Acyclovir 200 stada®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACYCLOVIR 200 STADA® (ACYCLOVIR 200 STADA®)

Composition:

Active substance: acyclovir;

One tablet contains 200 mg of acyclovir;

Excipients: microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), copovidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, biconvex tablets with the imprint "VS 1".

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 utilize acyclovir as a substrate, thus minimizing cytotoxic 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 converted into diphosphate and triphosphate forms by cellular enzymes. Acyclovir 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 immunocompromised patients, reduced sensitivity of certain viral strains to acyclovir may occur, leading to suboptimal treatment response. Most cases of resistance have been associated with deficiencies in viral thymidine kinase; however, there are reports of altered viral thymidine kinase and DNA polymerase. 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 susceptibility of herpes simplex virus strains and clinical outcomes of acyclovir therapy 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}) after 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 after 400 mg and 800 mg doses administered 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 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 occurs via both glomerular filtration and 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.

Drug concentrations in cerebrospinal fluid are approximately 50% of the corresponding plasma concentrations. Plasma protein binding is relatively low (9–33%) and is not altered by concomitant administration of other medicinal products.

No pharmacokinetic interactions were observed between acyclovir and zidovudine when co-administered 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 immunocompetent patients.
• 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 eliminated primarily 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 and AUC of acyclovir.

When acyclovir is used concomitantly with immunosuppressants such as mycophenolate mofetil, which is used in the treatment of organ transplant recipients, plasma levels of both acyclovir and the inactive metabolite of mycophenolate mofetil increase. However, due to the wide therapeutic index of acyclovir, dose adjustment is not required.

An experimental study in five men indicates that concomitant therapy with acyclovir increases the elimination half-life of fully administered theophylline by approximately 50%. It is recommended to monitor theophylline plasma concentrations during concomitant therapy with acyclovir.

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 their occurrence. Such reactions are generally reversible upon discontinuation of acyclovir therapy (see section "Adverse reactions").

Prolonged or repeated courses of acyclovir treatment in patients with severely compromised immune systems may lead to the emergence of viral strains with reduced sensitivity, 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.

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.

Post-marketing surveillance data from a pregnancy registry document the use of various acyclovir dosage forms during pregnancy. 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 during pregnancy only if 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 breastfed 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 ratio.

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 up to 1 g daily for 6 months did not reveal any clinically significant effects on sperm count, motility, or morphology.

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. The effect of acyclovir on reaction speed during driving or operating machinery has not been specifically studied. 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, it is necessary to maintain adequate hydration of the body.

Adults

Treatment of infections caused by herpes simplex virus

For treatment of infections caused by herpes simplex virus, take acyclovir tablets 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 those with impaired intestinal absorption, the dose may be doubled to 400 mg, or an 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 after the first signs of skin lesions appear.

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, take 200 mg tablets 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 after reducing the dose 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 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 herpes simplex virus infections

For prevention of herpes simplex virus infections in immunocompromised patients, take 200 mg tablets four times daily at 6-hour intervals. For patients with significant immunodeficiency (e.g., after bone marrow transplantation) or those with impaired intestinal absorption, the dose may be doubled to 400 mg or an appropriate intravenous dose may be administered.

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 and herpes zoster viruses, take 800 mg tablets 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 those with impaired intestinal absorption, intravenous administration is preferred.

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

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 varicella in children aged 6 years and older, administer 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.

A more precise dose can be calculated based on body weight: 20 mg/kg body weight per day (not exceeding 800 mg) of acyclovir in four divided doses.

This pharmaceutical form should not be used in 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.

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, oral doses that do not lead to accumulation of acyclovir above the safe level established for intravenous administration are recommended in patients with renal impairment. 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 treatment of Varicella zoster virus infections (varicella 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), 800 mg three times daily at approximately 8-hour intervals is recommended.

Children

Tablets are indicated for children with immunodeficiency aged 2 years and older.

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.

Overdose

Symptoms

Acyclovir is only partially absorbed from the gastrointestinal tract. Accidental oral intake of up to 20 g of acyclovir has been reported without toxic effects. However, accidental repeated oral overdose over several days may cause gastrointestinal (nausea and vomiting) and neurological (headache, confusion) symptoms.

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 to identify symptoms of intoxication. Since acyclovir is effectively eliminated from blood by hemodialysis, hemodialysis should be used in cases of overdose.

Side effects

The adverse reactions listed below are classified by system and organ and by frequency of occurrence. Frequency categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Blood and lymphatic system disorders:

very rare – anaemia, 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 for use").

Respiratory, thoracic and mediastinal disorders:

rare – dyspnoea.

Gastrointestinal disorders:

common – nausea, vomiting, diarrhoea, 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 accelerated hair loss (as hair loss may be associated with a variety of diseases and medications, a clear association with acyclovir has not been established);

rare – angioneurotic oedema.

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 medicinal product after the expiry date.

Storage conditions.

No special storage conditions required.

Keep out of the reach of children.

Packaging.

25 tablets in a blister; 4 blisters in a cardboard box;

5 tablets in a blister; 5 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

STADA Arzneimittel AG.

Manufacturer's address and place of business.

Stadachstrasse 2-18, 61118 Bad Vilbel, Germany.