Valacyclovir-Hetero tablets No. 30

Instructions for Valacyclovir-Hetero tablets No. 30

Composition

active ingredient: valacyclovir;

1 tablet contains 500 mg of valacyclovir (as valacyclovir hydrochloride);

excipients: microcrystalline cellulose, crospovidone, povidone, magnesium stearate; coating: Opadry White YS-1-7003 (titanium dioxide (E 171), hypromellose, polyethylene glycol 400, polysorbate 80).

Dosage form

Film-coated tablets.

Main physicochemical properties: white or almost white, capsule-shaped tablets, film-coated with the inscription "V" on one side and "500" on the other.

Pharmacotherapeutic group

Direct-acting antiviral drugs.

ATX code J05A B11.

Pharmacological properties

Pharmacodynamics.

Valacyclovir is an antiviral drug, the L-valine ester of acyclovir, which is an analogue of a purine (guanine) nucleoside. In the human body, valacyclovir is rapidly and almost completely converted to acyclovir and valine by valacyclovir hydrolase. Acyclovir is a specific inhibitor of herpes viruses with in vitro activity against herpes simplex viruses types I and II, Varicella zoster virus, cytomegalovirus, Epstein-Barr virus and human herpes virus type VI. Acyclovir inhibits viral DNA synthesis immediately after phosphorylation and conversion to the active form of triphosphatecyclovir. The first stage of phosphorylation requires the activity of a virus-specific enzyme. For herpes simplex virus, Varicella zoster virus and Epstein-Barr virus, this is viral thymidine kinase (TK), which is present only in cells infected with the virus. Partial selectivity of phosphorylation is preserved in cytomegalovirus infection and is mediated through the phosphotransferase gene product UL97. Activation of acyclovir by a specific viral enzyme largely explains its selectivity.

The process of phosphorylation of acyclovir (conversion from mono- to triphosphate) is carried out by cellular kinases. Acyclovir triphosphate competitively inhibits viral DNA polymerase and is incorporated into viral DNA, which leads to obligate (complete) chain termination, cessation of DNA synthesis, and, consequently, to blocking viral replication.

Resistance is due to a deficiency in the viral thymidine kinase, which leads to excessive proliferation of the virus in the host. Sometimes reduced susceptibility to acyclovir is due to the emergence of virus strains with a disrupted structure of the viral TC or DNA polymerase. The virulence of these variants of the virus resembles that of its wild-type strain.

Extensive monitoring of clinical isolates of herpes simplex virus and Varicella zoster virus in patients treated with acyclovir has made it possible to find out that in patients with normal immunity, a virus with reduced sensitivity to acyclovir is very rare and infrequently manifests itself only in patients with severe immune disorders, for example, after organ transplantation or in bone marrow recipients, during chemotherapy for malignant neoplasms and HIV-infected patients.

Valacyclovir accelerates the cessation of pain in the treatment of herpes zoster, reduces the duration of pain syndrome, as well as the number of patients with zoster-associated pain, including acute and postherpetic neuralgia.

Prophylaxis of cytomegalovirus infection with valacyclovir reduces the risk of acute transplant rejection (in kidney transplant patients), the incidence of opportunistic infections, and other infections caused by the herpes virus (herpes simplex virus and herpes zoster virus).

Pharmacokinetics.

Absorption

After oral administration, valaciclovir is well absorbed, rapidly and almost completely converted to acyclovir and valine. This conversion, apparently, occurs with the help of the enzyme valaciclovir hydrolase, isolated from the human liver. The bioavailability of acyclovir when taking 1 g of valaciclovir is 54% and is not reduced by food intake. The pharmacokinetics of valaciclovir are not dose-dependent. The rate and extent of absorption decrease with increasing dose, causing a less proportional increase in Cmax within the therapeutic dose range and a decrease in bioavailability when using doses greater than 500 mg. The average peak concentration of acyclovir is 10-37 μmol (2.2-8.3 μg / ml) after a single dose of 250-2000 mg of valaciclovir in healthy volunteers with normal renal function, and the median time to reach this concentration is 1-2 hours. Peak plasma concentrations of valacyclovir are only 4% of those of acyclovir and occur on average within 30-100 minutes, and decline below measurable levels within 3 hours. The pharmacokinetics of valacyclovir and acyclovir are similar after single and repeated administration.

Distribution

The binding of valaciclovir to plasma proteins is very low - 15%. Penetration into cerebrospinal fluid (CSF), determined by the ratio of CSF/plasma AUC, is approximately 25% for acyclovir and the metabolite 8-hydroxyacyclovir and 2.5% for the metabolite 9-carboxymethoxymethylguanine.

After oral administration, valaciclovir is converted to acyclovir and L-valine by first-pass metabolism in the intestine and/or liver. To a small extent, acyclovir is converted to the metabolites 9-carboxymethoxymethylguanine by alcohol and aldehyde dehydrogenase and to 8-hydroxycyclovir by aldehyde oxidase. Approximately 88% of the total plasma exposure is attributable to acyclovir, 11% to 9-carboxymethoxymethylguanine, and 1% to 8-hydroxycyclovir. Neither valaciclovir nor acyclovir is metabolized by cytochrome P450 enzymes.

Breeding

The half-life of acyclovir after single and multiple doses of valaciclovir in patients with normal renal function is approximately 3 hours. Valaciclovir is excreted in the urine mainly as acyclovir (more than 80% of the dose) and its metabolite 9-carboxymethoxymethylguanine.

Special patient groups

In patients with end-stage renal failure, the half-life of acyclovir is approximately 14 hours.

Herpes zoster virus and herpes simplex virus do not significantly alter the pharmacokinetics of acyclovir and valacyclovir following oral administration of valacyclovir.

In a study of the pharmacokinetics of valaciclovir and acyclovir during late pregnancy, the area under the acyclovir concentration-time curve in the plateau phase after administration of valaciclovir at a dose of 1000 mg was approximately 2 times higher than after administration of acyclovir orally at a dose of 1200 mg per day.

In patients with HIV infection, the pharmacokinetic characteristics of acyclovir after single or multiple doses of 1000 mg or 2000 mg of valaciclovir did not change compared to those in healthy subjects.

In organ transplant recipients receiving valaciclovir at a dose of 2000 mg 4 times / day, the maximum concentration of acyclovir was equal to or greater than that in healthy volunteers receiving the same dose of the drug, and the daily area under the "concentration-time" curve was significantly higher.

Indication

Treatment of shingles (Herpes zoster).

Treatment of infections of the skin and mucous membranes caused by the herpes simplex virus, including primary and recurrent genital herpes.

Treatment of labial herpes (cold sores).

Preventive treatment (suppression) of recurrences of skin and mucous membrane infections caused by the herpes simplex virus, including genital herpes.

Reducing transmission of genital herpes virus to a healthy partner when using valacyclovir as suppressive therapy in combination with safe sex.

Prevention of cytomegalovirus infection and disease after organ transplantation.

Contraindication

Valacyclovir is contraindicated in patients with hypersensitivity to valacyclovir, acyclovir, or any component of the drug.

Interaction with other medicinal products and other types of interactions

No clinically significant forms of interactions were identified.

Acyclovir is excreted mainly unchanged in the urine by active tubular secretion. Any drugs administered concurrently that affect this mechanism of excretion may increase the concentration of acyclovir in the blood plasma after the use of valacyclovir. After taking valacyclovir at a dose of 1 g and cimetidine and probenecid, which block tubular secretion, the area under the "concentration-time" curve of acyclovir increases and its renal clearance decreases, but there is no need to change the dose given the wide therapeutic index of acyclovir.

For patients receiving higher doses of valaciclovir (4 g or more per day), caution should be exercised when co-administering drugs that compete with acyclovir for elimination pathways, as this may lead to increased plasma levels of one or both drugs and their metabolites. Concomitant use with mycophenolate mofetil (an immunosuppressive drug used after organ transplantation) increases plasma levels of acyclovir and the inactive metabolite of mycophenolate mofetil.

Caution should also be exercised (with monitoring of changes in renal function) when co-administering high doses of valacyclovir (4 g or more) and other drugs that affect renal function (e.g. cyclosporine, tacrolimus).

Application features

Hydration: Adequate fluid intake should be maintained in patients at increased risk of dehydration, especially the elderly.

Use in renal impairment and elderly patients

Acyclovir is excreted by the kidneys, and therefore the dose of valaciclovir should be reduced in patients with impaired renal function (see section "Method of administration and dosage"). Elderly patients have reduced renal function and require dose adjustment. Patients with impaired renal function and elderly patients are at increased risk of developing neurological complications, they need careful monitoring for these effects. According to reports, such reactions are reversible in most cases after discontinuation of treatment (see section "Adverse reactions").

There are no data on the use of higher doses of valacyclovir (4 mg/day or more) in patients with liver disease, and caution should be exercised when prescribing higher doses of valacyclovir to such patients. Valacyclovir has not been specifically studied in liver transplantation; however, prophylaxis with high doses of acyclovir has been shown to reduce the incidence of cytomegalovirus infection and disease.

Use in the treatment of herpes zoster

When treating patients, especially those who are immunocompromised, clinical response should be closely monitored. If the response to treatment is inadequate, intravenous antiviral therapy is recommended. Patients with complicated herpes zoster, such as those with visceral involvement, viral dissemination, motor neuropathy, encephalitis, and cerebrovascular disorders, should be treated with intravenous antiviral agents.

In addition, immunocompromised patients who have herpetic ocular lesions or are at high risk of disease dissemination and visceral organ involvement should be treated with intravenous antiviral agents.

Reducing the risk of transmitting the genital herpes virus

Suppressive therapy with valacyclovir reduces the risk of transmission of genital herpes. It does not cure herpes infection, nor does it completely eliminate the risk of transmission of the virus. In addition to valacyclovir therapy, it is recommended that patients practice safe sex.

Use in cytomegalovirus infection

Efficacy data from the treatment of patients at high risk of CMV infection for prophylaxis after organ transplantation suggest that valaciclovir should be used in these patients if valganciclovir or ganciclovir has been discontinued for safety reasons. The high doses of valaciclovir required for CMV prophylaxis may be associated with a higher incidence of adverse reactions, including nervous system disorders, compared with the lower doses used for other indications. Patients should be closely monitored for renal function and the dose adjusted accordingly.

Use during pregnancy or breastfeeding

Fertility

Animal studies have shown that valacyclovir had no effect on fertility. However, high parenteral doses of acyclovir have been shown to cause testicular effects in animals.

Clinical studies investigating the effect of valacyclovir on human fertility have not been conducted, however, after 6 months of daily use of acyclovir at a dose of 400 mg to 1 g, no changes in sperm count, morphology, or motility were observed.

Pregnancy

Data on the use of valaciclovir during pregnancy are limited. Valaciclovir should be used in pregnant women only if the potential benefit to the mother outweighs the potential risk to the fetus. There are documented data from a registry of pregnant women exposed to valaciclovir or any form of acyclovir (the active metabolite of valaciclovir): 111 and 1,246 women, respectively (29 and 756 pregnant women, respectively, used valaciclovir or any form of acyclovir in the first trimester of pregnancy). According to the results of this observation, no increase in birth defects was observed in newborns whose mothers took acyclovir compared with the general population of such patients. Any birth defect was not of a unique or persistent nature that could be attributed to a single cause. Given the small number of pregnant women who were observed, a reliable and definitive conclusion regarding the safety of valaciclovir in pregnancy cannot be made (see section "Pharmacological properties").

Breast-feeding

Acyclovir, the main metabolite of valaciclovir, is excreted in breast milk. It was found that after daily administration of 500 mg of valaciclovir, the average peak concentration of acyclovir in breast milk was 0.5-2.3 (average 1.4) times higher than the concentration of acyclovir in maternal plasma. The ratio of acyclovir concentration in breast milk to maternal plasma is 1.4 to 2.6 (average 2.2). The average concentration of acyclovir in breast milk was 2.24 μg/ml (9.95 μmol). If the mother takes valaciclovir at a dose of 500 mg 2 times a day, the child will receive a dose of acyclovir with breast milk of approximately 0.61 μg/kg per day. The half-life of acyclovir from breast milk is similar to the half-life from plasma. Unchanged valaciclovir is not detected in maternal plasma, breast milk, or infant urine.

Valaciclovir should be administered with caution to breastfeeding women only if clinically necessary. However, acyclovir has been used to treat newborns with herpes simplex infections at intravenous doses of 30 mg/kg/day.

Ability to influence reaction speed when driving vehicles or other mechanisms

There are no clinical trial data on this issue, and the pharmacology of valacyclovir does not suggest any adverse effects. However, when assessing a patient's ability to drive or operate machinery, the patient's clinical condition and the side-effect profile of valacyclovir should be taken into account.

Method of administration and doses

Treatment of herpes zoster: adults should take 1000 mg (2 tablets) of the drug 3 times a day for 7 days.

Treatment of infections caused by the herpes simplex virus

Patients with normal immunity (adults): 500 mg (1 tablet) of the drug 2 times a day.

For recurrent cases, treatment should last 3 or 5 days. In the case of a primary course, which may be more severe, treatment should be continued for 5 to 10 days. Treatment should be started as early as possible. For recurrent forms of herpes simplex infections, the ideal would be to use the drug in the prodromal period or immediately after the first symptoms appear. Valaciclovir can prevent the development of lesions in recurrent herpes simplex infections, provided that treatment is started immediately after the first symptoms of the disease appear.

Alternatively, for the treatment of herpes labialis (cold sores), the effective dose of valaciclovir is 2000 mg (4 tablets) 2 times a day for 1 day. The second dose should be administered approximately 12 hours (not earlier than 6 hours) after the first dose. With this dosing regimen, the duration of treatment should not exceed 1 day, as it has been proven that longer use does not increase the clinical effectiveness of the treatment. Treatment should be initiated at the first early symptoms of herpes labialis (tingling, itching or burning sensation in the lip area).

Preventive treatment (suppression) of recurrences of infections caused by the herpes simplex virus:

- patients with normal immunity (adults) should be prescribed 500 mg (1 tablet) of the drug once a day;

- for immunocompromised patients (adults), prescribe a dose of 500 mg (1 tablet) 2 times a day.

Reducing transmission of the genital herpes virus.

For immunocompetent heterosexual adults who have 9 or fewer exacerbations per year, valacyclovir is prescribed to the infected partner at a dose of 500 mg once daily.

There is no data on the reduction of the risk of transmission of the genital herpes virus in other patient populations.

Prevention of cytomegalovirus infection and disease.

Adults and children 12 years of age and older: valaciclovir is prescribed at a dose of 2000 mg (4 tablets) 4 times a day, as early as possible after transplantation. In renal failure, the dose is reduced (see "Dosage in renal impairment"). The duration of treatment is usually 90 days, but may be extended for high-risk patients.

Dosage in renal impairment.

Valacyclovir should be administered with caution to patients with impaired renal function. Adequate hydration should be maintained.

The dosage regimen depends on creatinine clearance and indications and is given in the table.

*Use if 250 mg tablets are available.

Patients on intermittent hemodialysis are recommended to use the same doses of valaciclovir as those used in patients with creatinine clearance less than 15 ml/min. Doses should be administered after hemodialysis.

Creatinine clearance should be monitored regularly, especially during periods when renal function may change rapidly, such as immediately after transplantation, and the dose of valaciclovir should be adjusted accordingly.

Dosage in hepatic impairment

There is no need to change the dose in patients with mild or moderate cirrhosis (liver synthesis function is preserved). Pharmacokinetic parameters in the late stages of cirrhosis (with impaired liver synthesis function and signs of portal block) indicate that there is no need to change the dosage, but clinical experience is limited.

For the use of higher doses (4000 mg and more) per day, see the section "Special instructions for use".

The dose of valaciclovir requires adjustment to avoid possible renal impairment (see “Dosage in renal impairment”).

It is necessary to maintain an adequate level of hydration of the body.

Children

It is used in children aged 12 years and older to prevent cytomegalovirus infection and disease.

Overdose

Symptoms

Acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased mental status, and coma, have been reported with valaciclovir overdose. Nausea and vomiting may occur. Caution should be exercised when administering valaciclovir to patients with renal impairment or the elderly, in whom the dose was not reduced appropriately.

Treatment

Patients should be closely monitored for signs of toxicity. Hemodialysis significantly accelerates the removal of acyclovir from the blood and may therefore be considered the optimal treatment for symptomatic overdose.

Adverse reactions

The most common adverse reactions reported in clinical trials were headache and nausea. More serious adverse reactions included reports of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, acute renal failure, and neurological disorders.

The adverse reactions listed below are classified by system organ class and frequency. By frequency of occurrence, adverse reactions are divided into the following categories:

very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (<1/10000).

From the nervous system

Common: headache.

From the digestive tract

Common: nausea.

Blood and lymphatic system disorders

Very rare: leukopenia, thrombocytopenia.

Leukopenia is mainly observed in patients with immunodeficiency.

On the part of the immune system

Very rare: anaphylaxis.

Nervous system and mental disorders

Rare: dizziness, confusion, hallucinations, decreased mental abilities.

Very rare: agitation, tremor, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy, coma.

The above symptoms are reversible in most cases and are observed mainly in patients with renal insufficiency or other predisposing factors (see section "Special instructions for use"). In patients after organ transplantation who receive valaciclovir for the prevention of cytomegalovirus infection in high doses (8 g per day), neurological reactions occur more often than in patients receiving lower doses.

Respiratory and thoracic disorders

Uncommon: dyspnoea.

From the digestive tract

Rare: abdominal discomfort, vomiting, diarrhea.

Hepatobiliary system

Very rare: reversible increase in liver function tests.

This is occasionally described as hepatitis.

Skin and subcutaneous tissue disorders

Uncommon: rash, including photosensitivity reactions.

Rare: itching.

Very rare: urticaria, angioedema.

Renal and urinary disorders

Rare: renal dysfunction.

Very rare: acute renal failure, kidney pain, haematuria (often associated with other renal dysfunction).

Kidney pain may be associated with kidney failure.

Acyclovir precipitates have been reported to form in the renal tubules. Adequate fluid intake should be ensured during treatment (see section 4.4).

Other: There have been reports of renal failure, microangiopathic hemolytic anemia, and thrombocytopenia (sometimes in combination) in severely immunocompromised patients, particularly those with advanced HIV disease, who received high doses (8000 mg/day) of valaciclovir for prolonged periods in clinical trials. These events have also been observed in patients with the same conditions who were not treated with valaciclovir.

Expiration date

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25ºС, out of the reach of children.

Packaging

No. 10 (5×2), No. 30 (6×5) tablets in blisters, in a cardboard box.

Vacation category

According to the recipe.

Producer

Hetero Labs Limited, India / Hetero Labs Limited, India.

Location of the manufacturer and its business address

Unit III, Formulation Plot No. 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.