Aciclovir 800 stada®
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACYCLOVIR 800 STADA® (ACYCLOVIR 800 STADA®)
Composition:
Active substance: acyclovir;
1 tablet contains 800 mg of acyclovir;
Excipients: microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), copovidone, magnesium stearate.
Pharmaceutical form. Tablets.
Main physicochemical characteristics: white, elongated tablets with a score line on both sides and an imprint "VS 3".
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, Epstein-Barr virus, and cytomegalovirus. In cell culture, acyclovir exhibits 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 its toxic 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. After incorporation into viral DNA, acyclovir triphosphate interacts with viral DNA polymerase, resulting in termination of the viral DNA chain synthesis.
With prolonged or repeated treatment courses in severely ill patients with compromised immunity, reduced sensitivity of certain viral strains may occur, leading to suboptimal response to acyclovir therapy. Most cases of resistance have been associated with deficiency 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 treatment has not been fully established.
Pharmacokinetics.
Acyclovir is only partially absorbed in the gastrointestinal tract. The mean peak steady-state plasma concentration (Cssmax) following a 200 mg dose administered at 4-hour intervals is 3.1 µmol (0.7 µg/mL), with the corresponding trough plasma level (Cssmin) being 1.8 µmol (0.4 µg/mL). Corresponding Cssmax levels after 400 mg and 800 mg doses given at 4-hour intervals are 5.3 µmol (1.2 µg/mL) and 8 µmol (1.8 µg/mL), respectively, while the corresponding Cssmin levels are 2.7 µmol (0.6 µg/mL) and 4 µmol (0.9 µg/mL).
In adults, the terminal elimination half-life after 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.
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 remains unchanged when co-administered with other medicinal products.
No pharmacokinetic interactions were observed between acyclovir and zidovudine when used concomitantly in 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 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 other component of the drug.
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 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 the immunosuppressant mycophenolate mofetil, used in the treatment of organ transplant patients, 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 "Directions for use and dosage"). Elderly patients also have a higher probability of impaired renal function, so dose reduction may also be required in this patient group. Both of these groups (patients with renal impairment and elderly patients) are at risk of developing neurological adverse reactions and should therefore be closely monitored for their detection. 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 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 possible 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 with caution, considering 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 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 studied. However, the pharmacological profile of acyclovir provides no basis to expect any negative impact.
Method of Administration and Dosage.
The tablet should be taken whole, with water. When high doses of acyclovir are used, adequate hydration of the body must be maintained.
Adults
Treatment of infections caused by herpes simplex virus
For treatment of infections caused by herpes simplex virus, acyclovir tablets should be taken at a dose of 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 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 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, 200 mg tablets should be taken 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 when the dose of acyclovir is reduced 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 after taking a daily dose of acyclovir of 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, 200 mg tablets should be taken 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 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 and herpes zoster viruses, tablets should be taken at a dose of 800 mg 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 onset of disease; better outcomes are achieved when treatment is started 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 be given adult doses.
For treatment of varicella in children aged 6 years and older, 800 mg of acyclovir should be administered 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/day (not exceeding 800 mg) of acyclovir, divided into four doses.
This dosage form should not be used in children under 2 years of age.
Elderly Patients
Renal function impairment should be considered in elderly patients; dosage should be adjusted accordingly (see "Renal Impairment"). Adequate hydration must be maintained.
Renal Impairment
Acyclovir should be administered 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; for patients with moderate renal impairment (creatinine clearance 10–25 mL/min), 800 mg three times daily at approximately 8-hour intervals is recommended.
If a dose less than 400 mg is required, acyclovir in an appropriate dosage strength or pharmaceutical form should be used.
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 immunocompetent children.
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 result in 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 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 side effects listed below are classified by organs and systems and by their frequency of occurrence. Frequency categories: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and <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-mentioned neurological reactions are generally reversible and usually occur in patients with renal impairment or other risk factors (see section "Special precautions").
Respiratory system and thoracic 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 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 reach and sight of children.
Packaging.
5 tablets in a blister; 7 blisters in a cardboard box.
Prescription category. Prescription only.
Manufacturer.
STADA Arzneimittel AG.
Manufacturer's address and place of business.
Stadastrasse 2-18, 61118 Bad Vilbel, Germany.