Valtrex

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

Composition:

Active substance: valacyclovir;

One tablet contains 500 mg of valacyclovir (as valacyclovir hydrochloride);

Excipients: microcrystalline cellulose, crospovidone, povidone, magnesium stearate, colloidal anhydrous silicon dioxide, carnauba wax, white pigment concentrate (YS-1-18043): hypromellose, titanium dioxide (E 171), polyethylene glycol 400, polysorbate 80.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, film-coated, elongated biconvex tablets with a white or almost white core, without a score line, with embossing GX CF1.

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

Pharmacological Properties.

Pharmacodynamics.

Valacyclovir is an antiviral agent, the L-valyl ester of acyclovir, which is a purine (guanine) nucleoside analogue. In humans, 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 after phosphorylation and conversion into its active form, acyclovir triphosphate. The initial phosphorylation step requires 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, mediated by the UL97 gene product phosphotransferase. Activation of acyclovir by a specific viral enzyme 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, resulting in obligate (complete) chain termination, cessation of DNA synthesis, and thus blockade of viral replication.

Resistance is caused by a deficiency of viral thymidine kinase, leading to excessive viral spread in the host organism. Occasionally, reduced sensitivity to acyclovir results from the emergence of viral strains with altered viral TK or DNA polymerase structure. 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 immunosuppression, such as after organ transplantation or bone marrow recipients, during chemotherapy for malignant neoplasms, and in HIV-infected individuals.

Valtrex 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 Valtrex reduces the risk of acute transplant rejection (in kidney transplant recipients), the frequency of opportunistic infections, and other infections caused by herpesviruses (herpes simplex virus and Herpes zoster virus).

Pharmacokinetics.

Absorption

After oral administration, valacyclovir is well absorbed and rapidly and almost completely converted into acyclovir and valine. This conversion appears to be mediated by the enzyme valacyclovir hydrolase isolated from human liver. The bioavailability of acyclovir following a 1 g dose of valacyclovir is 54% and is not reduced when taken with food. The pharmacokinetics of Valtrex 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 greater than 500 mg are administered. The mean peak concentration of acyclovir ranges from 10–37 µmol (2.2–8.3 µg/mL) after a single 250–2000 mg dose of valacyclovir in healthy volunteers with normal renal function, with a median time to peak concentration of 1–2 hours. The peak plasma concentration of valacyclovir is only 4% of that of acyclovir, reached on average within 30–100 minutes, and decreases 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 – 15%. Penetration into cerebrospinal fluid (CSF), determined by the CSF/AUC plasma ratio, is approximately 25% for acyclovir and its metabolite 8-hydroxyacyclovir, and 2.5% for the metabolite 9-carboxymethoxymethylguanine.

Metabolism

Following oral administration, Valtrex is converted to acyclovir and L-valine via first-pass metabolism in the intestine and/or liver. A small fraction of acyclovir is converted to the metabolite 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 Valtrex 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 Valtrex.

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

In patients with HIV infection, the pharmacokinetic characteristics of acyclovir after single or multiple doses of 1000 mg or 2000 mg of Valtrex were not altered compared to healthy individuals.

In organ transplant recipients receiving valacyclovir 2000 mg four times daily, the maximum concentration of acyclovir was equal to or exceeded that observed 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 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 the risk of transmission of genital herpes virus to a healthy partner when Valtrex is used as suppressive therapy in combination with adherence to safe sex practices.

Prophylaxis of cytomegalovirus infection and disease following organ transplantation.

Contraindications.

Valtrex 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 interaction.

No clinically significant interactions have been identified.

Acyclovir is primarily eliminated unchanged in urine via active tubular secretion. Any drugs administered concomitantly that affect this elimination pathway may increase plasma concentrations of acyclovir after administration of Valtrex. Following administration of Valtrex at a dose of 1 g, cimetidine and probenecid, which block tubular secretion, increase the area under the plasma concentration-time curve (AUC) of acyclovir and reduce its renal clearance; however, dosage adjustment is not required due to the wide therapeutic index of acyclovir.

Caution should be exercised in patients receiving higher doses of Valtrex (4 g or more per day) when co-administered 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. When used concomitantly with mycophenolate mofetil (an immunosuppressive agent used after organ transplantation), plasma levels of both acyclovir and the inactive metabolite of mycophenolate mofetil are increased.

Caution (with monitoring of renal function) should also be exercised when high doses of Valtrex (4 g or more) are co-administered with other agents affecting 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. When prescribing the drug, patients should be informed about the possibility of developing such symptoms and advised to closely monitor skin reactions. If early signs or symptoms suggestive of DRESS syndrome occur, the drug should be discontinued immediately and alternative therapy initiated (if necessary). Valacyclovir must not be re-administered to patients who have previously developed DRESS syndrome during treatment with valacyclovir.

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 via the kidneys; therefore, the dose of valacyclovir should be reduced in patients with impaired renal function (see section "Dosage and administration"). Elderly patients often have reduced renal function and require dose adjustment. Patients with renal impairment and elderly patients are at increased risk of developing neurological complications and should be closely monitored for such effects. According to reported data, these reactions are mostly reversible upon discontinuation of treatment (see section "Side effects").

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 daily) for the treatment of patients with liver disease; therefore, higher doses of Valacyclovir should be prescribed with caution in such patients. Specific studies on the use of Valacyclovir in liver transplantation have not been conducted; however, it has been established that prophylaxis with high-dose acyclovir reduces the incidence of cytomegalovirus (CMV) infection and disease.

Use in the treatment of herpes zoster

Patients, especially those with compromised immune systems, should be carefully 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, immunocompromised patients with herpes infections involving the eye or at high risk of disease dissemination and visceral organ involvement should be treated with intravenous antiviral agents.

Reduction of genital herpes transmission

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

Use in cytomegalovirus infection

Data on efficacy in treating patients at high risk of cytomegalovirus infection for prophylaxis after organ transplantation indicate that valacyclovir should be used in these patients if valganciclovir or ganciclovir has been discontinued for safety reasons. The use of high-dose valacyclovir required for CMV 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 should be closely monitored, and appropriate dose adjustments should be made.

Use during pregnancy or breastfeeding

Fertility

Animal studies have shown that Valacyclovir has no effect on fertility. However, high parenteral doses of acyclovir have caused testicular effects in rats and dogs.

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

Pregnancy

Data on the use of Valacyclovir during pregnancy are limited. Valacyclovir 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 monitoring women who used valacyclovir or any form of acyclovir (active metabolite of valacyclovir): 111 and 1,246 women, respectively (29 and 756 pregnant women used valacyclovir or any form of acyclovir in the first trimester, respectively). According to this observational data, no increase in congenital malformations was observed in newborns of pregnant women who took acyclovir compared to the general population of such patients. No congenital malformation had a unique or consistent pattern that would allow identification of a single causative factor. Due to the limited number of observed pregnant women, a reliable and definitive conclusion regarding the safety of valacyclovir use during pregnancy cannot be made (see section "Pharmacological properties").

Breastfeeding

Acyclovir, the primary 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 receives 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.

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

Ability to affect reaction speed when driving or operating machinery

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

Dosage and Administration

Herpes zoster treatment: Adults should be given 1000 mg (2 tablets) three times daily for 7 days.

Treatment of infections caused by herpes simplex virus

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

For recurrent episodes, treatment should last 3 or 5 days. In primary episodes, 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 infections, optimal use of the drug is during the prodromal period or immediately after the first symptoms appear. Valtrex may prevent the development of lesions in recurrent herpes simplex infections if treatment is started immediately after the first symptoms occur.

Alternatively, for the treatment of herpes labialis (cold sores), an effective dose of Valtrex 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 (preventive) therapy for recurrent herpes simplex virus infections:

• Immunocompetent patients (adults): 500 mg (1 tablet) once daily;
• Immunocompromised patients (adults): 500 mg (1 tablet) twice daily.

Reduction of transmission of genital herpes virus.

For immunocompetent adult heterosexuals with 9 or fewer recurrences per year, Valtrex should be administered to the infected partner at a dose of 500 mg once daily.

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

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

Adults and children aged 12 years and older: Valtrex should be administered at a dose of 2000 mg (4 tablets) 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 in patients at high risk.

Dosage in Renal Impairment.

Valacyclovir should be administered 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).

Therapeutic indication	Creatinine clearance, mL/min	Valtrex dosage
Herpes zoster (treatment) in immunocompetent and immunocompromised adult patients	50 and above 30–49 10–29 less than 10	1 g three times daily 1 g twice daily 1 g once daily 500 mg once daily
Herpes simplex (treatment)
immunocompetent adult patients	30 and above less than 30	500 mg twice daily 500 mg once daily
Herpes labialis (treatment) immunocompetent adult patients	50 and above 30–49 10–29 less than 10	2 g twice daily 1 g twice daily 500 mg twice daily 500 mg once daily
Herpes simplex (prophylaxis)
immunocompetent adult patients	30 and above less than 30	500 mg once daily 250* mg once daily
immunocompromised adult patients	30 and above less than 30	500 mg twice daily 500 mg once daily
Prevention of cytomegalovirus infection	75 and above 50–75 25–50 10–25 Less than 10 or dialysis	2 g four times daily 1.5 g four times daily 1.5 g three times daily 1.5 g twice daily 1.5 g once daily

*administer if 250 mg tablets of the drug are available.

For patients undergoing intermittent hemodialysis, the same doses of Valtrax should be administered as for patients with a creatinine clearance of less than 15 ml/min. Doses should be given after hemodialysis sessions.

Creatinine clearance should be monitored continuously, especially during periods when renal function may change rapidly, such as immediately after transplantation. The dose of Valtrax should be adjusted accordingly.

Dosage in 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 administration of higher doses (4000 mg and above) per day, see section "Special precautions for use".

Elderly patients

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

Adequate hydration should be maintained.

Children

Valtrax is indicated for use in children aged 12 years and older for the prevention of cytomegalovirus infection and disease following organ transplantation.

Overdose.

Symptoms

Overdose with valacyclovir has been associated with the development of acute renal failure and neurological symptoms, including confusion, hallucinations, agitation, decreased mental abilities, and coma. Nausea and vomiting may also occur. Care should be taken to prevent accidental overdose. Many cases of overdose have been associated with administration of the drug to patients with renal impairment or elderly patients who did not receive appropriate dose reduction.

Treatment

Patients should be closely monitored for signs of toxicity. Hemodialysis significantly accelerates the elimination of acyclovir from the blood and therefore can be considered the optimal treatment method in cases of symptomatic overdose.

Side effects.

The most commonly reported adverse reactions in clinical trials were headache and nausea. Among the more serious adverse reactions, there have been reports of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, acute renal failure, neurological disorders, and DRESS syndrome.

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), not known (cannot be estimated from the available data).

From clinical trials

Nervous system disorders

Common: headache.

Gastrointestinal disorders

Common: nausea.

From post-marketing experience

Blood and lymphatic system disorders

Very rare: leukopenia, thrombocytopenia.

Leukopenia is mainly observed in patients with immunodeficiency.

Immune system disorders

Very rare: anaphylaxis.

Nervous system and psychiatric disorders

Uncommon: dizziness, confusion, hallucinations, cognitive decline.

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

The above symptoms are mostly reversible and are primarily observed in patients with renal impairment or other predisposing factors (see section "Special precautions"). Neurological reactions occur more frequently in organ transplant recipients receiving Valtrex for cytomegalovirus infection prophylaxis at high doses (8 g daily) compared to patients receiving lower doses.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea.

Gastrointestinal disorders

Rare: abdominal discomfort, vomiting, diarrhea.

Hepatobiliary disorders

Very rare: reversible increases in liver function tests.

This has occasionally been described as hepatitis.

Skin and subcutaneous tissue disorders

Uncommon: rash, including photosensitivity reactions.

Rare: pruritus.

Very rare: urticaria, angioneurotic edema.

Not known: drug reaction with eosinophilia and systemic symptoms (DRESS).

Renal and urinary disorders

Rare: renal dysfunction.

Very rare: acute renal failure, renal pain, hematuria (often associated with other renal function abnormalities).

Renal pain may be associated with renal impairment.

Not known: tubulointerstitial nephritis.

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

Other: there have been reports of renal failure, microangiopathic hemolytic anemia, and thrombocytopenia (sometimes in combination) in severely 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.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.

Packaging. 10 tablets in a blister, 1 blister per cardboard box; or 6 tablets in a blister, 7 blisters per cardboard box; or 14 tablets in a blister, 3 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer. Glaxo Wellcome S.A., Spain.

Manufacturer's address and place of business.

Glaxo Wellcome S.A., Avda. de Extremadura, 3, Pol. Ind. Allendeduero, 09400 Aranda de Duero, Burgos, Spain.