Orvix

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

Composition:

Active substance: valacyclovir in the form of valacyclovir hydrochloride;

1 tablet contains 500 mg or 1000 mg of valacyclovir (as valacyclovir hydrochloride);

Excipients: stearic acid, colloidal silicon dioxide, film coating: hypromellose, polyethylene glycol 8000, titanium dioxide (E 171), indigo carmine aluminum lake 12-14% (Blue No. 2) (E 132) (only for 500 mg tablets).

Pharmaceutical form.

Film-coated tablets.

Main physicochemical properties: 500 mg tablets: dark blue, capsule-shaped, biconvex, film-coated tablets;

1000 mg tablets: white, oval, biconvex, film-coated tablets.

Pharmacotherapeutic group. Direct-acting antiviral agents. ATC code J05AB11.

Pharmacological Properties

Pharmacodynamics

ORVIX 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 into acyclovir and valine by the action of 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 following phosphorylation and conversion into its 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 enzyme is viral thymidine kinase (TK), which is present only in virus-infected cells. Partial selectivity of phosphorylation is maintained in cytomegalovirus infection and is mediated by the UL97 gene product phosphotransferase. The activation of acyclovir by specific viral enzymes largely explains its selectivity.

The process of acyclovir phosphorylation (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 inhibition of viral replication.

Resistance is caused by a deficiency of viral thymidine kinase, resulting in uncontrolled viral spread in the host organism. Occasionally, reduced sensitivity to acyclovir is due to emergence of viral strains with altered structure of viral TK or DNA polymerase. 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 exceptionally rare in immunocompetent patients and occur infrequently, mainly in patients with severe immunosuppression, such as organ transplant recipients, bone marrow transplant recipients, patients undergoing chemotherapy for malignancies, and HIV-infected individuals.

ORVIX 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 ORVIX reduces the risk of acute transplant rejection (in kidney transplant patients), 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, 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 administration of 1 g valacyclovir is 54% and is not reduced when taken with food. 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 plasma concentration (Cmax) within the therapeutic dose range and reduced bioavailability when doses exceeding 500 mg are administered. The mean peak concentration of acyclovir ranges from 10 to 37 µmol (2.2–8.3 µg/mL) after a single dose of 250–2000 mg 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 4% of that of acyclovir, reached on average within 30–100 minutes, and declines below measurable levels within 3 hours. The pharmacokinetic parameters of valacyclovir and acyclovir are similar after single and repeated dosing.

Distribution

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

Metabolism

Following 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 total drug 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 Populations

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 ORVIX.

In a pharmacokinetic study of valacyclovir and acyclovir during late pregnancy, the acyclovir plateau-phase AUC after administration of 1000 mg valacyclovir was approximately twice higher than that 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 those in healthy volunteers.

In organ transplant recipients receiving valacyclovir 2000 mg four times daily, 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 herpes simplex virus infections of skin and mucous membranes, including primary and recurrent genital herpes.

Treatment of herpes labialis (cold sores).

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

Reduction of the risk of transmission of genital herpes virus to a healthy partner when ORVIX is used as suppressive therapy in combination with adherence to safe sex practices.

Prevention of cytomegalovirus infection and disease following organ transplantation.

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

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

No clinically significant interactions have been identified.

Acyclovir is primarily eliminated unchanged in the urine by active renal tubular secretion. Any drugs administered concomitantly that affect this elimination pathway may increase acyclovir plasma concentrations by approximately 25% and 45%, respectively, after drug administration, due to inhibition of active renal secretion of acyclovir. Other medicinal products (e.g., tenofovir) that are administered concomitantly and that compete for or inhibit active tubular secretion may increase acyclovir concentrations via this mechanism. Administration of 1 g of cimetidine and probenecid, which block tubular secretion, increases the AUC of acyclovir and reduces its renal clearance after valacyclovir intake; however, dose 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 co-administered with drugs competing 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 agent used after organ transplantation) increases plasma levels of acyclovir and the inactive metabolite of mycophenolate mofetil.

No changes in peak concentrations or AUC were observed when valacyclovir and mycophenolate mofetil were administered concomitantly in healthy volunteers. Clinical experience with this combination is limited.

Caution (with monitoring of renal function changes) should be exercised when high doses of valacyclovir (4 g or more) are co-administered with other drugs affecting renal function (e.g., cyclosporine, tacrolimus).

Special precautions for use.

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Cases of DRESS syndrome have been reported during treatment with valacyclovir, which may be life-threatening or fatal. Patients should be informed of 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 restarted in patients who have 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 renal impairment (see section "Dosage and administration"). Elderly patients often have reduced renal function and require dose adjustment. Patients with renal impairment and elderly patients are at increased risk of neurological adverse events and 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 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 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-related disease and infection.

Use in the treatment of herpes zoster

Patients, especially those with impaired immunity, should be closely monitored for clinical response during treatment. 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, patients with impaired immunity who have herpetic eye lesions or are at high risk of disease dissemination and visceral organ involvement should be treated with intravenous antiviral agents.

Reduction of transmission of genital herpes

Patients should be advised to avoid sexual contact during symptomatic periods, even if antiviral treatment has been initiated.

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 the treatment of ophthalmic infections caused by herpes simplex virus

Close monitoring of clinical response is required in such patients. If the response to oral administration is inadequate, intravenous antiviral therapy should be considered.

Use in cytomegalovirus infection

Data on efficacy in patients at high risk of cytomegalovirus infection (e.g., cytomegalovirus-positive donor/cytomegalovirus-negative recipient or use of antithymocyte globulin induction therapy) for prevention after organ transplantation (~200 patients) indicate that valacyclovir may be used in these patients if valganciclovir or ganciclovir has been discontinued for safety reasons. The high doses of valacyclovir required for cytomegalovirus infection prophylaxis may lead to a higher incidence of adverse reactions, including nervous system disorders, compared to lower doses used for other indications (see section "Adverse reactions"). Renal function should be closely monitored and appropriate dose adjustments made (see section "Dosage and administration").

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of valacyclovir during pregnancy are limited. ORVEX may be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. There are documented data from a pregnancy registry of women who used valacyclovir or any form of acyclovir (the active metabolite of valacyclovir): 111 and 1246 women, respectively (29 and 756 pregnant women, respectively, used valacyclovir or any form of acyclovir during the first trimester of pregnancy). Results from this registry did not show an increased risk 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 suggest a single cause. Due to the limited 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 peak concentration of acyclovir in breast milk was 0.5–2.3 times (on average 1.4 times) higher than the concentration in maternal plasma. The ratio of acyclovir concentration in breast milk to maternal plasma 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 takes valacyclovir at a dose of 500 mg 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.

ORVEX should be administered to breastfeeding women with caution and only when clinically necessary. However, acyclovir is used to treat newborns with 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 shown to cause testicular effects in rats and dogs.

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

Ability to influence reaction speed when driving or operating machinery

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

Method of Administration and Dosage.

Treatment of Herpes Zoster (Shingles):

For adults: 1000 mg three times daily for 7 days.

Treatment of Infections Caused by Herpes Simplex Virus:

Immunocompetent patients (adults): 500 mg of VALTREX twice daily.

The treatment course for recurrent episodes 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. Treatment should be initiated as early as possible. For recurrent infections, the drug should ideally be administered 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 promptly upon the first signs of recurrence.

As an alternative, for the treatment of labial herpes (cold sores), an effective dosage of valacyclovir is 2000 mg twice daily for 1 day. The second dose should be taken approximately 12 hours (but no sooner than 6 hours) after the first dose. With this dosing regimen, treatment 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).

Preventive Treatment (Suppression) of Recurrent Herpes Simplex 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 heterosexual adults who experience 9 or fewer recurrences per year, valacyclovir should be administered to the infected partner at a dose of 500 mg once daily.

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

Prophylaxis of Cytomegalovirus Infection and Disease after Organ Transplantation

Adults and children aged 12 years and older: valacyclovir should be administered at a dose of 2000 mg four times daily, initiated as soon as possible after transplantation. Dosage 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 (see table below).

*apply when tablets of the drug in a dose of 250 mg are available.

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 continuously, especially during periods when renal function may change rapidly, such as immediately after transplantation. Accordingly, the dose of valacyclovir should be adjusted accordingly.

Dosage in hepatic impairment

Dosage adjustment is not required in patients with mild to moderate cirrhosis (liver synthetic function preserved). Pharmacokinetic data in advanced stages of cirrhosis (with impaired liver synthetic function and signs of portal hypertension) suggest no need for dosage adjustment; 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 «Dosage in renal impairment»).

An adequate level of hydration should be maintained.

Children.

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 during administration. Many cases of overdose have been associated with administration of the drug to patients with renal impairment and elderly patients who did not receive appropriate dose reduction. In case of overdose, the patient should immediately seek emergency specialized medical care.

Treatment

Patients should be under close medical supervision to detect signs of toxicity. Hemodialysis significantly accelerates the elimination of acyclovir from the blood and therefore may 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 included reports of thrombotic thrombocytopenic purpura / hemolytic uremic syndrome, acute renal failure, neurological disorders, and DRESS (see section "Special Warnings and Precautions for Use").

Adverse reactions listed below are classified by system organ class and frequency of occurrence. Frequencies are categorized 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 available data).

Data from clinical trials were used to assign frequency categories to adverse reactions when evidence of a causal relationship with valacyclovir was established in those trials.

For adverse reactions identified from post-marketing surveillance but not observed in clinical trials, the most conservative point estimate ("rule of three") was used to assign the frequency category. For adverse reactions identified as related to valacyclovir from post-marketing experience and also observed in clinical trials, the frequency observed in trials was used to assign the frequency category. The clinical trial safety database is based on 5,855 subjects exposed to valacyclovir in clinical trials covering multiple indications (treatment of herpes zoster, treatment/suppression of genital herpes, and herpes simplex treatment).

From clinical trials

Nervous system disorders: Common: headache.

Gastrointestinal disorders: Common: nausea.

From post-marketing surveillance

Nervous system and psychiatric disorders: Common: dizziness; uncommon: confusion, hallucinations, decreased mental status, tremor, agitation; rare: ataxia, dysarthria, psychotic symptoms, seizures, encephalopathy, coma, delirium.

The above symptoms are mostly reversible and are primarily observed 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.

Gastrointestinal disorders: Uncommon: abdominal discomfort; common: vomiting, diarrhea.

Hepatobiliary disorders: Uncommon: reversible increases in liver function tests (e.g., bilirubin, liver enzymes).

Blood and lymphatic system disorders: Very rare: leukopenia, thrombocytopenia. Leukopenia is primarily observed in immunocompromised patients.

Immune system disorders: Very rare: anaphylaxis.

Respiratory, thoracic and mediastinal disorders: Uncommon: dyspnea.

Skin and subcutaneous tissue disorders: Common: rash, including photosensitivity reactions, pruritus; uncommon: urticaria; rare: 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, acute renal failure (particularly in elderly individuals and patients with renal impairment receiving doses exceeding recommended levels); uncommon: renal pain, hematuria (often associated with other renal function abnormalities). Tubulointerstitial nephritis – frequency not known.

Renal pain may be associated with renal impairment.

There have been reports of acyclovir crystal 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 (8,000 mg daily) of valacyclovir for prolonged periods in clinical trials. These same phenomena have also been observed in patients with similar conditions who were not treated with valacyclovir.

If adverse reactions occur, the patient should seek immediate medical advice.

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

Shelf life. 2 years.

Storage conditions. Store in a dry place, protected from light and out of reach of children, in the original packaging at a temperature not exceeding 25 °C.

Packaging.

500 mg tablets: 8 tablets in a blister; 1 blister in a cardboard box.

1000 mg tablets: 3 tablets in a blister; 7 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Apotex Inc.

Manufacturer's address and location of operations.

150 Signet Drive, Toronto, Ontario, Canada, M9L 1T9 /
150 Signet Drive, Toronto, Ontario, Canada, M9L 1T9.