Aciclovir 400 stada®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACYCLOVIR 400 STADA® (ACYCLOVIR 400 STADA®)

Composition:

Active ingredient: acyclovir;

1 tablet contains 400 mg of acyclovir;

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

Pharmaceutical form. Tablets.

Main physical and chemical properties: white, round, biconvex tablets with the imprint «VS 2».

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, 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 by cellular enzymes. Upon incorporation into viral DNA, acyclovir triphosphate interacts with viral DNA polymerase, resulting in termination of viral DNA chain synthesis.

With prolonged or repeated treatment courses in severely ill patients with compromised immunity, reduced sensitivity of certain viral strains to acyclovir may occur, leading to suboptimal treatment response. Most cases of resistance have been associated with viral thymidine kinase deficiency; however, there have been 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 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}) 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). The 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, 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 1 hour after 1 g 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 insufficiency, 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 the drug 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 medicinal products.

No changes in the pharmacokinetics of acyclovir or zidovudine were observed when both drugs were 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 components of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

No clinically significant interactions of acyclovir with other medicinal products have been identified.

Acyclovir is primarily eliminated 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 administered concomitantly with immunosuppressants such as mycophenolate mofetil, 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 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, dosage reduction is required in patients with renal impairment (see section "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 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 immunity may lead to the emergence of viral strains with reduced susceptibility that 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 increases 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 pregnancy registries document the outcomes of various acyclovir formulations used 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 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 only with caution, following careful assessment of the risk-benefit balance.

There is no information available regarding 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 showed no clinically significant effect 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, based on the pharmacological properties of acyclovir, there is no reason to expect any negative impact.

Dosage and Administration.

The tablet should be taken whole, with water. When using high doses of acyclovir, adequate hydration must be maintained.

Adults

Treatment of infections caused by herpes simplex virus

For treatment of infections caused by herpes simplex virus, take acyclovir tablets 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 those with impaired intestinal absorption, the dose may be doubled to 400 mg or the appropriate intravenous dose should 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

In patients with normal immunity, to prevent recurrences of herpes simplex virus infections, take 200 mg tablets 4 times daily at 6-hour intervals.

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

Therapy remains effective even when the dose of acyclovir is reduced to 200 mg taken 3 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 infections caused by herpes simplex virus

For prevention of herpes simplex virus infections in immunocompromised patients, take 200 mg tablets 4 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 the appropriate intravenous dose should 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 and herpes zoster viruses, take 800 mg tablets 5 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 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 with immunodeficiency aged 2 years and older may receive adult doses.

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

A more precise dose can be calculated based on body weight: 20 mg/kg/day (not exceeding 800 mg) of acyclovir in 4 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 must be maintained.

Renal impairment

Acyclovir should be used with caution in patients with renal impairment. Adequate hydration must be maintained.

For prophylaxis and treatment of herpes simplex virus infections in patients with renal impairment, oral doses that do not lead to accumulation of acyclovir above the safe level established for intravenous administration are recommended. 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, and for patients with moderate renal impairment (creatinine clearance 10–25 mL/min), 800 mg 3 times daily at approximately 8-hour intervals.

If a dose lower than 400 mg is required, acyclovir in an appropriate dosage or pharmaceutical form should be used.

Children

Tablets may be used in immunocompromised children 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. Accidental repeated oral overdosage over several days may cause gastrointestinal (nausea and vomiting) and neurological (headache and 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 thoroughly examined for signs of intoxication. Since acyclovir is effectively eliminated from the blood by hemodialysis, hemodialysis should be used in cases of overdose.

Adverse Reactions

The adverse reactions listed below are classified by system organ class and 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").

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 non-scarring alopecia (since hair loss may be associated with a large number 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.

5 tablets in a blister; 5 or 7 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

STADA Arzneimittel AG.

Manufacturer's address and place of business.

Stadaweg 2-18, 61118 Bad Vilbel, Germany.