Lipster

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

Composition:

Active substance: acyclovir;

One tablet contains acyclovir, recalculated to 100% anhydrous substance, 200 mg, or 400 mg, or 800 mg;

Excipients: microcrystalline cellulose, povidone, sodium starch glycolate (type A), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

200 mg tablets: round, biconvex tablets, white or almost white;

400 mg tablets: round, biconvex tablets, white or almost white;

800 mg tablets: elongated, biconvex tablets, with a score line on one side, white or almost white.

Pharmacotherapeutic group. Antiviral agents for systemic use.

ATC code J05A B01.

Pharmacological Properties

Pharmacodynamics

Aciclovir 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, aciclovir demonstrates the highest activity against herpes simplex virus type I, followed in descending order of activity against herpes simplex virus type II, varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus.

The inhibitory activity of aciclovir against the aforementioned viruses is highly selective. The enzyme thymidine kinase in normal, uninfected cells does not use aciclovir 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 aciclovir into aciclovir monophosphate—a nucleoside analogue—which is then sequentially transformed into diphosphate and triphosphate forms by cellular enzymes. After incorporation into viral DNA, aciclovir 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 to aciclovir may occur, leading to suboptimal treatment response. Most clinical cases of resistance are associated with deficient viral thymidine kinase activity, although there are reports of altered viral thymidine kinase and DNA polymerase. In vitro, exposure of certain herpes simplex virus strains to aciclovir 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 aciclovir treatment has not been fully established.

Pharmacokinetics

Aciclovir is only partially absorbed from the gastrointestinal tract. Approximately 20% of the administered dose is absorbed shortly after dosing. With doses of 600 mg or higher, absorption of aciclovir is relatively low. The mean peak steady-state plasma concentration (C_{ss max}) 4 hours after a 200 mg dose is 3 µmol/L, and the trough concentration (C_{ss min}) is 1.6 µmol/L. After administration of an 800 mg dose, the corresponding concentrations are 6.9 µmol/L and 3.5 µmol/L, respectively. The majority of the drug is excreted unchanged by the kidneys.

In a group of neonates receiving aciclovir at a dose of 15 mg/kg every 8 hours, the following values were observed: C_max = 83.5 µmol (18.8 µg/mL), C_min = 14.1 µmol (3.2 µg/mL).

The renal clearance of aciclovir is significantly higher than creatinine clearance, indicating that the drug is eliminated not only by glomerular filtration but also by tubular secretion. The elimination half-life of aciclovir in plasma is approximately 3 hours under conditions of normal renal function. The only significant metabolite of aciclovir detectable in urine is 9-carboxymethoxymethylguanine, which accounts for 10–15% of the administered dose.

In chronic renal failure, the terminal elimination half-life of the drug increases to 19.5 hours. Aciclovir plasma concentrations decrease by approximately 60% during dialysis.

In elderly individuals, clearance decreases with age, paralleling the decline in creatinine clearance, but the terminal elimination half-life remains nearly unchanged. When aciclovir and zidovudine are administered concomitantly in HIV patients, no changes in the pharmacokinetics of either drug have been observed.

In mutagenicity studies, a positive effect was observed in 2 out of 11 mammalian cell tests when concentrations were applied that were 25 times (after intravenous administration) and 150 times (after oral administration) higher than the drug levels found in human plasma.

Clinical characteristics.

Indications.

• Skin and mucous membrane infections caused by Herpes simplex virus, including primary genital herpes infections and recurrences (excluding neonatal Herpes simplex infections and severe Herpes simplex infections in immunocompromised children).
• Prevention of recurrent Herpes simplex infections in patients with normal immunity.
• Prevention of Herpes simplex infections 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.

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 acyclovir AUC.

When acyclovir was co-administered with mycophenolate mofetil, an immunosuppressant used in transplant patients, increased AUC of acyclovir and of the inactive metabolite of mycophenolate mofetil was observed. However, due to the wide therapeutic index of acyclovir, dose adjustment is not required.

In an experimental study of concomitant administration of acyclovir and theophylline in 5 subjects, an increase of approximately 50% in the total AUC of theophylline was observed. Monitoring of plasma theophylline levels is recommended during concomitant treatment with acyclovir.

Special precautions for use

Hydration: Adequate fluid intake should be ensured in patients receiving high oral or parenteral doses of acyclovir.

Concomitant use of other nephrotoxic drugs increases the risk of renal impairment.

Use in patients with renal impairment and elderly patients: Acyclovir is eliminated by the kidneys; therefore, dosage reduction is required in patients with renal impairment. Since the likelihood of impaired renal function is higher in elderly patients, dosage adjustment may also be necessary in this population. Elderly patients and patients with renal impairment have an increased risk of developing neurological adverse reactions; therefore, careful monitoring for such reactions is required. In reported cases, these reactions were generally reversible upon discontinuation of therapy.

In patients with severe immunodeficiency, prolonged treatment with acyclovir or repeated intermittent courses of acyclovir may lead to the emergence of viral strains with reduced sensitivity to acyclovir. In such cases, continued treatment with acyclovir may be ineffective.

Available clinical 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 pregnancy registry data document the outcomes of various acyclovir formulations used during pregnancy. No increased incidence of congenital malformations has been observed in children whose mothers received acyclovir during pregnancy. In standard animal studies, systemic acyclovir did not produce embryotoxic or teratogenic effects in rabbits, rats, or mice. In a non-standardized study in rats, fetal abnormalities were observed only after administration of high subcutaneous doses that were toxic to the mother. The clinical relevance of these findings is unknown.

Breastfeeding

After oral administration of 200 mg five times daily, acyclovir is excreted into breast milk at concentrations ranging from 0.6 to 4.1 times the plasma levels. The potential daily dose of acyclovir received by a breastfed infant is up to 0.3 mg/kg/day. Therefore, acyclovir should be administered to breastfeeding mothers with caution, taking into account the risk-benefit ratio.

Fertility

The effect of oral or parenteral administration of acyclovir on female fertility is unknown. In a study of men receiving oral acyclovir 1 g daily for 6 months, no clinically significant effect on sperm count, motility, or morphology was observed.

Ability to affect reaction rate while driving or operating machinery

When considering the ability to drive or operate machinery, the patient's clinical status and the drug's adverse effect 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. Furthermore, the pharmacological profile of acyclovir does not suggest any expected negative impact.

Administration and dosage.

The tablet should be taken whole, with water.

Treatment of Herpes simplex infection

Adults: 1 tablet of 200 mg 5 times daily every 4 hours, except during nighttime. Treatment should last for 5 days; in severe primary infections, it may be prolonged. The first dose should be taken as soon as possible upon development of infection or recurrence — at the first signs of infection or immediately after appearance of blisters.

Pediatric patients: For treatment of Herpes simplex infection in children aged 2 years and older, the adult dose may be used.

Geriatric patients: When treating elderly patients, possible presence of renal impairment should be considered and dose adjustment evaluated accordingly. Patients receiving high oral doses of acyclovir should maintain adequate hydration.

Renal impairment: Acyclovir should be used with caution in patients with renal impairment. Adequate hydration must be ensured. For treatment of Herpes simplex infection in patients with severe renal impairment (glomerular filtration rate < 10 mL/min), the dosage should be reduced to 200 mg twice daily every 12 hours.

Prophylaxis of Herpes simplex infection in patients with normal immune response

Prophylaxis should be administered to patients with laboratory-confirmed frequent recurrences of Herpes simplex.

Adults: 1 tablet of 200 mg 4 times daily every 6 hours. An alternative regimen is 400 mg tablets twice daily at 12-hour intervals. Prophylaxis may also be effective with a reduced daily dose of 600 mg: 200 mg 3 times daily every 8 hours, or even 200 mg twice daily every 12 hours. In some patients, suppression of infection may be achieved with a daily dose of 800 mg.

Geriatric patients: When treating elderly patients, possible presence of renal impairment should be considered and dose adjustment evaluated accordingly. Patients receiving high oral doses of acyclovir should maintain adequate hydration.

Renal impairment: Acyclovir should be used with caution in patients with renal impairment. Adequate hydration must be ensured.

Prophylaxis of Herpes simplex infection in patients with impaired immune response

Adults: 1 tablet of 200 mg 4 times daily every 6 hours. For patients with severe immunodeficiency (e.g., after bone marrow transplantation) or with reduced intestinal absorption of the drug, a dosage of 400 mg 4 times daily may be used, or alternatively, an appropriate dose of acyclovir in intravenous formulation may be administered. The duration of prophylactic acyclovir therapy should be determined based on the duration of the risk period.

Pediatric patients: For prophylaxis of Herpes simplex virus infections in immunocompromised children aged 2 years and older, the adult dose may be used.

There are no adequate 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.

Geriatric patients: When treating elderly patients, possible presence of renal impairment should be considered and dose adjustment evaluated accordingly. Patients receiving high oral doses of acyclovir should maintain adequate hydration.

Renal impairment: Acyclovir should be used with caution in patients with renal impairment. Adequate hydration must be ensured. For treatment and prophylaxis of Herpes simplex infection in patients with severe renal impairment (glomerular filtration rate < 10 mL/min), the dose should be reduced to 200 mg twice daily every 12 hours. In such patients, the elimination half-life of acyclovir is approximately 20 hours; therefore, with longer intervals between doses, the recommended single dose does not lead to higher plasma levels.

Treatment of herpes zoster and varicella

Adults: 1 tablet of 800 mg 5 times daily every 4 hours, except during nighttime. Treatment duration — 7 days.

For patients with significant immunosuppression (e.g., after bone marrow transplantation) or malabsorption, intravenous administration of acyclovir should be considered.

Treatment should be initiated as early as possible after onset of disease; best results are achieved when treatment is started as soon as possible after appearance of skin symptoms.

Pediatric patients

For children aged 6 years and older: 1 tablet of 800 mg 4 times daily; for children aged 2–6 years: 1 tablet of 400 mg 4 times daily. Treatment duration is 5 days. The dose may be more precisely calculated based on body weight as 20 mg/kg body weight (not exceeding 800 mg) of acyclovir 4 times daily.

Geriatric patients: When treating elderly patients, possible presence of renal impairment should be considered and dose adjustment evaluated accordingly. Patients receiving high oral doses of acyclovir should maintain adequate hydration.

Renal impairment: Acyclovir should be used with caution in patients with renal impairment. Adequate hydration must be ensured. For patients with moderate renal impairment (glomerular filtration rate 10–25 mL/min), the recommended dosage is 800 mg 3 times daily every 8 hours. For patients with severe renal impairment (glomerular filtration rate < 10 mL/min), the recommended dosage is 800 mg twice daily every 12 hours.

Acyclovir is not suitable for prophylaxis of varicella in healthy individuals.

Children

Acyclovir tablets may be administered to children aged 2 years and older, as specified in the section "Dosage and administration".

Overdose

Symptoms

Acyclovir is only partially absorbed from the gastrointestinal tract. Cases of accidental oral intake of up to 20 g of acyclovir in adults have been reported without resulting in toxic effects. Accidental repeated overdose of oral acyclovir over several days may cause gastrointestinal (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 monitored for signs of intoxication. Since acyclovir is efficiently eliminated from the blood by hemodialysis, this method should be employed in cases of overdose.

Side effects

Side effects are classified by frequency as follows: very common ≥ 1/10; common ≥ 1/100, < 1/10; uncommon ≥ 1/1000, < 1/100; rare ≥ 1/10 000, < 1/1000; very rare < 1/10 000.

Blood and lymphatic system disorders

Very rare: anaemia, leucopenia, thrombocytopenia.

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-mentioned neurological reactions are usually reversible and generally 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 enzyme levels.

Very rare: hepatitis, jaundice.

Skin and subcutaneous tissue disorders

Common: itching, rash (including photosensitivity).

Uncommon: urticaria, diffuse alopecia.

Diffuse alopecia has been associated with many diseases and drugs; a clear association with aciclovir 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 and administration site conditions

Common: fatigue, fever.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. The product does not require special storage conditions.

Keep out of the reach of children.

Packaging. 10 tablets in a blister pack. 2 blisters in a carton.

Prescription category. Prescription only.

Manufacturer. JSC "Farmak".

Address of the manufacturer and location of its place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine