Valcycon^® (Tablets) Instructions for Use

Marketing Authorization Holder

Vertex, JSC (Russia)

Contact Information

VERTEX JSC (Russia)

ATC Code

J05AB11 (Valaciclovir)

Active Substance

Valaciclovir (Rec.INN registered by WHO)

Dosage Form

Valcycon®

Film-coated tablets, 500 mg: 10, 20, 30, 40, 42, 50, or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex; the core on the cross-section is white or almost white.

Excipients: microcrystalline cellulose – 95 mg, crospovidone – 28 mg, hypromellose (hydroxypropylcellulose) – 14 mg, magnesium stearate – 7 mg.

Film coating composition: hypromellose – 10.5 mg, talc – 4.12 mg, hypromellose (hydroxypropylcellulose) – 4.07 mg, titanium dioxide – 2.31 mg or a dry mix for film coating containing hypromellose – 50%, hypromellose (hydroxypropylcellulose) – 19.4%, talc – 19.6%, titanium dioxide – 11%.

5 pcs. – blister packs (2) – cardboard boxes.
5 pcs. – blister packs (4) – cardboard boxes.
5 pcs. – blister packs (6) – cardboard boxes.
10 pcs. – blister packs (1) – cardboard boxes.
10 pcs. – blister packs (2) – cardboard boxes.
10 pcs. – blister packs (3) – cardboard boxes.
10 pcs. – blister packs (4) – cardboard boxes.
10 pcs. – blister packs (5) – cardboard boxes.
10 pcs. – blister packs (6) – cardboard boxes.
14 pcs. – blister packs (3) – cardboard boxes.

Clinical-Pharmacological Group

Antiviral drug

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; nucleosides and nucleotides, excluding reverse transcriptase inhibitors

Pharmacological Action

Valaciclovir is the L-valine ester of acyclovir. Acyclovir is a purine nucleoside (guanine) analogue. In the human body, Valaciclovir is rapidly and almost completely converted to acyclovir and valine, presumably under the influence of the enzyme valaciclovir hydrolase.

Acyclovir is a specific inhibitor of herpes viruses with in vitro activity against Herpes simplex virus types 1 and 2, Varicella zoster virus, Cytomegalovirus, Epstein-Barr virus, and Human herpesvirus type 6.

Acyclovir inhibits viral DNA synthesis immediately after phosphorylation and conversion to the active form, acyclovir triphosphate. The first stage of phosphorylation requires the activity of virus-specific enzymes. For Herpes simplex, Varicella zoster, and Epstein-Barr viruses, this enzyme is viral thymidine kinase, which is present only in virus-infected cells. Partial phosphorylation selectivity is maintained for cytomegalovirus indirectly through the product of the UL97 phosphotransferase gene. This requirement for acyclovir activation by a specific viral enzyme largely explains its selectivity.

The process of acyclovir phosphorylation (conversion from mono- to triphosphate) is completed by cellular kinases. Acyclovir triphosphate competitively inhibits viral DNA polymerase and, being a nucleoside analogue, is incorporated into viral DNA, leading to obligatory chain termination, cessation of DNA synthesis, and consequently, blocking of virus replication.

Resistance to acyclovir is usually due to thymidine kinase deficiency, leading to excessive spread of the virus in the host organism. In rare cases, reduced sensitivity to acyclovir is due to the emergence of virus strains with altered viral thymidine kinase or DNA polymerase structure. The virulence of these virus variants resembles that of its wild-type strain.

Based on an extensive study of Herpes simplex and Varicella zoster virus strains isolated from patients treated with acyclovir or using it for prophylaxis, it was found that viruses with reduced sensitivity to valaciclovir are extremely rare but may be detected in rare cases in patients with severe immunodeficiency, such as recipients of bone marrow or organ transplants, patients receiving chemotherapy for malignant neoplasms, and HIV-infected individuals.

Valaciclovir helps relieve pain syndrome: it reduces its duration and decreases the percentage of patients with pain caused by herpes zoster, including acute postherpetic neuralgia.

Pharmacokinetics

Absorption

After oral administration, Valaciclovir is well absorbed from the gastrointestinal tract, rapidly and almost completely converted to acyclovir and valine. This conversion is probably carried out by a liver enzyme, valaciclovir hydrolase.

When valaciclovir is taken at a dose of 1000 mg, the bioavailability of acyclovir is 54% and is not reduced by food intake. The pharmacokinetics of valaciclovir are not dose-dependent. The rate and extent of absorption decrease with increasing dose, leading to a less than proportional increase in plasma C_max compared to the therapeutic dose range and a decrease in bioavailability at doses above 500 mg.

Table 1. Results of the assessment of acyclovir pharmacokinetics after single doses of valaciclovir from 250 mg to 2000 mg in healthy volunteers with normal liver function

C_max and AUC values reflect the mean standard deviation.

Values for T_max reflect the median value and range of values.

The C_max of valaciclovir in plasma is only 4% of the acyclovir concentration, the median time to reach it is from 30 to 100 minutes after taking the drug. 3 hours after taking the drug, the concentration of valaciclovir reaches the level of quantitation or below. Valaciclovir and acyclovir have similar pharmacokinetic parameters after single and multiple doses. Varicella zoster and Herpes simplex viruses do not significantly alter the pharmacokinetics of valaciclovir and acyclovir after oral administration of valaciclovir.

Distribution

The degree of binding of valaciclovir to plasma proteins is very low (15%). The degree of penetration into cerebrospinal fluid (CSF) is defined as the ratio of AUC in CSF to AUC in plasma and is about 25% for acyclovir and the metabolite 8-hydroxyacyclovir (8-OH-ACV); about 2.5% for the metabolite 9-(carboxymethoxy)methylguanine (CMMG).

Metabolism

After oral administration, Valaciclovir is converted to acyclovir and L-valine via presystemic metabolism in the intestine and/or hepatic metabolism. Acyclovir is converted to minor metabolites: CMMG under the influence of alcohol and aldehyde dehydrogenase; 8-OH-ACV under the influence of aldehyde oxidase. Approximately 88% of the total cumulative exposure to plasma is accounted for by acyclovir, 11% by CMMG, and 1% by 8-OH-ACV. Valaciclovir and acyclovir are not metabolized by cytochrome P450 system isoenzymes.

Excretion

In patients with normal renal function, the T_1/2 of acyclovir from plasma after single or multiple doses of valaciclovir is about 3 hours. Less than 1% of the administered dose of valaciclovir is excreted by the kidneys unchanged. Valaciclovir is excreted from the body by the kidneys mainly in the form of acyclovir (more than 80% of the administered dose) and the acyclovir metabolite, CMMG.

Pharmacokinetics in special patient groups

Patients with impaired renal function. The excretion of acyclovir correlates with renal function, acyclovir exposure increases with increasing severity of renal failure. In patients with end-stage renal disease, the mean T_1/2 of acyclovir after valaciclovir administration is about 14 hours compared to about 3 hours with normal renal function.

Exposure to acyclovir and its metabolites CMMG and 8-OH-ACV in plasma and CSF was assessed at steady state after multiple doses of valaciclovir in 6 patients with normal renal function (mean CrCl 111 mL/min, range 91-144 mL/min) receiving 2000 mg every 6 hours, and in 3 patients with severe renal impairment (mean CrCl 26 mL/min, range 17-31 mL/min) receiving 1500 mg every 12 hours. In severe renal impairment compared to normal renal function, concentrations of acyclovir, CMMG, and 8-OH-ACV in plasma, as well as in CSF, were 2, 4, and 5-6 times higher, respectively. There was no difference in the degree of penetration of acyclovir into CSF (defined as the ratio of AUC in CSF to AUC in plasma), CMMG, and 8-OH-ACV between the two populations: with severe renal impairment and normal renal function.

Patients with impaired liver function. Pharmacokinetic data show that in patients with hepatic insufficiency, the rate of conversion of valaciclovir to acyclovir decreases, but not the extent of this conversion. The T_1/2 of acyclovir does not depend on liver function.

Pregnancy. In a pharmacokinetic study of valaciclovir and acyclovir in late pregnancy, an increase in the daily AUC value at steady state with daily intake of valaciclovir at a dose of 1000 mg/day was established, which was approximately 2 times higher than the AUC with oral acyclovir at a dose of 1200 mg/day.

HIV infection. In patients with HIV infection, the distribution and pharmacokinetic characteristics of acyclovir after oral administration of single or multiple doses of 1000 mg or 2000 mg of valaciclovir remain unchanged compared to healthy volunteers.

Organ transplantation. The C_max of acyclovir in patients after organ transplantation receiving 2000 mg of valaciclovir 4 times/day was comparable to or higher than the C_max observed in healthy volunteers receiving the same dose. The established daily AUC values can be characterized as significantly higher.

Indications

Adults and adolescents aged 12 to 18 years

• Treatment of skin and mucous membrane infections caused by Herpes simplex virus, including primary and recurrent genital herpes, as well as labial herpes;
• Prevention (suppression) of recurrences of skin and mucous membrane infections caused by Herpes simplex virus, including genital herpes, including in adults with immunodeficiency;
• Prevention of cytomegalovirus infections and diseases after transplantation of parenchymal organs.

Adults

• Treatment of herpes zoster and ophthalmic herpes zoster.

ICD codes

Dosage Regimen

The drug Valcycon^® is taken orally, regardless of meals, with water.

Treatment of skin and mucous membrane infections caused by Herpes simplex virus, including primary and recurrent genital herpes, as well as labial herpes

Immunocompetent adults and adolescents aged 12 to 18 years

The recommended dose is 500 mg twice daily. In case of recurrences, treatment should continue for 3 or 5 days. In case of primary herpes, which may be more severe, treatment should be started as early as possible, and its duration should be increased from 5 to 10 days.

For recurrences of Herpes simplex virus infections, the most correct approach is to prescribe valaciclovir in the prodromal period or immediately after the first symptoms of the disease appear. The use of valaciclovir can prevent the development of lesions if used at the first signs and symptoms of a Herpes simplex virus recurrence.

As an alternative treatment for labial herpes, the administration of valaciclovir at a dose of 2000 mg twice daily for 1 day is effective. The second dose should be taken approximately 12 hours (but not earlier than 6 hours) after the first dose. When using this dosage regimen, the duration of treatment should not exceed 1 day, as exceeding the duration of this course of treatment does not lead to additional clinical benefit.

Therapy should be started at the earliest symptoms of labial herpes (i.e., tingling, itching, burning).

Prevention (suppression) of recurrences of skin and mucous membrane infections caused by Herpes simplex virus, including genital herpes, including in adults with immunodeficiency

Immunocompetent adults and adolescents aged 12 to 18 years

In immunocompetent patients, the recommended dose is 500 mg once daily. After 6-12 months of treatment, the effectiveness of therapy should be assessed.

Adults with immunodeficiency

In adult patients with immunodeficiency, the recommended dose is 500 mg twice daily. After 6-12 months of treatment, the effectiveness of therapy should be assessed.

Prevention of cytomegalovirus infections and diseases after transplantation of parenchymal organs

Adults and adolescents aged 12 to 18 years

The recommended dose is 2000 mg four times daily, prescribed as soon as possible after transplantation. The dose should be reduced depending on CrCl. The duration of treatment is usually 90 days, but in patients at high risk, the course of treatment may be extended.

Treatment of herpes zoster and ophthalmic herpes zoster

Adults

The recommended dose is 1000 mg three times daily for 7 days.

Special patient groups

Children. The effectiveness of valaciclovir treatment in children has not been studied.

Elderly patients. Possible impairment of renal function in elderly patients should be considered – the dose of valaciclovir should be adjusted accordingly. Adequate hydration should be maintained.

Patients with impaired renal function. The dose of valaciclovir is recommended to be reduced in patients with significant renal impairment (see dosage regimen in Table 2). In such patients, adequate hydration should be maintained.

Table 2. Dose adjustment of valaciclovir for use in adults and adolescents from 12 to 18 years with impaired renal function

Additional information for the indication: treatment of skin and mucous membrane infections caused by Herpes simplex virus, including primary and recurrent genital herpes, as well as labial herpes

There is no experience with the use of valaciclovir in children with CrCl values less than 50 mL/min/1.73 m².

Additional information for the indication: prevention of cytomegalovirus infections and diseases after transplantation of parenchymal organs

CrCl should be determined frequently, especially during periods when renal function is changing rapidly, for example, immediately after transplantation or engraftment of the transplant, and the dose of valaciclovir should be adjusted according to CrCl values.

Additional information for the indication: treatment of herpes zoster and ophthalmic herpes zoster

Valaciclovir should be administered after hemodialysis in patients undergoing intermittent hemodialysis.

Patients with impaired liver function

Based on a study with a single dose of valaciclovir 1000 mg in adult patients with mild or moderate liver cirrhosis (with preserved liver synthetic function), no adjustment of the valaciclovir dose is required. Pharmacokinetic data in adult patients with severe liver impairment (decompensated cirrhosis), with impaired liver synthetic function and the presence of portacaval anastomoses also do not indicate the need for valaciclovir dose adjustment, but clinical experience with these pathologies is limited.

Information on doses higher than 4000 mg/day for patients with Herpes simplex virus and cytomegalovirus infections is provided in the “Special Instructions” section.

Adverse Reactions

Adverse reactions are listed below according to the classification by organ systems and frequency of occurrence, which was defined as follows: very common (≥1 in 10), common (≥1 in 100 and <1 in 10), uncommon (≥1 in 1000 and <1 in 100), rare (≥1 in 10000 and <1 in 1000), very rare (<1 in 10000).

Clinical Trial Data

Nervous System Disorders Common – headache.

Gastrointestinal Disorders Common – nausea.

Post-Marketing Data

Blood and Lymphatic System Disorders Very rare – leukopenia, thrombocytopenia. Leukopenia was observed mainly in patients with compromised immune systems.

Immune System Disorders Very rare – anaphylaxis.

Nervous System and Psychiatric Disorders Rare – dizziness, confusion, hallucinations, depressed level of consciousness; very rare – agitation, tremor, ataxia, dysarthria, psychotic symptoms, convulsions, encephalopathy, coma. The symptoms listed above are mainly reversible and are usually observed in patients with impaired renal function or in the presence of other predisposing conditions. In adult transplant patients receiving high doses of valacyclovir (8 g/day) for the prevention of cytomegalovirus infection, neurological reactions occur more frequently than with lower doses.

Respiratory, Thoracic and Mediastinal Disorders Uncommon – dyspnea.

Gastrointestinal Disorders Rare – abdominal discomfort, vomiting, diarrhea.

Hepatobiliary Disorders Very rare – reversible liver function test abnormalities, which are sometimes interpreted as manifestations of hepatitis.

Skin and Subcutaneous Tissue Disorders Uncommon – rash, including manifestations of photosensitivity; rare – pruritus; very rare – urticaria, angioedema.

Renal and Urinary Disorders Uncommon – hematuria (often associated with other renal disorders); rare – renal impairment; very rare – acute renal failure, renal colic. Renal colic may be associated with renal impairment. Cases of acyclovir crystal deposition in the renal tubule lumen have been reported. Adequate hydration should be maintained during treatment.

General Disorders and Administration Site Conditions In patients with severe immune deficiency, particularly in adult patients with advanced HIV infection receiving high doses of valacyclovir (8 g daily) for prolonged periods, cases of renal failure, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination) have been observed. Similar complications have been noted in patients with the same underlying and/or concomitant diseases but not receiving Valaciclovir.

Contraindications

• Hypersensitivity to valacyclovir, acyclovir or any other component of the drug;
• Children under 12 years of age;
• Children under 18 years of age for the treatment of herpes zoster and ophthalmic zoster.

With caution

• Renal impairment;
• Concomitant use of nephrotoxic drugs;
• Clinically significant forms of HIV infection.

Use in Pregnancy and Lactation

Pregnancy

There are limited data on the use of valacyclovir in pregnancy. Valaciclovir should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

Pregnancy registries have documented pregnancy outcomes in women who took Valaciclovir or other drugs containing acyclovir (acyclovir is the active metabolite of valacyclovir), 111 and 1246 observations, respectively (of which 29 and 756, respectively, took the drugs in the first trimester of pregnancy), representing prospectively recorded pregnancy outcomes. Analysis of data from the acyclovir exposure pregnancy registry did not reveal an increase in the number of birth defects in their children compared to the general population, and no specificity or pattern was identified for any of the malformations suggesting a common cause. Because the pregnancy registry includes only a small number of women who took Valaciclovir during pregnancy, no reliable and definitive conclusions can be drawn regarding the safety of valacyclovir use in pregnancy.

Breastfeeding period

Acyclovir, the main metabolite of valacyclovir, passes into breast milk. After oral administration of valacyclovir 500 mg, C_max in breast milk was 0.5-2.3 times (on average 1.4 times) higher than the corresponding acyclovir concentrations in maternal plasma. The ratios of acyclovir AUC in breast milk to AUC in maternal serum ranged from 1.4 to 2.6 (mean 2.2). The mean concentration of acyclovir in breast milk was 2.24 µg/ml (9.95 µmol/L). When the mother takes valacyclovir 500 mg twice daily, breastfed infants are exposed to acyclovir equivalent to an oral dose of about 0.61 mg/kg/day. The T_1/2 of acyclovir from breast milk is the same as from plasma. Valaciclovir in unchanged form was not detected in maternal plasma, breast milk, or infant urine.

Valaciclovir should be prescribed with caution to women during breastfeeding.

Nevertheless, intravenous acyclovir is used to treat diseases caused by Herpes simplex virus in infants at a dose of 30 mg/kg/day.

Fertility

In animal studies, Valaciclovir did not affect fertility. However, administration of high doses of acyclovir parenterally caused testicular effects in rats and dogs.

Studies on the effect of valacyclovir on human fertility have not been conducted. However, no changes in sperm count, motility, or morphology were reported in 20 patients after 6 months of daily use of valacyclovir at doses ranging from 400 mg to 1000 mg.

Use in Hepatic Impairment

In adult patients with mild or moderate hepatic cirrhosis (with preserved liver synthetic function), no dose adjustment of valacyclovir is required.

Pharmacokinetic data in adult patients with severe hepatic impairment (decompensated cirrhosis), impaired liver synthetic function and portacaval shunts also do not indicate the need for valacyclovir dose adjustment, but clinical experience with these pathologies is limited.

Use in Renal Impairment

The drug should be used with caution in renal failure.

Pediatric Use

The use of the drug is contraindicated in children under 12 years of age, as well as under 18 years of age for the treatment of herpes zoster and ophthalmic zoster.

Geriatric Use

Elderly patients may have impaired renal function, so a dose reduction should be considered for this patient group.

Special Precautions

Hydration

In patients at risk of dehydration, especially elderly patients, adequate water and electrolyte balance must be ensured.

Use in patients with renal impairment and elderly patients

Since acyclovir is eliminated by the kidneys, the dose of valacyclovir should be reduced in patients with renal impairment. Elderly patients may have impaired renal function, so a dose reduction should be considered for this patient group. Both elderly patients and patients with renal impairment are at increased risk of neurological complications. Such patients require careful medical supervision. As a rule, these reactions are mainly reversible upon drug withdrawal.

Treatment of labial herpes and prevention of cytomegalovirus infection and disease

Use of high doses of valacyclovir in hepatic impairment and after liver transplantation. There are no data on the use of valacyclovir in high doses (4000 mg/day and above) in patients with liver disease, so high doses of valacyclovir should be prescribed with caution to such patients.

Special studies on the effect of valacyclovir in liver transplantation have not been conducted. However, it has been established that prophylactic administration of acyclovir in high doses reduces the manifestations of cytomegalovirus infection and disease.

Use in genital herpes. Patients should be advised to refrain from sexual intercourse in the presence of symptoms, even if treatment with valacyclovir has already been started.

Suppressive therapy with valacyclovir reduces the risk of transmission of genital herpes but does not completely eliminate the risk of infection and does not lead to a complete cure. Therapy with valacyclovir is recommended in combination with reliable barrier contraception.

Effect on ability to drive and use machines

The patient’s clinical condition and the profile of adverse reactions of valacyclovir should be taken into account when assessing the patient’s ability to drive a car or operate machinery.

Overdose

Symptoms acute renal failure and neurological disorders, including confusion, hallucinations, agitation, depressed level of consciousness and coma, as well as nausea and vomiting, have been observed in patients who received valacyclovir doses exceeding the recommended ones. Such conditions were more frequently noted in patients with renal impairment and elderly patients who received repeated supratherapeutic doses of valacyclovir due to non-compliance with the dosage regimen.

Treatment patients should be under close medical supervision. Hemodialysis significantly enhances the removal of acyclovir from plasma and can be considered the method of choice in the management of patients with valacyclovir overdose.

Drug Interactions

No clinically significant interaction has been established.

Acyclovir is eliminated by the kidneys, mainly unchanged, via active renal secretion. Concomitant use of drugs with this elimination mechanism may lead to increased plasma concentrations of acyclovir.

After administration of valacyclovir 1000 mg and drugs such as cimetidine, probenecid, which are eliminated by the same pathway as Valaciclovir, an increase in acyclovir AUC and thus a decrease in renal clearance of acyclovir is observed. However, due to the wide therapeutic index of acyclovir, no adjustment of the valacyclovir dose is required.

When treating labial herpes, and preventing and treating cytomegalovirus diseases, caution should be exercised in case of concomitant use of valacyclovir in higher doses (4000 mg/day and above) and drugs that compete with acyclovir for the elimination pathway, as there is a potential threat of increased plasma concentrations of one or both drugs, or their metabolites. An increase in the AUC of acyclovir and the inactive metabolite of mycophenolate mofetil (an immunosuppressant used in post-transplant patients) has been observed with concomitant use of these drugs.

Concomitant use of valacyclovir with nephrotoxic drugs, including aminoglycosides, organic platinum compounds, iodine-containing contrast media, methotrexate, pentamidine, foscarnet, cyclosporine and tacrolimus, should be done with caution, especially in patients with renal impairment, and requires regular monitoring of renal function.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.