 33%.

In patients with healthy kidneys, 62–91% of acyclovir is excreted unchanged, and 10–15% is excreted as 9-carboxymethoxymethylguanine. The elimination half-life after intravenous administration in adults is 2.87 ± 0.76 hours. When acyclovir was administered 1 hour after a 1 g dose of probenecid, the plasma elimination half-life increased by 18%, and the area under the concentration-time curve (AUC) increased by 40%. With a bioavailability of approximately 20%, about 80% of the total dose of acyclovir is excreted in feces.

In patients with chronic renal insufficiency, the mean plasma elimination half-life is approximately 19.5 hours. During hemodialysis, the half-life is reduced to 5.7 hours, and plasma acyclovir concentration decreases by approximately 60%.

The concentration of the drug in cerebrospinal fluid is approximately 50% of the corresponding plasma concentration. The extent of plasma protein binding is relatively low (9–33%) and remains unchanged during co-administration with other medicinal agents.

No pharmacokinetic interactions were observed when acyclovir and zidovudine were administered concomitantly in HIV-infected patients.

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 herpes simplex virus infections in patients with normal immunity.

Prevention of herpes simplex virus infections in immunocompromised patients.

Treatment of infections caused by Varicella zoster virus (herpes zoster and varicella).

Contraindications.

Hypersensitivity to acyclovir or to any excipient of the medicinal product.

Prophylactic use in patients with severe renal impairment or anuria.

Interaction with other medicinal products and other forms of interactions.

Clinically significant interactions between acyclovir and other medicinal products have not been identified.

Acyclovir is excreted predominantly unchanged by the kidneys via tubular secretion; therefore, any medicinal products with a similar elimination mechanism may increase acyclovir plasma concentrations. Probenecid and cimetidine prolong the elimination half-life and AUC of acyclovir. When administered concomitantly with immunosuppressants during treatment of organ transplant recipients, plasma levels of both acyclovir and the inactive metabolite of the immunosuppressive agent are also increased; however, due to the wide therapeutic index of acyclovir, dose adjustment is not required.

Concomitant therapy with acyclovir increases the AUC of coadministered theophylline by approximately 50%. Monitoring of plasma concentrations is recommended during concomitant therapy with acyclovir.

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. Elderly patients are also more likely to have reduced renal function, so dose adjustment may be necessary in this patient group as well. Patients with renal impairment and elderly patients are at increased risk of developing neurological adverse reactions and should be closely monitored by a physician. Available data indicate that such reactions are generally reversible upon discontinuation of acyclovir therapy.

Acic® tablets contain lactose and therefore should not be administered to patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Prolonged or repeated courses of acyclovir treatment in individuals with severely impaired immune function may lead to the emergence of viral strains with reduced sensitivity, which may not respond to continued acyclovir therapy.

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.

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

There have been several case reports in which acyclovir use has been strongly suspected as the cause of acute generalized exanthematous pustulosis (AGEP). In two published case reports, this association was confirmed by patch testing. Since this condition may be mistaken for herpetic rash, it is important to be aware that acyclovir may potentially cause a skin reaction.

Use during pregnancy or breastfeeding

During the post-marketing surveillance period, various pharmaceutical forms of Acic® have been used in pregnant women. No increased incidence of congenital malformations has been observed in children whose mothers used Acic® during pregnancy compared to the general population. However, Acic® 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 receive 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.

There is no available information on the effect of acyclovir on female fertility. In a study of 20 male patients with normal sperm counts, oral administration of up to 1 g acyclovir 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

Until individual response to the drug is known (possible nervous system side effects), caution is recommended when driving vehicles or operating complex machinery.

Method of administration and dosage.

Tablets should be taken whole, with water, after meals. 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, Acyc® tablets should be administered at a dose of 200 mg 5 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 for patients with reduced intestinal absorption, the dose may be doubled to 400 mg or the appropriate intravenous dose may be used.

Treatment should be initiated as early as possible after onset of infection. In recurrent herpes, treatment should ideally be started 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, to prevent recurrences of infections caused by herpes simplex virus, Acyc® tablets should be taken at 200 mg 4 times daily at 6-hour intervals. For convenience, most patients may take 400 mg 2 times daily at 12-hour intervals.

Therapy may remain effective even when the dose of Acyc® tablets is reduced to 200 mg taken 3 times daily at 8-hour intervals, or even 2 times daily at 12-hour intervals. In some patients, significant improvement is observed with a daily dose of Acyc® 800 mg.

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

Prevention of infections caused by herpes simplex virus

For prevention of infections caused by herpes simplex virus in immunocompromised patients, Acyc® tablets at a dose of 200 mg should be taken 4 times daily at 6-hour intervals.

For patients with significant immunodeficiency (e.g., after bone marrow transplantation) or for patients with reduced intestinal absorption, the dose may be doubled to 400 mg or the 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, acyclovir should be administered at a dose of 800 mg 5 times daily at 4-hour intervals, excluding the nighttime period. Treatment should last 7 days.

For patients after bone marrow transplantation or for patients with reduced intestinal absorption, intravenous administration is preferred.

Treatment should be initiated as early as possible after onset of disease. Optimal results are achieved when treatment is started within the first 72 hours after the appearance of rash.

Children

For treatment and prevention of infections caused by herpes simplex virus, children aged 2 years and older with immunodeficiency may receive the same doses as adults.

For treatment of varicella in children aged 6 years and older, Acyc® 800 mg should be administered 4 times daily. Children aged 2 to 6 years may receive 400 mg of Acyc® 4 times daily. Treatment duration is 5 days.

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

The individual dose of the drug can be more precisely calculated based on the child's body weight as 200 mg/kg body weight (not exceeding 800 mg) of acyclovir 4 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 varicella-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 may occur in elderly patients; therefore, the dose should be adjusted accordingly. Adequate hydration should be maintained.

Renal impairment

Acyc® should be prescribed with caution to patients with renal impairment. Adequate hydration should be maintained.

For treatment of patients with impaired renal function, a reduced dose of acyclovir may be sufficient (see table).

Children.

The medicinal product is used in children from 2 years of age.

Overdose.

Symptoms: in accidental overdose of acyclovir over several days, gastrointestinal (such as nausea and vomiting) and neurological symptoms occur.

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

Treatment: the patient should be carefully examined to identify symptoms of intoxication. Gastric lavage and symptomatic treatment are recommended. Since acyclovir is effectively eliminated by hemodialysis, it should be used in cases of overdose.

Side effects.

The frequency categories of adverse reactions listed below are approximate estimates. For most reactions, the amount of information available for assessment was insufficient.

The frequency of adverse reactions is classified as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders.

Very rare: anaemia, thrombocytopenia, leukopenia.

Immune system disorders.

Rare: anaphylactic reactions.

Nervous system disorders.

Common: headache, dizziness.

Uncommon: hallucinations, somnolence, disorientation in time and space.

Rare: insomnia.

Very rare: agitation, tremor, ataxia, psychotic symptoms, convulsions, encephalopathy, coma, confusion, dysarthria.

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

Respiratory system disorders.

Rare: dyspnoea.

Gastrointestinal disorders.

Common: nausea, vomiting, diarrhoea, abdominal pain.

Hepatobiliary disorders.

Rare: reversible increase in bilirubin and liver enzyme levels.

Very rare: jaundice, hepatitis.

Skin and subcutaneous tissue disorders.

Common: pruritus, rash (including photosensitivity).

Uncommon: urticaria, accelerated diffuse hair loss.

Rare: angioneurotic oedema.

Since hair loss may be associated with the use of multiple medications, a definite link with acyclovir has not been established.

In several reports, there have been a few cases where acyclovir use could be undoubtedly suspected as the cause of HUS/HUS-like syndrome (HUS: haemolytic uraemic syndrome).

Renal and urinary disorders.

Rare: increased plasma urea and creatinine levels.

Very rare: acute renal failure, renal pain which may be associated with renal impairment and crystalluria.

General disorders.

Uncommon: increased fatigue, fever.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

200 mg tablets: 5 tablets in a blister; 5 blisters in a cardboard box.

400 mg tablets: 5 tablets in a blister; 7 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Salutas Pharma GmbH.

Manufacturer's address and place of business.

Otto-von-Guericke-Allee 1, 39179 Barleben, Germany.