Valacyclovir-ACOS, 500 mg 40 pcs

Pharmacotherapeutic group: antiviral medicine

ATX code: J05AB11

Pharmacological properties

Pharmacodynamics

The mechanism of action

Valacyclovir is an antiviral agent, it is an L-valine ester of acyclovir. Acyclovir is an analog of the purine nucleoside (guanine).

In the human body, valacyclovir is rapidly and almost completely converted to acyclovir and valine, presumably by the enzyme valacyclovirhydrolase.

Aciclovir is a specific herpes virus inhibitor with in vitro activity against herpes simplex virus (HPV) types 1 and 2; Varicella zoster virus (VZV); cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpes virus type 6. Acyclovir inhibits the synthesis of viral DNA immediately after phosphorylation and transformation into the active form – acyclovirtriphosphate.

The first stage of phosphorylation requires activity of virus-specific enzymes. For HPV, VZV and VEB, this enzyme is viral thymidine kinase, which is present only in virus-affected cells. Part of the phosphorylation selectivity is maintained in cytomegalovirus indirectly through the product of the phosphotransferase gene UL97. This need for activation of acyclovir 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 analog, is incorporated into viral DNA, which leads to obligate breaking of the chain, cessation of DNA synthesis and, consequently, to blocking of virus replication.

Resistance to acyclovir is usually due to thymidine kinase deficiency, which leads to excessive spread of the virus in the host. In rare cases, decreased sensitivity to acyclovir is due to the emergence of virus strains with disrupted viral thymidine kinase or DNA polymerase structure. The virulence of these strains of the virus is similar to that of its wild strain.

. In an extensive study of HBV and EHV strains sampled from patients treated with acyclovir or used as prophylaxis, it was found that viruses with hypersensitivity to Valacyclovir are extremely rare but may be found in rare cases in patients with severe immune impairments, such as bone marrow or organ transplant recipients, patients receiving chemotherapy for malignancies, and HIV-infected individuals.

Valacyclovir helps control pain: It reduces the duration of pain and decreases the percentage of patients with pain caused by herpes zoster, including acute post-herpetic neuralgia.

Pharmacokinetics

Intake

After oral administration, valacyclovir is well absorbed from the gastrointestinal tract,

converting quickly and almost completely to acyclovir and valine. This conversion is probably carried out by the liver enzyme valacyclovir hydrolase.

The bioavailability of acyclovir is 54% when taking valacyclovir at a dose of 1000 mg or more and is not reduced by food intake. Valacyclovir pharmacokinetics is not dose-dependent. The rate and extent of absorption decrease with increasing dose, leading to a less proportional increase in maximum plasma concentration (C_max) compared to the therapeutic dose range and decreased bioavailability at doses above 500 mg.

Table 1. Results of acyclovir pharmacokinetics assessment of single doses of valacyclovir from 250 mg to 2,000 mg in healthy volunteers with normal hepatic function

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C_max – maximum plasma concentration;

T_max – time to reach maximum plasma concentration;

AUC – area under the pharmacokinetic concentration-time curve. The C_max and AUC values reflect the mean standard deviation. The values for T_max reflect the median value and range of values.

The maximum plasma concentration of valacyclovir is only 4% of that of acyclovir, with a median time of 30 to 100 min after drug administration. Within 3 hours after drug administration, valacyclovir concentration reaches the level of quantification or lower.

Valacyclovir and acyclovir have similar pharmacokinetic parameters after single and multiple dosing. VZV and HPV do not significantly change the pharmacokinetics of valacyclovir and acyclovir after oral valacyclovir administration.

Distribution

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

Metabolism

After oral administration, valacyclovir is converted to acyclovir and L-valine via presystemic metabolism in the intestine and/or hepatic metabolism. Acyclovir is converted into minor metabolites: CMG by ethyl alcohol and aldehyde dehydrogenase; 8-OH-ACV by aldehydoxidase. Approximately 88% of the total cumulative effect on blood plasma is attributable to acyclovir, 11% to CMG, and 1% to 8-OH-ACV. Valacyclovir and acyclovir are not metabolized by cytochrome P450 isoenzymes.

In patients with normal renal function the elimination half-life of acyclovir from the blood plasma after single or multiple doses of valacyclovir is about 3 hours. Less than 1% of the administered dose of valacyclovir is excreted unchanged by the kidneys. Valacyclovir is excreted by the kidneys primarily as acyclovir (more than 80% of the dose taken) and acyclovir metabolite – SMMG.

Patients with impaired renal function

Aciclovir excretion correlates with renal function, exposure to acyclovir increases with the severity of renal failure. In patients with end-stage renal failure, the average half-life of acyclovir after valacyclovir administration is about 14 hours, compared to about 3 hours with normal renal function.

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

Patients with impaired hepatic function

Pharmacokinetic data show that in patients with hepatic impairment the rate of conversion of valacyclovir to acyclovir is reduced, but not the extent of this conversion. The half-life of acyclovir is independent of hepatic function.

Pregnancy

A study of the pharmacokinetics of valacyclovir and acyclovir in late pregnancy found an increase in the steady state daily AUC of valacyclovir at a daily dose of 1000 mg daily, which was approximately 2 times the AUC when acyclovir was taken orally at a dose of 1200 mg daily.

HIV infection

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

Organ transplantation

The maximum concentration of acyclovir in patients after organ transplantation receiving 2000 mg valacyclovir 4 times daily was comparable to or higher than the maximum concentration observed in healthy volunteers receiving the same dose. The established daily AUC values can be characterized as markedly higher.

Indications

Adults and adolescents aged 12 to 18 years

– Treatment of skin and mucous membrane infections caused by HPV, including newly diagnosed and recurrent genital herpes (Herpes genitalis), as well as labial herpes (Herpes labialis).

– Prevention (suppression) of recurrent infections of the skin and mucous membranes caused by HPV, including genital herpes, including in adults with immunodeficiency.

Prevention of infections caused by cytomegalovirus (CMV) and diseases after parenchymal organ transplantation.

Adults

– Treatment of herpes zoster (Herpes zoster) and ophthalmic herpes zoster.

Active ingredient

Composition

Composition of the core:

The active substance: valacyclovir hydrochloride – 556.2 mg (in terms of valacyclovir – 500 mg);

Excipients: Calcium stearate, povidone-K90 (collidon 90 F, plasdon K90), crosspovidone, colloidal silica (aerosil), talc, microcrystalline cellulose;

Shell composition: Hypromellose (hydroxypropyl methylcellulose), macrogol – 4000 (polyethylene oxide 4000, polyethylene glycol 4000), titanium dioxide (titanium dioxide).

How to take, the dosage

The drug Valacyclovir-ACOS is taken regardless of meals, the tablets should be washed down with water.

The treatment of infections of the skin and mucous membranes caused by HPV, including newly diagnosed and recurrent genital herpes (Herpes genitalis) as well as labial herpes (Herpes labialis)./p>

Immunocompetent adults and adolescents aged 12 to 18 years

The recommended dose is 500 mg twice daily.

In cases of relapses, treatment should continue for 3 or 5 days. In the case of primary herpes, which may be more severe, treatment should be started as soon as possible, and its duration should be increased from 5 to 10 days. In case of recurrent HPV, it is most correct to prescribe Valacyclovir-ACOS in the prodromal period or immediately after the appearance of the first symptoms of the disease. Valacyclovir use can prevent lesions from developing if used at the first signs and symptoms of relapse caused by HPV.

As an alternative treatment for labial herpes, Valacyclovir-ACOS is effective at a dose of 2,000 mg twice daily for 1 day. The second dose should be taken approximately 12 hours (but not earlier than 6 hours) after the first dose. When using this dosing regimen, the duration of treatment should not exceed 1 day, since exceeding this duration of treatment does not result in additional clinical benefit.

The therapy should be started when the earliest symptoms of labial herpes (i.e., tingling, itching, burning) appear.

Prevention (suppression) of recurrent infections of the skin and mucous membranes caused by HPV, including genital herpes, including in adults with immunodeficiency

Immunodeficiency/p>

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 evaluated.

Adults with immunodeficiency

In adult patients with immunodeficiency, the recommended dose is 500 mg 2 times daily.

After 6-12 months of treatment, the effectiveness of therapy should be evaluated.

Prophylaxis of infections caused by CMV and disease after parenchymal organ transplantation

Adults and adolescents aged 12 to 18 years

The recommended dose is 2000 mg 4 times daily, administered as soon as possible after transplantation. The dose should be reduced depending on creatinine clearance.

The duration of treatment is usually 90 days, but in high-risk patients the course of treatment may be extended.

The treatment of herpes zoster and ophthalmic herpes zoster

Adults

The recommended dose is 1000 mg 3 times daily for 7 days.

Special patient groups

Children

The efficacy of treatment with Valacyclovir-ACOS has not been studied in children.

Elderly patients

Possible impairment of renal function in elderly patients must be taken into account; the dose of Valacyclovir-ACOS must be adjusted accordingly.

The adequate water-electrolyte balance should be maintained.

Patients with impaired renal function

The dose of Valacyclovir-ACOS should be reduced in patients with significant renal impairment (see dosing regimen in Table 2). In these patients an adequate water-electrolyte balance should be maintained.

Table 2. Dose adjustment of Valacyclovir-ACOS for use in adults and adolescents aged 12 to 18 years with impaired renal function

Indications

Creatinine clearance, mL/min

Dose of Valacyclovir-ACOS

Herpes zoster and ophthalmic herpes zoster in immunocompetent adults (treatment)

at least 50

30 to 49

10 to 29/p>

less than 10

1000 mg 3 times daily

1000 mg 2 times daily

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1000 mg once daily

500 mg once daily

HPV (treatment)

Immunocompetent adults and adolescents ages 12 to 18

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at least 30

less than 30

500 mg 2 times daily

500 mg once daily

Labial herpes in immunocompetent adults and adolescents aged 12 to 18 years (treatment)

500 mg once daily/p>

at least 50

30 to 49

10 to 29

less than 10

/td>

2000 mg 2 times a day

1000 mg 2 times a day

500 mg 2 times a day

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500 mg once daily

HPV (prevention (suppression))

Immunocompetent adults and adolescents aged 12 to 18 years

at least 30

less than 30

500 mg once daily

500 mg once every two days

Adults with immunodeficiency

at least 30

less than 30

500 mg 2 times daily

500 mg once daily

Prevention of infections caused by CMV in adults and adolescents aged 12 to 18 years

at least 75

50 to 75

25 to 50

10 to 25

less than 10 or in patients on hemodialysis

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2000 mg 4 times daily

1500 mg 4 times daily

1500 mg 3 times daily

1500 mg 2 times daily

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1500 mg once daily

Additional information for the indication: Treatment of skin and mucous membrane infections caused by HPV, including newly diagnosed and recurrent genital herpes (Herpes genitalis) as well as labial herpes (Herpes labialis)

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There is no experience with Valacyclovir-ACOS in children with creatinine clearance values less than 50 mL/min/1.73 m2.

Further information for the indication: Prevention of infections caused by CMV and disease after parenchymal organ transplantation

Creatinine clearance should be determined frequently, especially during times when renal function changes rapidly, such as immediately after transplantation or graft engraftment, and the dose of Valacyclovir-ACOS is adjusted according to creatinine clearance values.

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

Valacyclovir-ACOS should be used after hemodialysis in patients receiving intermittent hemodialysis.

Patients with impaired liver function

Based on a study using a single dose of valacyclovir 1000 mg in adult patients with mild to moderate cirrhosis (with preserved synthetic liver function), no dose adjustment of Valacyclovir-ACOS is necessary.

Pharmacokinetic data in adult patients with severe hepatic impairment (decompensated cirrhosis), impaired hepatic synthetic function and presence of portocaval anastomoses also do not indicate the need to adjust the dose of Valacyclovir-ACOS, but clinical experience with these pathologies is limited.

Information on doses greater than 4000 mg daily for patients with infections caused by HPV and CMV is listed in the section “Special Indications”.

Interaction

No clinically significant interactions have been established.

Acyclovir is excreted by the kidneys, mostly unchanged by active renal secretion. Concomitant use of medicinal products with this excretion mechanism may lead to increased concentrations of acyclovir in blood plasma.

After prescribing valacyclovir at a dose of 1000 mg and the drugs cimetidine, probenecid, which are excreted by the same route as valacyclovir, there is an increase in the AUC of acyclovir and thus the renal clearance of acyclovir is reduced. However, due to the wide therapeutic index of acyclovir, no dose adjustment of valacyclovir is required.

In the treatment of labial herpes, prevention and treatment of diseases caused by CMV, caution should be exercised in the case of concomitant use of valacyclovir at higher doses (4000 mg daily and above) and drugs that compete with acyclovir for the excretion route, since there is a potential risk 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 patients after organ transplantation) has been noted when these drugs are used simultaneously.

The concomitant use of valacyclovir with nephrotoxic drugs, including aminoglycosides, organic platinum compounds, iodinated contrast agents, methotrexate, pentamidine, foscarnet, cyclosporine and tacrolimus should be performed with caution, especially in patients with impaired renal function, and requires regular monitoring of renal function.

Special Instructions

Hydration

In patients at risk of dehydration, especially elderly patients, an adequate water-electrolyte balance should be maintained.

Patient use in patients with impaired renal function and elderly patients

Because acyclovir is excreted by the kidneys, the dose of Valacyclovir-ACOS should be reduced in patients with impaired renal function. Elderly patients may have impaired renal function, so dose reduction should be considered for this group of patients. Both elderly patients and patients with impaired renal function are at increased risk of developing neurological complications, such patients should be closely monitored by a physician. As a rule, these reactions are mostly reversible if the drug is withdrawn.

The treatment of labial herpes and prevention of CMV infections and diseases

The use of high doses of Valacyclovir-ACOS in liver dysfunction and after liver transplantation

There are no data on the use of Valacyclovir-ACOS in high doses (4000 mg per day and more) in patients with liver disease; therefore in such patients high doses of Valacyclovir-ACOS should be prescribed with caution. No special studies have been conducted to study the effect of Valacyclovir-ACOS in patients with liver transplantation. However, prophylactic administration of acyclovir at high doses has been found to reduce manifestations of CMV infection and disease.

The use in genital herpes

Patients should be advised to refrain from sexual intercourse in the presence of symptoms, even if treatment with the antiviral drug Valacyclovir-ACOS has already been initiated. Suppressive therapy with Valacyclovir-ACOS reduces the risk of genital herpes transmission, but does not completely eliminate the risk of infection and does not lead to a complete cure. Therapy with Valacyclovir-ACOS is recommended in combination with reliable barrier contraception.

Impact on driving, operating machinery

When treating, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities.

There have been no specific studies. The patient’s clinical condition and the adverse reaction profile of valacyclovir should be considered when assessing the patient’s ability to drive or operate machinery.

Synopsis

Oval-shaped, biconvex, film-coated tablets are white or almost white. On cross section the inner layer is white or almost white.

Contraindications

– Hypersensitivity to valacyclovir, acyclovir or any other component of the drug.

– Childhood under 12 years of age.

– Childhood under 18 years of age when treating herpes zoster and ophthalmic herpes zoster.

With caution

Concomitant use with nephrotoxic drugs, renal failure, pregnancy, lactation, clinically significant forms of HIV infection.

Side effects

Unwanted reactions are listed below according to the classification by major systems and organs and frequency of occurrence, which has been defined as follows: Very common: > 1 per 10, common: > 1 per 100 and < 1 per 10, infrequent: > 1 per 1000 and < 1 per 100, rare: > 1 per 10000 and < 1 per 1000, very rare: < 1 per 10000.

Clinical study data

Nervous system disorders

Often: headache.

Gastrointestinal tract disorders

Often: nausea.

Post-marketing study data

Blood and hematopoietic system disorders

Very rare: leukopenia, thrombocytopenia. Mostly leukopenia was observed in patients with reduced immunity.

Immune system disorders

Very rare: anaphylaxis.

Nervous system and mental disorders

Rarely: dizziness, confusion, hallucinations, depression of consciousness.

Very rare: agitation, tremor, ataxia, dysarthria, psychotic symptoms, seizures, encephalopathy, coma. The above symptoms are mostly reversible and usually seen in patients with impaired renal function or other predisposing conditions. Adult patients with an organ transplant who receive high doses (8 g per day) of valacyclovir to prevent CMV infection develop neurological reactions more often than those receiving lower doses.

Respiratory and mediastinal system disorders

Infrequent: dyspnea.

Gastrointestinal tract disorders

Rarely: abdominal discomfort, vomiting, diarrhea.

Hepatic and biliary tract disorders

Very rare: reversible abnormalities of functional liver function tests, which are sometimes regarded as manifestations of hepatitis.

Skin and subcutaneous fatty tissue disorders

Infrequent: rashes, including photosensitivity.

Rarely: itching.

Very rare: urticaria, angioedema.

Urinary system disorders

Infrequent: hematuria (often associated with other renal disorders).

Rarely: impaired renal function.

very rarely: acute renal failure, renal colic. Renal colic may be associated with impaired renal function.

Cases of deposition of acyclovir crystals in the lumen of the renal tubules have been reported. It is necessary to observe an adequate drinking regime during treatment.

Others: cases of renal failure, microangiopathic hemolytic anemia and thrombocytopenia (sometimes in combination) have been reported in patients with severe immune disorders, especially in adult patients with advanced HIV infection receiving high doses of valacyclovir (8 g daily) for a long period of time. Similar complications have been noted in patients with the same underlying and/or comorbidities but not receiving valacyclovir.

Overdose

Symptoms

Acute renal failure and neurological disorders, including confusion, hallucinations, agitation, depression and coma, as well as nausea and vomiting, have been observed in patients who have received doses of valacyclovir in excess of recommended doses. These conditions occurred more frequently in patients with impaired renal function and in elderly patients who received repeated doses of valacyclovir in excess of the recommended doses due to non-compliance with the dosing regimen.

Treatment

Patients must be under close medical supervision. Hemodialysis contributes significantly to excretion of acyclovir from the blood and may be considered the method of choice in the management of patients with overdose of the drug.

Pregnancy use

Fertility

In animal studies, valacyclovir had no effect on fertility. However, the use of high doses of acyclovir when administered parenterally caused testicular effects in rats and dogs.

There have been no studies on the effect of valacyclovir on fertility in humans. 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 1,000 mg.

Pregnancy

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

Pregnancy registries have documented pregnancy outcomes in women taking valacyclovir or other drugs containing acyclovir (acyclovir is the active metabolite of valacyclovir), 111 and 1246 observations, respectively (of which 29 and 756 took the drugs in the first trimester of pregnancy), representing pregnancy outcomes reported prospectively. Analysis of the data presented in the registry of pregnant women exposed to acyclovir showed no increase in birth defects in their children compared to the general population, and no specificity or pattern indicating a common cause was found for any of the malformations. Because the pregnancy registry included a small number of women who took valacyclovir during pregnancy, reliable and definitive conclusions about the safety of valacyclovir in pregnancy cannot be drawn.

Breastfeeding period

Acyclovir, the main metabolite of valacyclovir, penetrates into breast milk. After oral administration of valacyclovir at a dose of 500 mg, Cmax in breast milk was 0.5-2.3 times (1.4 times on average) higher than the corresponding concentrations of acyclovir in maternal plasma. The ratio of AUC values of acyclovir in breast milk to AUC values in maternal blood 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 at a dose of 500 mg twice daily, breastfed infants are exposed to the same acyclovir as when it is taken orally at a dose of about 0.61 mg/kg/day. The half-life of acyclovir from breast milk is the same as that from blood plasma.

Valacyclovir was not detected unchanged in maternal plasma, breast milk or baby’s urine.

Valacyclovir should be used with caution in women during breastfeeding.

Accyclovir for intravenous injection is, however, used to treat HPV in infants at a dose of 30 mg/kg/day.

Similarities