Valacyclovir-ACOS pills 500mg, 40pcs

Composition

Core composition:

Active ingredient: valacyclovir hydrochloride-556.2 mg (based on valacyclovir-500 mg);

Excipients: calcium stearate, povidone-K 90 (collidone 90 F, plasdon K 90), crospovidone, colloidal silicon dioxide (aerosil), talc, microcrystalline cellulose;

Shell composition: hypromellose (hydroxypropylmethylcellulose), macrogol-4000 (polyethylene oxide 4000, polyethylene glycol 4000), titanium dioxide (titanium dioxide).

Pharmacological action

Pharmacotherapeutic group: antiviral agent

ATX code: J05AB11

Pharmacological properties

Pharmacodynamics

Mechanism of action

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

In humans, valacyclovir is rapidly and almost completely converted to acyclovir and valine, presumably under the influence of the enzyme valacyclovir hydrolase.

Acyclovir is a specific inhibitor of herpes viruses with in vitro activity against herpes simplex viruses (HSV) 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 conversion to the active form-acyclovir triphosphate.

The first stage of phosphorylation requires the activity of virus-specific enzymes. For HSV, VZV, and EBV, such an enzyme is viral thymidine kinase, which is present only in virus-affected cells. Partially, phosphorylation selectivity is maintained in cytomegalovirus indirectly through the phosphotransferase gene product UL97. This need for activation of acyclovir by a specific viral enzyme largely explains its selectivity.

The process of phosphorylation of acyclovir (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 an obligate chain break, stopping DNA synthesis and, consequently, blocking viral replication.

Acyclovir resistance is usually caused by a thymidine kinase deficiency, which leads to excessive spread of the virus in the host. In rare cases, a decrease in sensitivity to acyclovir is due to the appearance of virus strains with a violation of the structure of viral thymidine kinase or DNA polymerase. The virulence of these varieties of the virus is similar to that of its wild strain.

Based on the results of an extensive study of HSV and VZV strains selected from patients who received acyclovir therapy or used it for prevention, it was found that viruses with reduced sensitivity to valacyclovir are extremely rare, but can be detected in rare cases in patients with severe immune disorders, such as bone marrow or organ transplant recipients, patients receiving chemotherapy for malignancies, and HIV-infected people.

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

Pharmacokinetics

Suction

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

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

When taking valacyclovir at a dose of 1000 mg or more, the bioavailability of acyclovir is 54% and does not decrease with food intake. The pharmacokinetics of valacyclovir are not dose-dependent. The rate and degree of absorption decrease with increasing dose, resulting in a less proportional increase in the maximum plasma concentration (with_max) compared to the therapeutic dose range and a decrease in bioavailability at doses above 500 mg.

Table 1. Results of evaluating the pharmacokinetics of acyclovir when taking single doses of valacyclovir from 250 mg to 2000 mg in healthy volunteers with normal liver function

Pharmacokinetic parameters of acyclovir		250 mg (N=15)	500 mg (N=15)	1000 mg (N=15)	2000 mg (N=8)
Withmax	µmol/l	of 9.78 ± 1,71	15,0 ± of 4.23	23,1 ± 8,53	of 36.9 ± 6,36
	µg/ml	of 2.20 ± 0,38	3,37 ± 0,95	5,20 ± 1,92	8,30 ± 1,43
Tmax	watch (HR)	of 0.75 (0,75-1,5)	1,0 (0,75-2,5)	2,0 (0,75-3,0)	2,0 (1,5-3,0)
AUC	h ∙ µmol/l	and 24.4 ± 3,65	49,3 ± 7,77	83,9 ± 20,1	131 ± 28,3
	h ∙ µg/ml	5,50 ± 0,82	11,1 ± 1,75	18,9 ± 4,51	29,5 ± 6,36

C_max – maximum concentration in blood plasma;

T_max – time to reach the maximum concentration in blood plasma;

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

The maximum concentration of valacyclovir in blood plasma is only 4% of the concentration of acyclovir, 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 valacyclovir reaches the level of quantitative determination or lower.

Valacyclovir and acyclovir have similar pharmacokinetic parameters after single and multiple use. VZV and HSV did not significantly alter the pharmacokinetics of valacyclovir and acyclovir after oral valacyclovir use.

Distribution

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

Metabolism

After oral use, valacyclovir is converted to acyclovir and L-valine through presystemic intestinal and/or hepatic metabolism. Acyclovir is converted to small metabolites: SMMG under the influence of ethyl alcohol and aldehyde dehydrogenase; 8-OH-ACV under the influence of aldehyde oxidase. Approximately 88% of the total cumulative plasma exposure is accounted for by acyclovir,11% by SMMG, and 1% by 8-OH-ACV. Valacyclovir and acyclovir are not metabolized by cytochrome P450 isoenzymes.

Deduction

In patients with normal renal function, the plasma half-life of acyclovir after a single or multiple dose of valacyclovir is approximately 3 hours. Less than 1% of the valacyclovir dose is excreted unchanged by the kidneys. Valacyclovir is mainly excreted by the kidneys in the form of acyclovir (more than 80% of the dose taken) and the metabolite of acyclovir-SMMG.

Special patient groups

Patients with impaired renal function

Acyclovir elimination correlates with renal function, and acyclovir exposure increases with increasing severity of renal failure. In patients with end-stage renal failure, the average elimination half-life of acyclovir after valacyclovir use is about 14 hours, compared to about 3 hours for normal renal function.

Exposure to acyclovir and its metabolites CMMG and 8-OH-ACV in blood plasma and CSF was assessed in stable condition after repeated use 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 insufficiency (mean creatinine clearance 26 ml/min, range 17-31 ml/min), receiving 1500 mg every 12 hours.In patients with severe renal insufficiency, plasma concentrations of acyclovir, SMMG, and 8-OH-ACV were 2,4, and 5-6 times higher than in patients with normal renal function, as well as in CSF, respectively. There was no difference in the degree of CSF penetration of acyclovir (defined as the ratio of CSF AUC to plasma AUC), SMMG, or 8-OH-ACV between the two populations with severe renal insufficiency and normal renal function.

Patients with impaired liver function

Pharmacokinetic data show that in patients with hepatic insufficiency, the rate of conversion of valacyclovir to acyclovir decreases, but not the degree of this conversion. The elimination half-life of acyclovir is independent of liver function.

Pregnancy

In a study of the pharmacokinetics of valacyclovir and acyclovir in late pregnancy, an increase in the daily AUC value in a stable state was found when valacyclovir was taken daily at a dose of 1000 mg per day, which was approximately 2 times higher than the AUC when acyclovir was taken orally at a dose of 1200 mg per day.

HIV infection

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

Organ transplantation

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

Indications

Adults and adolescents aged 12-18 years

– Treatment of skin and mucosal infections caused by HSV, including first-time 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 HSV, including genital herpes, including in adults with immunodeficiency.

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

Adults

– Treatment of herpes zoster and ophthalmic herpes zoster.

Use during pregnancy and lactation

Fertility

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

Studies on the effect of valacyclovir on fertility in humans 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.

Pregnancy

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

Pregnancy outcomes were documented in the pregnancy registers for women who took valacyclovir or other drugs containing acyclovir (acyclovir is the active metabolite of valacyclovir),111 and 1246 cases, respectively (of which 29 and 756 took drugs in the first trimester of pregnancy), were pregnancy outcomes recorded prospectively. Analysis of the data presented in the register of pregnant women exposed to acyclovir did not reveal an increase in the number of 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. Since the register of pregnant women included a small number of women who took valacyclovir during pregnancy, reliable and definite conclusions about the safety of using valacyclovir during pregnancy cannot be made.

Lactation

: Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. After taking valacyclovir at a dose of 500 mg orally, the_max in breast milk was 0.5-2.3 times (on average,1.4 times) higher than the corresponding concentrations of acyclovir in maternal blood plasma. The ratio of acyclovir AUC in breast milk to maternal serum AUC ranged from 1.4 to 2.6 (mean 2.2). The mean acyclovir concentration in breast milk was 2.24 mcg / ml (9.95 mcmol / L). When the mother takes valacyclovir at a dose of 500 mg 2 times a day, children who are breastfed are exposed to the same effect of acyclovir as when taking it orally at a dose of about 0.61 mg/kg/day. The elimination half-life of acyclovir from breast milk is the same as from blood plasma.

Valacyclovir was not detected unchanged in the mother’s blood plasma, breast milk, or urine of the child.

Valacyclovir should be administered with caution to women who are breast-feeding.

However, acyclovir for intravenous use is used for the treatment of HSV in children at a dose of 30 mg / kg / day.

Contraindications

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

– Children under 12 years of age.

– Children under 18 years of age in the treatment of herpes zoster and ophthalmic herpes zoster.

With caution

When used concomitantly with nephrotoxic drugs, renal failure, pregnancy, lactation, clinically expressed forms of HIV infection.

Side effects

Adverse reactions are listed below according to the classification by major systems and organs and frequency, which was determined as follows: very common: > 1 in 10, common: > > 1 in 100 and >>< 1 in 10, uncommon: > 1 in 1000 and < 1 in 10, uncommon: > < 1 in 100, rare: > 1 in 10000 and < 1 in 100, rare: >< 1 in 1000, very rare:

Data from clinical trials

From the nervous system

Often: headache.

From the gastrointestinal tract

Often: nausea.

Post-marketing research data

From the side of the blood system and hematopoietic organs

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

From the immune system

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 symptoms listed above are mostly reversible and usually occur in patients with impaired renal function or other predisposing conditions. In adult organ transplant patients receiving high doses (8 g per day) of valacyclovir for the prevention of CMV infection, neurological reactions develop more often than with lower doses.

Respiratory and mediastinal disorders

Infrequently: shortness of breath.

From the gastrointestinal tract

Rarely: abdominal discomfort, vomiting, diarrhea.

Liver and biliary tract disorders

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

Skin and subcutaneous fat disorders

Infrequently: rashes, including photosensitivity reactions.

Rare: itching.

Very rare: urticaria, angioedema.

From the urinary system

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

Rare: impaired renal function.

Very rare: acute renal failure, renal colic. Renal colic may be associated with impaired renal function.

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

Other services: 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 who receive high doses of valacyclovir (8 g daily) for a long period of time. Similar complications have been reported in patients with the same underlying and / or comorbidities but not treated with valacyclovir.

Interaction

No clinically significant interactions have been established.

Acyclovir is mainly excreted unchanged by the kidneys through active renal secretion. The combined use of drugs with this mechanism of elimination may lead to an increase in the concentration of acyclovir in blood plasma.

After prescribing valacyclovir at a dose of 1000 mg and cimetidine, probenecid, which are eliminated in the same way as valacyclovir, the AUC of acyclovir increases and, thus, the renal clearance of acyclovir decreases. However, due to the broad 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 in higher doses (4000 mg per day or higher) and drugs that compete with acyclovir for the elimination route, since 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 an inactive metabolite of mycophenolate mofetil (an immunosuppressant used in patients after organ transplantation) was observed with simultaneous use of these drugs.

Concomitant use of valacyclovir with nephrotoxic drugs, including aminoglycosides, organic platinum compounds, iodized contrast agent, methotrexate, pentamidine, foscarnet, cyclosporine and tacrolimus should be carried out with caution, especially in patients with impaired renal function, and requires regular monitoring of renal function.

How to take, course of use and dosage

The drug Valacyclovir-AKOS is taken regardless of food intake, tablets should be washed down with water.

Treatment of skin and mucosal infections caused by HSV, including first-time and recurrent genital herpes( Herpes genitalis), as well as labial herpes (Herpes labialis)

Immunocompetent adults and adolescents aged 12-18 years

The recommended dose is 500 mg 2 times a day.

In case of relapses, treatment should continue for 3 or 5 days. In the case of primary herpes, which can occur in a more severe form, treatment should begin as early as possible, and its duration should be increased from 5 to 10 days. In case of HSV relapses, the most correct prescription is Valacyclovir-ACOS in the prodromal period or immediately after the first symptoms of the disease appear. The use of valacyclovir can prevent the development of a lesion if it is used at the first signs and symptoms of HSV-related relapse.

As an alternative treatment for labial herpes, it is effective to prescribe Valacyclovir-ACOS at a dose of 2000 mg 2 times a day 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 dosage regimen, the duration of treatment should not exceed 1 day, since exceeding the duration of this course of treatment does not lead to additional clinical benefits.

Therapy should be initiated when the earliest symptoms of labial herpes appear (i. e. tingling, itching, burning).

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

Immunocompetent adults and adolescents aged 12-18 years

In immunocompetent patients, the recommended dose is 500 mg once a day.

After 6-12 months of treatment, it is necessary to evaluate the effectiveness of therapy.

Adults with immunodeficiency

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

After 6-12 months of treatment, it is necessary to evaluate the effectiveness of therapy.

Prevention of CMV infections and diseases after parenchymal organ transplantation

Adults and adolescents aged 12-18 years

The recommended dose is 2000 mg 4 times a day, prescribed as early 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.

Treatment of herpes zoster and ophthalmic herpes zoster

Adults

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

Special patient groups

Children

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

Elderly patients

Possible renal impairment in elderly patients should be considered, and the dose of Valacyclovir-ACOS should be adjusted accordingly.

It is necessary to maintain an adequate water-electrolyte balance.

Patients with impaired renal function

The dose of Valacyclovir-ACOS is recommended to be reduced in patients with severe renal impairment (see dosage regimen in Table 2). In such patients, it is necessary to maintain an adequate water-electrolyte balance.

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	Valacyclovir-ACOS dosage
Herpes zoster and ophthalmic herpes zoster in immunocompetent adults (treatment)	at least 50 30 to 49 10 to 29 less than 10	1000 mg 3 times a day 1000 mg 2 times a day 1000 mg 1 time a day 500 mg 1 time a day
HSV (treatment)
Immunocompetent adults and adolescents aged 12-18 years	at least 30 less than 30	500 mg 2 times a day 500 mg 1 time a day
Labial herpes in immunocompetent adults and adolescents aged 12-18 years (treatment)	at least 50 30 to 49 10 to 29 less than 10	2000 mg 2 times a day 1000 mg 2 times a day 500 mg 2 times a day 500 mg 1 time a day
HSV (prevention (suppression))
Immunocompetent adults and adolescents aged 12-18 years	at least 30 less than 30	500 mg once a day 500 mg once every two days
Adults with an immunodeficiency	of at least 30 less than 30	500 mg 2 times a day 500 mg 1 time a day
Prevention of infections caused by CMV in adults and adolescents aged 12 to 18 years of age	at least 75 50 to 75 25 to 50 10 to 25 or less than 10 patients on hemodialysis	2000 mg 4 times daily 1500 mg 4 times a day and 1500 mg 3 times a day and 1500 mg 2 times a day and 1500 mg 1 time per day

Additional information for indications: treatment of skin and mucosal infections caused by HSV, including newly diagnosed and recurrent genital herpes( Herpes genitalis), as well as labial herpes (Herpes labialis)

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

Additional information for indications: prevention of CMV infections and diseases after parenchymal organ transplantation

Creatinine clearance should be measured frequently, especially when renal function changes rapidly, for example, immediately after transplantation or graft implantation, and the dose of Valacyclovir-ACOS is adjusted according to creatinine clearance indicators.

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

Valacyclovir-ACOS should be used after hemodialysis in patients undergoing periodic hemodialysis.

Patients with impaired liver function

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

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

For information on doses exceeding 4000 mg / day for patients with HSV and CMV infections, see the section “Special Instructions”.

Overdose

Symptoms

Acute renal failure and neurological disorders, including confusion, hallucinations, agitation, depression of consciousness and coma, as well as nausea and vomiting, were observed in patients who received doses of valacyclovir that exceeded the recommended dose. Such conditions were more frequently observed in patients with impaired renal function and elderly patients who received repeated doses of valacyclovir exceeding the recommended dosage, due to non-compliance with the dosage regimen.

Treatment

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

Description

Tablets are oval in shape, biconvex, covered with a film-coated white or almost white color. On a cross-section, the inner layer is white or almost white in color.

Special instructions

Hydration

Adequate water and electrolyte balance should be maintained in patients at risk of dehydration, especially in the elderly.

Use in patients with impaired renal function and in elderly patients

Since acyclovir is excreted by the kidneys, it is necessary to reduce the dose of Valacyclovir-ACOS in patients with impaired renal function. Elderly patients may experience 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 an increased risk of developing neurological complications, and such patients should be carefully monitored. As a rule, these reactions are mostly reversible if the drug is discontinued.

Treatment of labial herpes and prevention of CMV infections and diseases

Use of high doses of Valacyclovir-ACOS in patients with impaired liver function and after liver transplantation

There are no data on the use of Valacyclovir-ACOS in high doses (4000 mg per day and above) in patients with liver disease, so such patients should be prescribed high doses of Valacyclovir-ACOS with caution. Special studies on the effect of Valacyclovir-ACOS in liver transplantation have not been conducted. However, high-dose prophylactic use of acyclovir has been shown to reduce the symptoms of CMV infection and disease.

Use for genital herpes

Patients should be advised to refrain from sexual contact 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 transmission of genital herpes, but does not completely eliminate the risk of infection and does not lead to a complete cure. Valacyclovir-ACOS therapy is recommended in combination with reliable means of barrier contraception.

Influence on the ability to drive vehicles and mechanisms

During treatment, care should be taken when driving vehicles and engaging in other potentially dangerous activities.

No special studies were conducted. It is necessary to take into account the clinical condition of the patient and the profile of adverse reactions of valacyclovir when assessing the patient’s ability to drive vehicles and mechanisms.

Storage conditions

Store in a dark place at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf

life is 3 years.

Do not use after the expiration date.

Active ingredient

Valacyclovir

Conditions of release from pharmacies

By prescription

Dosage form

Tablets