Valcik

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

Composition:

Active substance: valacyclovir;

1 tablet contains valacyclovir 500 mg in the form of valacyclovir hydrochloride;

Excipients: microcrystalline cellulose, crospovidone, magnesium stearate, hydroxypropylmethylcellulose, Opadry blue coating;

Coating composition: indigo carmine (E 132), titanium dioxide (E 171), macrogol, polysorbate, hydroxypropylmethylcellulose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: blue, oval-shaped film-coated tablets, marked "VC" and "500" on one side, smooth or smooth on both sides.

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

Pharmacological Properties

Pharmacodynamics

Valacyclovir is an antiviral agent, the L-valine ester of acyclovir, which is a guanine nucleoside analogue. In humans, valacyclovir is rapidly and almost completely converted to acyclovir and L-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 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 a virus-specific enzyme 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, resulting in obligate (complete) chain termination, cessation of DNA synthesis, and thus blockade of viral replication.

Resistance to acyclovir is caused by viral thymidine kinase deficiency, leading to excessive viral spread in the body. Occasionally, reduced sensitivity to acyclovir results from 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 predominantly in immunocompromised individuals, such as organ transplant recipients, bone marrow transplant recipients, patients undergoing chemotherapy for malignancies, and 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 to acyclovir and L-valine. This conversion appears to occur via the enzyme valacyclovir hydrolase isolated from human liver. The bioavailability of acyclovir following administration of 1 g 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 Cmax within the therapeutic dose range and reduced bioavailability when doses exceeding 500 mg are administered. The mean peak concentration of acyclovir ranges from 10–37 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 about 4% of the acyclovir concentration, occurring on average 30–100 minutes after dosing and decreasing below measurable levels within 3 hours. Pharmacokinetic parameters of valacyclovir and acyclovir are similar after single and repeated administration.

Distribution. Plasma protein binding of valacyclovir is very low (15%). Penetration into cerebrospinal fluid (CSF), determined by the CSF/plasma AUC ratio, 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 fraction 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 attributable 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 following oral administration of Valcivir.

In a pharmacokinetic study of valacyclovir and acyclovir during late pregnancy, the steady-state area under the concentration-time curve (AUC) of acyclovir after administration of 1000 mg valacyclovir was approximately twice as high as 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 healthy individuals.

In organ transplant recipients receiving valacyclovir 2000 mg four times daily, the maximum concentration of acyclovir was equal to or higher than that 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 herpes labialis (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 Valcivir is used as suppressive therapy in combination with safe sex practices.

Prophylaxis of cytomegalovirus infection and disease following organ transplantation.

Contraindications.

Hypersensitivity to valacyclovir, acyclovir, or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

No clinically significant interactions have been identified.

Dose adjustment of valacyclovir is not recommended when co-administered with digoxin, antacids, thiazide diuretics, cimetidine, or probenecid in patients with normal renal function.

Acyclovir is primarily excreted unchanged in urine via active tubular secretion. Any drugs administered concomitantly that affect this elimination pathway may increase plasma concentrations of acyclovir following valacyclovir administration. With concomitant administration of cimetidine or probenecid, which block tubular secretion, administration of valacyclovir at a dose of 1 g increases the area under the plasma concentration-time curve (AUC) of acyclovir and decreases its renal clearance; 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 administered concomitantly with 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 agent used after organ transplantation) increases plasma levels of acyclovir and the inactive metabolite of mycophenolate mofetil.

Caution (with monitoring of renal function) is also advised when high doses of valacyclovir (4 g or more) are administered concomitantly with other drugs affecting renal function (e.g., cyclosporine, tacrolimus).

Special precautions for use.

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Cases of DRESS syndrome associated with valacyclovir therapy have been reported; this condition can be life-threatening or fatal. When prescribing the medicinal product, patients should be informed about the signs and symptoms, and skin reactions should be closely monitored. If symptoms indicating DRESS syndrome occur, valacyclovir should be discontinued immediately, and alternative treatment should be considered (if necessary). If a patient develops DRESS syndrome during valacyclovir therapy, valacyclovir must never be re-administered to this patient.

Hydration.

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

Hepatic impairment.

Dosage adjustment is not required in patients with mild to moderate liver cirrhosis (preserved synthetic liver function). Pharmacokinetic data in advanced cirrhosis (with impaired synthetic liver function and signs of portal hypertension) suggest no need for dose adjustment; however, clinical experience is limited.

There are no data on the use of higher doses of the drug (4 g or more per day) for the treatment of patients with liver disease. Therefore, higher doses 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 infections and disease.

Renal impairment.

Acyclovir, the active metabolite of valacyclovir, is eliminated by the kidneys; therefore, the dose of valacyclovir in patients with renal impairment must be reduced according to creatinine clearance.

Patients with renal impairment are at increased risk of developing neurological complications and should be closely monitored for early detection. These complications are usually reversible and resolve after discontinuation of the drug. Caution should be exercised when prescribing valacyclovir to patients with renal impairment or to patients receiving nephrotoxic agents, as this may increase the risk of renal function deterioration and/or reversible neurological adverse reactions.

When treating labial herpes with valacyclovir, special attention should be paid to elderly patients and patients with renal impairment. Treatment should not exceed 1 day (2 doses of 2000 mg within 24 hours). Therapy longer than 1 day will not provide additional clinical benefit.

Elderly patients.

Elderly patients have reduced renal function and require dose adjustment.

For elderly patients, dosing should be based on creatinine clearance data, and adequate hydration should be maintained.

The risk of neurological complications is increased in patients with renal impairment and in elderly patients; careful monitoring is required to detect these effects. According to reported data, such reactions are mostly reversible after discontinuation of treatment (see section "Adverse reactions").

Reduction of genital herpes virus transmission.

Suppressive therapy with valacyclovir reduces the risk of transmission of genital herpes. However, it does not cure herpes infection nor completely eliminate the risk of virus transmission. In addition to valacyclovir therapy, patients are advised to use barrier contraceptive methods.

Use in the treatment of herpes zoster.

Careful monitoring of clinical response is necessary when treating patients, especially those with impaired immunity. If the response to treatment is inadequate, intravenous antiviral therapy is recommended. Patients with complicated herpes zoster, e.g., with visceral organ involvement, viral dissemination, motor neuropathy, encephalitis, or cerebrovascular disorders, should be treated with intravenous antiviral agents.

Furthermore, patients with impaired immunity who have herpes eye lesions or are at high risk of disease dissemination and visceral organ involvement should be treated with intravenous antiviral agents.

Use in cytomegalovirus infection.

Data on drug efficacy in 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-dose valacyclovir required for cytomegalovirus prophylaxis may lead to a higher incidence of adverse reactions, including those affecting the nervous system, compared to lower doses used for other indications. Renal function in patients should be closely monitored, and appropriate dose adjustments should be made.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of valacyclovir during pregnancy are limited. Valacyclo politic should be used in pregnant women only when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. Breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration.

Valacyclovir should be administered orally, independent of food intake.

Treatment of herpes zoster: Adults should be given 1000 mg (2 tablets) three times daily for 7 days.

Treatment of herpes simplex virus infections: Immunocompetent patients (adults): 500 mg (1 tablet) twice daily for 5–10 days in cases of primary infection, which may be severe; for recurrent episodes, treatment duration is 3 or 5 days.

Therapy should be initiated as early as possible. For recurrent herpes simplex virus infections, optimal treatment involves administration during the prodromal phase or immediately upon the first symptoms. Valacyclovir may prevent lesion development in recurrent herpes simplex virus infections if treatment is started promptly after the onset of initial symptoms.

Treatment of herpes labialis (cold sores): Alternatively, for the treatment of herpes labialis (cold sores), an effective 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 herpes labialis (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 transmission of genital herpes to healthy sexual partners.

For immunocompetent adult heterosexuals with 9 or fewer recurrences per year, the recommended dose is 500 mg once daily.

There are no data on reduction of transmission of genital herpes in other patient groups.

Prophylaxis of cytomegalovirus infection and disease following organ transplantation.

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

Dosage in Renal Impairment.

Valacyclovir should be administered with caution in patients with impaired renal function, and adequate hydration must be maintained. The dosing regimen depends on creatinine clearance and the indication, and is specified in the table.

* valacyclovir can be used in other dosage forms allowing such dosing (tablets 250 mg).

For patients undergoing intermittent hemodialysis, the same doses are recommended 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, for example, immediately after transplantation. Accordingly, the drug dosage should be adjusted.

Dosage in hepatic impairment

Dosage adjustment is not required in patients with mild to moderate cirrhosis (liver synthetic function preserved). Pharmacokinetic data in advanced 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".

Children

Safety and efficacy of the drug in children under 12 years of age have not been established.

Elderly patients

Drug dosage may require adjustment to avoid potential renal function disturbances (see "Dosage in renal impairment").

Adequate hydration should be maintained.

Missed dose.

If a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is approaching, the missed dose should not be compensated, and the regular dosing schedule should be resumed.

Children.

Valacyclovir may be used in children aged 12 years and older for prophylaxis of cytomegalovirus infection and disease following organ transplantation.

Overdose.

Symptoms. Overdose of valacyclovir has been associated with acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, loss of consciousness, and coma. Nausea and vomiting have also been reported. To prevent inadvertent overdose, caution should be exercised when administering high doses. Many cases of overdose occurred in patients with renal impairment and elderly patients who did not receive appropriate dose reduction.

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 treatment of choice in symptomatic valacyclovir overdose.

In cases of acute renal failure and anuria, hemodialysis may be effective.

Adverse Reactions

The most commonly reported adverse reactions during valacyclovir administration are headache and nausea. More serious adverse events that have been reported include thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, acute renal failure, neurological disorders, and DRESS syndrome (see section "Special precautions" and section "Dosage and administration").

Neurological complications have been reported rarely. Elderly patients and patients with renal impairment are at increased risk of developing neurological adverse reactions.

The 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, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000).

From clinical trials 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 patients with immunodeficiency.

Immune system disorders: very rare – acute allergic reactions, including anaphylaxis, angioedema, urticaria.

Nervous system disorders: rare – headache, dizziness, confusion, hallucinations, decreased cognitive abilities; very rare – tremor, ataxia, dysarthria, seizures, encephalopathy, coma, psychotic symptoms.

Psychiatric disorders: rare – agitation, aggressive behavior.

The above symptoms are in most cases reversible and are primarily observed in patients with renal impairment or other predisposing factors. In organ transplant patients receiving the drug for cytomegalovirus infection prophylaxis at high doses (8 g daily), neurological reactions occur more frequently than in patients receiving lower doses.

Respiratory system disorders: uncommon – dyspnea.

Gastrointestinal disorders: common – nausea, abdominal discomfort; uncommon – vomiting, diarrhea.

Skin and subcutaneous tissue disorders: uncommon – rash, photosensitivity reactions; rare – pruritus, urticaria, angioedema; very rare – erythema multiforme exudativum; frequency not known – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions").

Renal and urinary disorders: rare – renal dysfunction, increased creatinine; very rare – acute renal failure, flank pain, hematuria (often associated with other renal function abnormalities); frequency not known – tubulointerstitial nephritis.

Flank pain may be associated with renal impairment.

Cases of acyclovir precipitation in renal tubules have been reported. Adequate fluid intake should be maintained during treatment (see section "Special precautions").

Hepatobiliary disorders: very rare – reversible increases in liver function tests.

Occasionally described as hepatitis.

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 events have also been observed in patients with similar conditions who were not treated with valacyclovir.

Laboratory test parameters

No effect on laboratory test parameters has been established.

Shelf life.

4 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in a place inaccessible to children.

Packaging.

10 tablets in a blister, 1 blister per cardboard box; 42 tablets in bottles.

Prescription status.

Prescription only.

Manufacturer.

Pharmascience Inc.

Manufacturer's address and place of business.

6111 Royalmount Avenue, Suite 100, Montreal, Quebec H4P 2T4, Canada.