Acloherp

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT A CLOHERP (ACLOHERP)

Composition:

Active ingredient: aciclovir (aciclovir);

1 tablet contains 200 mg or 400 mg of aciclovir;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

200 mg tablets: round, biconvex, uncoated tablets, white to almost white in colour, with the imprint «AR 200» on one side and smooth on the other side (tablet size: approximately 9.5 mm);

400 mg tablets: round, biconvex, uncoated tablets, white to almost white in colour, with the imprint «AR» and «400» separated by a break line on one side and smooth on the other side (tablet size: approximately 11.8 mm).

Pharmacotherapeutic group. Direct-acting antiviral agents, nucleosides and nucleotides, excluding reverse transcriptase inhibitors. 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 use acyclovir as a substrate, thus minimizing cytotoxic effects on host cells. However, thymidine kinase encoded by herpes simplex viruses, varicella-zoster virus, and shingles virus converts acyclovir into acyclovir monophosphate—a nucleoside analogue—which is then sequentially converted into diphosphate and triphosphate by cellular enzymes. After 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 immunocompromised patients, reduced sensitivity of certain viral strains, which may not respond to acyclovir therapy, may occur. Most clinical cases of resistance are associated with a deficiency 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 susceptibility of herpes simplex virus strains and clinical outcomes of acyclovir treatment has not been fully established.

Pharmacokinetics

Acyclovir is only partially absorbed from 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 a corresponding trough plasma level (C_{ss min}) of 1.8 µmol (0.4 µg/mL). 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, and the corresponding C_{ss min} levels are 2.7 µmol (0.6 µg/mL) and 4 µmol (0.9 µg/mL).

In adults, the terminal elimination half-life (t_1/2) of acyclovir following intravenous administration 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 t_1/2 and the area under the plasma concentration-time curve (AUC) increase by 18% and 40%, respectively.

In patients with chronic renal impairment, the mean terminal t_1/2 is 19.5 hours. The mean t_1/2 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 interaction with other drugs. When acyclovir is administered concomitantly with zidovudine in HIV-infected patients, no changes in the pharmacokinetics of either drug have been observed.

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 of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Clinically significant interactions of acyclovir with other medicinal products have not been identified. Acyclovir is excreted predominantly 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 t1/2 of acyclovir and increase its AUC. When acyclovir is administered concomitantly with an immunosuppressant used in transplant patients—mycophenolate mofetil—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 AUC of orally administered theophylline by approximately 50%. Monitoring of plasma concentrations is recommended 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 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 such events. Available data indicate that these reactions are generally reversible upon discontinuation of acyclovir treatment (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.

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.

Pregnancy. Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Post-marketing surveillance data from pregnancy registries document the outcomes of various acyclovir formulations used during pregnancy. No increase in congenital malformations has been observed in children whose mothers used acyclovir during pregnancy compared to the general population. Any congenital defects reported were not unique and did not share common features suggesting a common origin.

Breastfeeding period. 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 plasma level. A nursing infant may potentially ingest up to 0.3 mg/kg body weight per day of acyclovir. Therefore, acyclovir should be administered to breastfeeding women only with caution, after careful consideration of the benefit-risk balance. Fertility. 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 up to 1 g daily for six months did not reveal any 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 or operate machinery, the patient's clinical status and the drug's adverse reaction profile should be taken into account. Clinical studies specifically evaluating 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. Nevertheless, the adverse reaction profile should be considered.

Dosage and Administration.

The tablet should be taken whole, with water. 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, acyclovir tablets 200 mg should be taken 5 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 impaired 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 onset of infection. In recurrent herpes, treatment should ideally be started during the prodromal phase or immediately upon appearance of the first skin lesions.

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

In immunocompetent patients, to prevent recurrences of herpes simplex virus infections, acyclovir tablets 200 mg are taken 4 times daily at approximately 6-hour intervals.

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

Therapy may remain effective even when the dose is reduced to 200 mg of acyclovir 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 total 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, acyclovir tablets 200 mg should be taken 4 times daily at approximately 6-hour intervals. For patients with severe immunodeficiency (e.g., after bone marrow transplantation) or impaired intestinal absorption, the dose may be doubled to 400 mg or the 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-zoster virus and herpes zoster, acyclovir tablets 800 mg should be taken 5 times daily at approximately 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 impaired intestinal absorption, intravenous administration is preferred.

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

Children.

For treatment of herpes simplex virus infections 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, 800 mg of Aklogerp is administered 4 times daily; for children aged 2 to 6 years, 400 mg of Aklogerp 4 times daily may be used. Treatment duration is 5 days.

The individual dose may be more precisely calculated based on body weight as 20 mg/kg (not exceeding 800 mg) of Aklogerp 4 times daily. There are no specific data on the use of Aklogerp for prophylaxis (prevention of recurrences) of herpes simplex virus infections or for treatment of herpes zoster virus infections in immunocompetent children.

For treatment of herpes virus infections in neonates and children under 3 months of age, acyclovir for infusion is used.

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.

Renal impairment.

Acyclovir should be used 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 level established for intravenous administration. However, for patients with severe renal impairment (creatinine clearance less than 10 mL/min), the recommended dose is 200 mg twice daily at approximately 12-hour intervals.

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), the recommended dose is 800 mg twice daily at approximately 12-hour intervals; for patients with moderate renal impairment (creatinine clearance 10–25 mL/min), the dose is 800 mg 3 times daily at approximately 8-hour intervals.

Children.

Acyclovir tablets are indicated for children aged 2 years and older.

Overdose.

Symptoms. Acyclovir is only partially absorbed from the gastrointestinal tract. Accidental ingestion of up to 20 g of acyclovir by patients has been reported without toxic effects. Accidental repeated overdose of oral acyclovir over several days may result in 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 blood levels of acyclovir are effectively removed by hemodialysis, this method should be used in cases of overdose.

Adverse Reactions

The adverse reactions listed below are classified by organ system and frequency of occurrence. Frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

Blood and lymphatic system disorders

Very rare: anaemia, thrombocytopenia, leucopenia.

Immune system disorders

Rare: anaphylaxis.

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 increases in bilirubin and liver enzymes.

Very rare: jaundice, hepatitis.

Skin and subcutaneous tissue disorders

Common: pruritus, rash (including photosensitivity).

Uncommon: urticaria, diffuse alopecia. Since hair loss may be associated with a wide range 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.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

5 tablets per blister pack, 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Aurobindo Pharma Limited, Formulation, Unit-XV/Aurobindo Pharma Limited, Formulation Unit-XV.

Manufacturer's address and place of business.

Block A and Block B, Plot No 17a, E Bonangi Village, Parawada Mandal, Anakapalli District, Anakapalli, 531021, India / Block A and B, Plot No 17a, E Bonangi Village, Parawada Mandal, Anakapalli District, Anakapalli, 531021, India.