Uviromed

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT UVIROMED (UVIROMED)

Composition:

Active substance: valacyclovir;

One film-coated tablet contains valacyclovir (as valacyclovir hydrochloride) 1000 mg;

Excipients: microcrystalline cellulose type 101, povidone K30, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: Opadry® II 85F18422 White (polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), polyethylene glycol (macrogol), talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: elongated biconvex film-coated tablets of white color, engraved with "U1000" on one side and a score line on the other side.

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

Pharmacological Properties.

Pharmacodynamics.

Valacyclovir is an antiviral agent, the L-valine ester of acyclovir, which is a purine (guanine) nucleoside analogue. In the human body, valacyclovir is rapidly and almost completely converted into 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 immediately after phosphorylation and conversion into the active form, acyclovir triphosphate. The initial phosphorylation step requires the activity of a virus-specific enzyme. For herpes simplex virus, Varicella zoster virus, and Epstein-Barr virus, this is the viral 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 phosphotransferase gene product. The activation of acyclovir by specific viral enzymes largely explains its selectivity.

The phosphorylation process 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, leading to obligate (complete) chain termination, cessation of DNA synthesis, and thus blocking viral replication.

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

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 occur extremely rarely in immunocompetent patients and are observed infrequently only in patients with severe immunodeficiency, such as after organ transplantation or bone marrow recipients, during chemotherapy for malignant neoplasms, and in HIV-infected individuals.

Valacyclovir accelerates pain resolution during treatment of herpes zoster, reducing the duration of pain syndrome. It also reduces 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 occur via the enzyme valacyclovir hydrolase isolated from human liver. The bioavailability of acyclovir following administration of 1 g of valacyclovir is 54% and is not reduced by food intake. The pharmacokinetics of valacyclovir is not dose-dependent. The rate and extent of absorption decrease with increasing dose, resulting in a less than proportional increase in maximum concentration (Cmax) within the therapeutic dose range and reduced bioavailability when doses greater than 500 mg are administered. The Cmax of acyclovir ranges from 10–37 µmol (2.2–8.3 µg/mL) after a single dose of 250–2000 mg of valacyclovir in healthy volunteers with normal renal function, with a median time to reach this concentration of 1–2 hours. The Cmax of valacyclovir in plasma is only 4% of the acyclovir concentration, reached on average within 30–100 minutes, and decreases below measurable levels within 3 hours. Pharmacokinetic parameters of valacyclovir and acyclovir are similar after both single and repeated administration.

Distribution.

Plasma protein binding of valacyclovir is very low – 15%. Penetration into cerebrospinal fluid (CSF), determined by the CSF/AUC (area under the plasma concentration-time curve) ratio, is approximately 25% for acyclovir and its metabolite 8-hydroxyacyclovir, and 2.5% for the metabolite 9-carboxymethoxymethylguanine.

Metabolism.

After oral administration, valacyclovir is converted to acyclovir and L-valine through first-pass metabolism in the intestine and/or liver. A small portion of acyclovir is further converted to the metabolite 9-carboxymethoxymethylguanine by alcohol and aldehyde dehydrogenase, and to 8-hydroxyacyclovir by aldehyde oxidase. Approximately 88% of total valacyclovir exposure in plasma is attributed 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 plateau-phase AUC of acyclovir 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 of valacyclovir were unchanged compared to those in healthy volunteers.

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

Clinical characteristics.

Indications.

• Treatment of herpes zoster (Herpes zoster).
• Treatment of skin and mucosal infections caused by herpes simplex virus, including primary and recurrent genital herpes.
• Treatment of herpes labialis (cold sores).
• Prophylactic treatment (suppression) of recurrent skin and mucosal infections caused by herpes simplex virus, including genital herpes.
• Reduction of the risk of transmission of genital herpes virus to an uninfected partner when valacyclovir is used as suppressive therapy in combination with safe sex practices.
• Prevention of cytomegalovirus infection and disease following organ transplantation.

Contraindications.

Hypersensitivity to valacyclovir, acyclovir, and/or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

No clinically significant interactions have been reported.

Acyclovir is primarily excreted unchanged in urine via active tubular secretion. Any medicinal products administered concurrently that affect this elimination pathway may increase acyclovir plasma concentrations. Following administration of 1 g valacyclovir, coadministration of cimetidine and probenecid—both of which inhibit tubular secretion—increases the AUC of acyclovir and decreases its renal clearance. However, dosage adjustment is not required due to the wide therapeutic index of acyclovir.

Caution is advised in patients receiving higher doses of valacyclovir (4 g or more per day) when administered concomitantly with medicinal products that compete with acyclovir for elimination pathways, as this may lead to increased plasma levels of one or both medicinal products and their metabolites.

Concomitant administration with mycophenolate mofetil (an immunosuppressive agent used after organ transplantation) increases plasma concentrations of acyclovir and the inactive metabolite of mycophenolate mofetil.

Caution is also advised (and monitoring of renal function changes is recommended) when high doses of valacyclovir (4 g or more) are used concomitantly with other medicinal products that affect renal function (e.g., cyclosporine, tacrolimus).

Special precautions for use.

Drug reaction with eosinophilia and systemic symptoms (DRESS).

Cases of DRESS syndrome, which may be life-threatening or fatal, have been reported during treatment with valacyclovir. Patients should be informed about the signs and symptoms of DRESS syndrome, and closely monitored for possible skin reactions, including fever, severe rash, skin peeling, facial swelling, lymphadenopathy, flu-like symptoms, jaundice, dyspnea, dry cough, chest pain or discomfort, dehydration, and eosinophilia. If signs or symptoms suggestive of DRESS syndrome occur, the drug 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, during treatment with this medicinal product.

Use in patients with renal impairment and elderly patients.

Acyclovir is eliminated by the kidneys; therefore, the dose of the drug 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, who should be closely monitored for such effects. 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 impairment 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, the drug should be used 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 (CMV)-related infection and disease.

Use in the treatment of herpes zoster.

Patients, especially those who are immunocompromised, should be carefully monitored for clinical response during treatment with this medicinal product. 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 ocular herpes lesions or those at high risk of disease dissemination and visceral organ involvement should receive intravenous antiviral therapy.

Use to reduce 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 drug therapy, patients should be advised to follow safe sex practices.

Use in cytomegalovirus infection.

Data on the efficacy of valacyclovir in high-risk patients for CMV infection following organ transplantation indicate that the drug may be used in these patients if valganciclovir or ganciclovir has been discontinued for safety reasons. The use of high-dose valacyclovir required for CMV infection prophylaxis may lead to a higher incidence of adverse reactions, including nervous system disorders, compared to lower doses used for other indications. Renal function should be closely monitored during treatment, and appropriate dose adjustments should be made.

Use during pregnancy or breastfeeding.

Clinical studies on the effects 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 of 400 mg to 1 g.

Pregnancy.

Data on the use of valacyclovir during pregnancy are limited. The drug should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. Data from a pregnancy registry include 111 women exposed to valacyclovir and 1,246 women exposed to any form of acyclovir (the active metabolite of valacyclovir), of whom 29 and 756, respectively, received valacyclovir or any form of acyclovir during the first trimester of pregnancy. Results from this registry did not show an increased incidence of congenital malformations in newborns of women who took acyclovir compared to the general population. No specific or consistent pattern of congenital malformations was observed that would indicate a single causative factor. Due to the small number of pregnant women observed, a definitive and reliable conclusion on the safety of valacyclovir use during pregnancy cannot be made (see section "Pharmacological properties").

Breastfeeding period.

Acyclovir, the main metabolite of valacyclovir, is excreted into breast milk. After daily administration of 500 mg valacyclovir, the average Cmax of acyclovir in breast milk was 0.5–2.3 times (on average 1.4 times) higher than the plasma concentration in the mother. The ratio of acyclovir concentration in breast milk to maternal plasma concentration ranges from 1.4 to 2.6 (average 2.2). The average concentration of acyclovir in breast milk was 2.24 µg/mL (9.95 µmol). When the mother receives 500 mg valacyclovir twice daily, the infant receives approximately 0.61 µg/kg/day of acyclovir via breast milk. The elimination half-life of acyclovir in breast milk is similar to that in plasma. Unchanged valacyclovir is not detected in maternal plasma, breast milk, or infant urine.

Valacyclovir should be used with caution during breastfeeding and only when clinically necessary. However, acyclovir is used to treat neonatal herpes simplex virus infections via intravenous administration at doses of 30 mg/kg/day.

Fertility.

Animal studies indicate that valacyclovir has no effect on fertility. However, high parenteral doses of acyclovir have been associated with testicular effects in rats and dogs.

Ability to influence reaction speed when driving or operating machinery.

Clinical data on this issue are lacking. The pharmacological profile of valacyclovir does not suggest any expected negative impact. 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.

Administration and Dosage

The medicinal product is intended for oral administration.

Treatment of herpes zoster.

The medicinal product should be administered at a dose of 1000 mg three times daily for 7 days.

Treatment of infections caused by herpes simplex virus.

Patients with normal immunity (adults).

The medicinal product should be administered at a dose of 500 mg (1/2 tablet) twice daily.

For recurrent episodes, treatment should last 3 or 5 days. In primary infections, which may be more severe, treatment should be extended from 5 to 10 days. Treatment should be initiated as early as possible. For recurrent herpes simplex virus infections, optimal administration of the medicinal product is during the prodromal phase or immediately after the onset of the first symptoms. Valacyclovir may prevent the development of lesions in recurrent herpes simplex virus infections if treatment is initiated immediately after the first symptoms appear.

Alternative treatment of labial herpes (cold sores).

The medicinal product should be administered at a dose of 2000 mg 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 (tingling, itching, or burning around the lips).

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

Patients with normal immunity (adults).

The medicinal product should be administered at a dose of 500 mg (1/2 tablet) once daily.

Immunocompromised patients (adults).

The medicinal product should be administered at a dose of 500 mg (1/2 tablet) twice daily.

Reduction of transmission of genital herpes virus.

Immunocompetent adult heterosexuals who have 9 or fewer recurrences per year.

The medicinal product should be administered at a dose of 500 mg (1/2 tablet) once daily.

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

Prophylaxis of cytomegalovirus infection and disease following organ transplantation.

Adults and children aged 12 years and older.

The medicinal product should be administered at a dose of 2000 mg four times daily, initiated as soon as possible after transplantation. Doses should be reduced in patients with renal impairment (see "Dosage in renal impairment"). The usual duration of treatment is 90 days, but may be extended for patients at high risk.

Special patient categories.

Patients with renal impairment.

The medicinal product should be used with caution in patients with impaired renal function. Adequate hydration must be maintained.

The dosing regimen depends on creatinine clearance and the indication (see table below).

*Use other dosage forms that allow such dosing (tablets 250 mg).

For patients undergoing intermittent hemodialysis, it is recommended to use the same doses of valacyclovir as for 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. The dosage of the drug should be adjusted accordingly.

Patients with hepatic impairment.

Dosage 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 dosage adjustment is not necessary; however, clinical experience is limited.

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

Elderly patients.

Dosage of the drug may require adjustment to avoid potential renal function impairment (see "Dosage in renal impairment"). Adequate hydration should be maintained.

Children.

The drug can be used in children aged 12 years and older for prophylaxis of cytomegalovirus infection and disease following organ transplantation.

Overdose.

Symptoms.

Overdose with valacyclovir has been associated with acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased mental abilities, and coma. Nausea and vomiting may also occur. To prevent accidental overdose, caution should be exercised when administering the drug. Many cases of overdose have occurred in patients with renal impairment and elderly patients who did not receive appropriate dose reduction.

Treatment.

In case of overdose, 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 symptomatic overdose.

Adverse Reactions.

The most commonly reported adverse reactions in clinical trials of valacyclovir were headache and nausea. Serious adverse reactions included reports of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, acute renal failure, neurological disorders, and DRESS syndrome (see section "Special Warnings and Precautions for Use").

The adverse reactions listed below are classified by system organ class and frequency of occurrence. Frequencies 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), frequency not known (cannot be estimated from the available data).

From clinical trial data.

Nervous system disorders:

Common – headache.

Gastrointestinal disorders:

Common – nausea.

From post-marketing surveillance data.

Blood and lymphatic system disorders:

Very rare – leukopenia, thrombocytopenia.

Leukopenia is primarily observed in immunocompromised patients.

Immune system disorders:

Very rare – anaphylaxis.

Nervous system and psychiatric disorders:

Uncommon – dizziness, confusion, hallucinations, decreased intellectual abilities; very rare – agitation, tremor, ataxia, dysarthria, psychotic symptoms, seizures, encephalopathy, coma.

The above symptoms are mostly reversible and primarily occur in patients with renal impairment or other predisposing factors (see section "Special Warnings and Precautions for Use"). Neurological reactions occur more frequently in organ transplant recipients 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 elevation of liver function tests.

This has occasionally been described as hepatitis.

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) (see section "Special Warnings and Precautions for Use").

Renal and urinary disorders:

Rare – renal dysfunction; very rare – acute renal failure, renal pain, hematuria (often associated with other renal function abnormalities); frequency not known – tubulointerstitial nephritis. Renal pain may be associated with renal impairment.

There have been reports of acyclovir precipitation in renal tubules. Adequate hydration should be maintained during treatment (see section "Special Warnings and Precautions for Use").

Other.

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

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

7 tablets per blister, 3 or 6 blisters per cardboard box; 10 tablets per blister, 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICIN ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.