Valacyclovir-hetero

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VACICLOVIR-HETERO (VALACICLOVIR-HETERO)

Composition:

Active substance: valaciclovir;

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

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

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group. Direct-acting antiviral agents. ATC code J05A B11.

Pharmacological Properties.

Pharmacodynamics.

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

The 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, resulting in obligate (complete) chain termination, cessation of DNA synthesis, and thus blockade of viral replication.

Resistance is caused by a deficiency of viral thymidine kinase, leading to uncontrolled viral spread in the host organism. Occasionally, reduced sensitivity to acyclovir results from emergence of viral strains with altered viral TK or DNA polymerase structure. The virulence of these viral variants resembles that of wild-type strains.

Extensive monitoring of clinical isolates of herpes simplex virus and Varicella zoster virus in patients treated with acyclovir has shown that viruses with reduced sensitivity to acyclovir are very rare in immunocompetent patients and occur infrequently only in those with severe immunosuppression, such as after organ transplantation, bone marrow recipients, during chemotherapy for malignancies, and in HIV-infected individuals.

Valacyclovir accelerates pain resolution in the treatment of herpes zoster, reduces the duration of pain syndrome, and decreases 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 recipients), the frequency of opportunistic infections, and other infections caused by herpesviruses (herpes simplex virus and Herpes zoster virus).

Pharmacokinetics.

Absorption. After oral administration, valacyclovir is well absorbed and rapidly and almost completely converted into acyclovir and valine. This conversion appears to be mediated by the enzyme valacyclovir hydrolase, isolated from human liver. The bioavailability of acyclovir following a 1 g dose of valacyclovir is 54% and is not reduced by food intake. The pharmacokinetics of valacyclovir are not dose-proportional. The rate and extent of absorption decrease with increasing dose, resulting in less than proportional increases in maximum concentration (C_max) within the therapeutic dose range and reduced bioavailability when doses greater than 500 mg are administered. The mean peak concentration of acyclovir ranges from 10–37 µmol (2.2–8.3 µg/mL) after a single 250–2000 mg dose of valacyclovir in healthy volunteers with normal renal function, with a median time to peak concentration of 1–2 hours. The peak plasma concentration of valacyclovir is only about 4% of the acyclovir concentration and is reached on average within 30–100 minutes; it decreases below measurable levels within 3 hours. Pharmacokinetic parameters of valacyclovir and acyclovir are similar after single and repeated dosing.

Distribution. Plasma protein binding of valacyclovir is very low — 15%. Penetration into cerebrospinal fluid (CSF), determined by the CSF/AUC ratio, is approximately 25% for acyclovir and the metabolite 8-hydroxyacyclovir, and 2.5% for the metabolite 9-carboxymethoxymethylguanine.

Metabolism. After oral administration, valacyclovir is converted to acyclovir and L-valine via first-pass metabolism in the intestine and/or liver. A small portion of acyclovir is further metabolized to 9-carboxymethoxymethylguanine by alcohol and aldehyde dehydrogenase, and to 8-hydroxyacyclovir by aldehyde oxidase. Approximately 88% of the total drug concentration in plasma corresponds to acyclovir, 11% to 9-carboxymethoxymethylguanine, and 1% to 8-hydroxyacyclovir. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes.

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

Special patient groups. In patients with end-stage renal disease, the elimination 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 after oral administration of valacyclovir.

In a pharmacokinetic study of valacyclovir and acyclovir during late pregnancy, the area under the concentration-time curve (AUC) of acyclovir at steady state after administration of 1000 mg valacyclovir was approximately twice higher than after oral administration of 1200 mg acyclovir per day.

In HIV-infected patients, the pharmacokinetic characteristics of acyclovir after single or multiple doses of 1000 mg or 2000 mg valacyclovir were unchanged compared to healthy volunteers.

In organ transplant recipients receiving valacyclovir 2000 mg four times daily, the C_max of acyclovir was equal to or higher than in healthy volunteers receiving the same dose, and daily AUC values were significantly greater.

Clinical characteristics.

Indications.

Treatment of herpes zoster (Herpes zoster).

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

Treatment of labial herpes (cold sores).

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

Reduction of transmission of genital herpes virus to healthy partners when valacyclovir is used as suppressive therapy in combination with safe sex practices.

Prophylaxis of cytomegalovirus (CMV) infection and disease following organ transplantation.

Contraindications.

The medicinal product is contraindicated in patients with hypersensitivity to valacyclovir, acyclovir, or to any excipient of the formulation.

Interaction with other medicinal products and other types of interactions.

The combination of valacyclovir with nephrotoxic medicinal products should be used with caution, especially in patients with impaired renal function, with regular monitoring of renal function. This applies to concomitant use with aminoglycosides, platinum-containing compounds, iodinated contrast agents, methotrexate, pentamidine, foscarnet, cyclosporine, and tacrolimus.

Acyclovir is predominantly excreted unchanged in urine via active tubular secretion. After administration of 1000 mg of valacyclovir, cimetidine and probenecid reduce the renal clearance of acyclovir and increase acyclovir AUC by approximately 25% and 45%, respectively, by inhibiting active renal secretion of acyclovir. Cimetidine and probenecid administered together with valacyclovir increased acyclovir AUC by approximately 65%. Other concomitantly administered medicinal products that compete for or inhibit active tubular secretion (e.g., tenofovir) may increase acyclovir concentrations via this mechanism. Similarly, valacyclovir administration may increase plasma concentrations of co-administered substances.

Caution is required when patients are exposed to higher acyclovir exposure than from valacyclovir (e.g., doses used for treatment of herpes zoster or CMV prophylaxis) in combination with agents that inhibit active renal tubular secretion.

When these drugs were co-administered, increased AUC of acyclovir and of the inactive metabolite of mycophenolate mofetil, an immunosuppressant used in transplant patients, was observed. However, in healthy volunteers, no changes in Cmax or AUC were observed when valacyclovir and mycophenolate mofetil were administered together. Clinical experience with this combination is limited.

Special precautions for use.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome)

DRESS syndrome has been reported with the use of valacyclovir, which may be life-threatening or fatal. Patients should be informed about the signs and symptoms of DRESS syndrome when valacyclovir is prescribed, and potential skin reactions should be closely monitored. If signs or symptoms suggestive of DRESS syndrome occur, valacyclovir should be discontinued immediately and alternative therapy considered if necessary. Valacyclovir must not be re-administered to patients who have previously experienced DRESS syndrome.

Hydration

Adequate fluid intake should be maintained in patients at increased risk of dehydration, particularly elderly patients.

Use in patients with renal impairment and elderly patients

Acyclovir is eliminated by the kidneys; therefore, the dose of valacyclovir should be reduced in patients with impaired renal function (see section "Dosage and administration"). Elderly patients often have reduced renal function and require dose adjustment. The risk of neurological complications is increased in patients with renal impairment and in elderly patients; careful monitoring for such effects is required. According to reported data, these reactions are mostly reversible upon discontinuation of treatment (see section "Adverse reactions").

Use of higher doses of valacyclovir in hepatic insufficiency and liver transplantation

There are no data on the use of higher doses of valacyclovir (4 g or more per day) for the treatment of patients with liver disease; therefore, higher doses of valacyclovir should be prescribed with caution in such patients. Specific studies on the use of valacyclovir in liver transplantation have not been conducted; however, it has been established that prophylaxis with high-dose acyclovir reduces the incidence of cytomegalovirus-related infection and disease.

Use in the treatment of herpes zoster

Careful monitoring of clinical response is required when treating patients, especially those who are immunocompromised. If the response to treatment is inadequate, intravenous antiviral therapy should be considered. Patients with complicated herpes zoster, such as visceral organ involvement, viral dissemination, motor neuropathy, encephalitis, or cerebrovascular complications, should be treated with intravenous antiviral agents.

Additionally, immunocompromised patients with herpetic eye lesions or those at high risk of disease dissemination and visceral organ involvement should be treated with intravenous antiviral agents.

Reduction of the risk of transmission of genital herpes

Suppressive therapy with valacyclovir reduces the risk of transmission of genital herpes. However, it does not cure herpes infection and does not completely eliminate the risk of viral transmission. In addition to valacyclovir therapy, patients are advised to follow safe sex practices.

Use in cytomegalovirus infection

Data on efficacy obtained from treating patients at high risk of cytomegalovirus infection for prophylaxis after organ transplantation indicate that valacyclovir should be used in these patients if valganciclovir or ganciclovir have been discontinued for safety reasons. The use of high doses of valacyclovir required for cytomegalovirus prophylaxis may lead to a higher frequency of adverse reactions, including those affecting the nervous system, compared to lower doses used for other indications. Renal function should be closely monitored and appropriate dose adjustments made.

Use during pregnancy or breastfeeding

Fertility

Animal studies indicate that valacyclovir has no effect on fertility. However, high parenteral doses of acyclovir have caused testicular effects in animals.

Clinical studies evaluating the effect of valacyclovir on human fertility have not been conducted. However, no changes in sperm count, morphology, or motility were observed after 6 months of daily administration of acyclovir at doses ranging from 400 mg to 1 g.

Pregnancy

Limited data on the use of valacyclovir and a moderate amount of data on the use of acyclovir during pregnancy (pregnancy outcomes in women who received valacyclovir or acyclovir—the active metabolite of valacyclovir—either orally or intravenously), as well as post-marketing experience, indicate no evidence of developmental abnormalities or fetal/neonatal toxicity. Animal studies have not shown reproductive toxicity with valacyclovir. Valacyclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breastfeeding period

Acyclovir, the primary metabolite of valacyclovir, is excreted in breast milk. However, when therapeutic doses of valacyclovir are administered, no adverse effects are expected in breastfed newborns/infants, as the dose received by the infant is less than 2% of the therapeutic dose of intravenous acyclovir used to treat neonatal herpes. Valacyclovir should be used with caution during breastfeeding and only when clinically indicated.

Ability to affect reaction speed when driving or operating machinery

Clinical data on this issue are lacking, and the pharmacology of valacyclovir does not suggest any expected negative effect. However, when assessing a patient's ability to drive or operate machinery, their clinical condition and the adverse effect profile of valacyclovir should be taken into account.

Dosage and Administration

Herpes zoster treatment: Adults should take 1000 mg (2 tablets) of the drug three times daily for 7 days.

Treatment of infections caused by herpes simplex virus

Immunocompetent patients (adults): 500 mg (1 tablet) of the drug twice daily.

For recurrent episodes, treatment should last 3 or 5 days. In cases of primary infection, which may be more severe, treatment should be extended from 5 to 10 days. Therapy should be initiated as early as possible. For recurrent infections caused by herpes simplex virus, optimal treatment involves administering the drug during the prodromal phase or immediately after the first symptoms appear. Valacyclovir may prevent lesion development in recurrent herpes simplex virus infections if treatment is started immediately upon onset of the first symptoms.

Alternatively, for the treatment of labial herpes (cold sores), an effective valacyclovir regimen is 2000 mg (4 tablets) twice daily for 1 day. The second dose should be taken approximately 12 hours (but not earlier than 6 hours) after the first dose. With this dosing regimen, treatment duration should not exceed 1 day, as prolonged administration has not been shown to increase clinical efficacy. Treatment should be initiated at the first sign of early symptoms of labial herpes (such as tingling, itching, or burning around the lips).

Suppressive (prophylactic) therapy for recurrent herpes simplex virus infections:

• For immunocompetent patients (adults): 500 mg (1 tablet) once daily;
• For immunocompromised patients (adults): 500 mg (1 tablet) twice daily.

Reduction of genital herpes virus transmission

For immunocompetent adult heterosexuals who experience 9 or fewer recurrences per year, the infected partner should be prescribed valacyclovir 500 mg once daily.

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

Prophylaxis of cytomegalovirus infection and disease

Adults and children aged 12 years and older: valacyclovir should be administered at a dose of 2000 mg (4 tablets) four times daily, as soon as possible after transplantation. Doses should be reduced in cases of renal impairment (see "Dosage in Renal Impairment" below). The usual duration of treatment is 90 days, but may be extended for patients at high risk.

Dosage in Renal Impairment

Valacyclovir should be used with caution in patients with impaired renal function. Adequate hydration must be maintained.

The dosage regimen depends on creatinine clearance and the indication, and is specified in the table below.

*Use when 250 mg tablets of the drug are available.

For patients undergoing intermittent hemodialysis, the same doses of valacyclovir are recommended as for patients with a creatinine clearance of 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. The dose of valacyclovir should be adjusted accordingly.

Dosing in hepatic impairment

Dose adjustment is not required in patients with mild to moderate cirrhosis (preserved synthetic liver function). Pharmacokinetic data in advanced cirrhosis (with impaired synthetic liver function and signs of portal hypertension) suggest that dose adjustment is not necessary; however, clinical experience is limited.

For use of higher doses (4000 mg and above) per day, see section "Special precautions".

Elderly patients

Valacyclovir dosage may require adjustment to avoid potential renal function impairment (see "Dosing in renal impairment" above).

Adequate hydration should be maintained.

Children.

Valacyclovir is indicated for children aged 12 years and older for the prevention of cytomegalovirus infection and disease.

Overdose.

Symptoms

Overdose with valacyclovir has been associated with acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, reduced intellectual abilities, and coma. Nausea and vomiting may also occur. Caution should be exercised to prevent unintentional overdose. Many cases of overdose have been reported in patients with renal impairment and in elderly patients who did not receive appropriate dose reduction.

Treatment

Patients should be closely monitored under medical supervision for signs of toxicity. Hemodialysis significantly accelerates the elimination of acyclovir from the blood and may therefore be considered the optimal treatment approach in cases of symptomatic overdose.

Adverse Reactions

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

Adverse reactions listed below are classified by system organ class and frequency of occurrence. Frequency categories are defined as follows: 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), and frequency not known (cannot be estimated from available data).

Nervous system disorders

Common: headache.

Gastrointestinal disorders

Common: nausea.

Blood and lymphatic system disorders

Very rare: leukopenia, thrombocytopenia.

Leukopenia is primarily observed in patients with immunodeficiency.

Immune system disorders

Very rare: anaphylaxis.

Nervous system and psychiatric disorders

Rare: dizziness, confusion, hallucinations, cognitive decline.

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

Neurological disorders, sometimes severe, may be associated with encephalopathy and may include confusion, agitation, seizures, hallucinations, and coma. These symptoms are mostly reversible and primarily occur in patients with renal impairment or other predisposing factors (see section "Special precautions for use"). Neurological reactions occur more frequently in post-transplant patients receiving high-dose valacyclovir (8 g daily) for cytomegalovirus infection prophylaxis than in patients receiving lower doses.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea.

Gastrointestinal disorders

Rare: abdominal discomfort, vomiting, diarrhea.

Hepatobiliary disorders

Very rare: reversible increases in liver function tests (e.g., bilirubin, liver enzymes).

Skin and subcutaneous tissue disorders

Uncommon: rash, including photosensitivity reactions.

Rare: pruritus.

Very rare: urticaria, angioneurotic edema.

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP).

Renal and urinary disorders

Rare: renal dysfunction, acute renal failure (particularly in elderly patients or patients with impaired renal function receiving doses higher than recommended), flank pain, hematuria (often associated with other renal function abnormalities).

Frequency not known: tubulointerstitial nephritis.

Flank pain may be associated with renal impairment.

Crystalluria and acyclovir precipitation in renal tubules have been reported. Adequate hydration should be maintained during treatment (see section "Special precautions for use").

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 receiving high doses (8000 mg daily) of valacyclovir for prolonged periods in clinical trials. Similar events have also been observed in patients with the same conditions who were not treated with valacyclovir.

Reporting of adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

Blister packs of 10 (5×2) and 30 (6×5) tablets in cardboard boxes.

Prescription status. Prescription only.

Manufacturer. Hetero Labs Limited, India.

Manufacturer's address and location of operations.

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