Valmik - instructions for use, dose, side effects, contraindications

The core of the tablet: active substance: valaciclovir hydrochloride (corresponding to valaciclovir 250,000 mg or 500,000 mg) - 278,1375 mg / 556.275 mg; Excipients: crospovidone - 7.550 mg / 15.100 mg; cellulose microcrystalline - 52.7825 mg / 105.565 mg; Povidone K 90 - 12,390 mg / 24,780 mg; magnesium stearate 2,140 mg / 4,280 mg; tablet shell: opadrai white 13В58802 (hypromellose - 59,750%, titanium dioxide - 31,250%, macrogol-400 - 8,000%, polysorbate-80 - 1,000%) - 7,000 mg / 14,000 mg.

Description:

250 mg tablets: White or almost white, oblong biconvex tablets, film-coated, smooth on both sides. View of the fracture: white.

Tablets 500 mg: white or almost white, oblong biconvex tablets, film-coated, smooth on one side and engraved "500" on the other side. View of the fracture: white,

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.B.11 Valaciclovir

J.05.A.B Nucleosides and nucleotides

Pharmacodynamics:

Valaciclovir is an antiviral drug that is L-valine ester of acyclovir. Acyclovir - analogue of purine nucleoside. Valaciclovir quickly and almost completely turns people into acyclovir and Lvaline under the action of the enzyme valacyclovir-hydrolase.

Acyclovir is a specific inhibitor of herpes viruses, which has activity in vitro in respect of herpes simplex viruses (HSV, HSV) of type 1 and type 2, Varicella zoster virus (VZV, VZV), cytomegalovirus (CMV, CMV), the Epstein-Barr virus (EBV, VEB) and Human Herpes Virus type 6 (HHV-6, HHV). Acyclovir inhibits the synthesis of the DNA of the herpes virus as soon as it is phosphorylated to the active triphosphate form.

The first stage of phosphorylation requires the activity of a virus-specific enzyme. When HSV (HSV), VZV (VWB) and EBV (EBV), this enzyme is viral thymidine kinase (TK), which is present only in cells infected with the virus. Partial selectivity of phosphorylation is preserved in CMV (CMV) and mediated through the product of the phosphotransferase gene UL97. This requirement for the activation of acyclovir by a virus-specific enzyme largely explains this selectivity.

The phosphorylation process is performed (conversion from monodotriphosphate) by cellular kinases. Acyclovir triphosphate competitively inhibits viral DNA polymerase, and the incorporation of this nucleoside analogue leads to chain termination indispensable, stopping the viral DNA synthesis and thus blocking viral replication. Prevention CMV (CMV) valacyclovir significantly reduces the possibility of disease HSV in patients with renal transplants.

Monitoring of clinical isolates HSV (HSV) and VZV (VZV) from patients who received therapy or prevention with acyclovir,found that viruses with reduced sensitivity to acyclovir are extremely rare in patients with preserved immunity and are sometimes found in persons with severe impairment of immunity, for example, organ recipients or bone marrow, patients receiving chemotherapy for malignant neoplasms, and HIV-infected patients. Resistance is caused by a deficiency of thymidine kinase of the virus, which leads to excessive spread of the virus in the host organism. Sometimes a decrease in sensitivity to acyclovir is due to the appearance of strains of the virus with a violation of the structure of the viral thymidine kinase or DNA polymerase. The virulence of these varieties of the virus resembles that of its wild strain.

Pharmacokinetics:

Absorption is high, quickly and almost completely turns into acyclovir and L-valine. Bioavailability of acyclovir when taking valaciclovir 1000 mg is 54% (3-5 times higher than when taking acyclovir by mouth), does not decrease with food intake. After using valaciclovir in a dose of 1 g 4 times a day, the area under the concentration-time curve (AUC) is approximately equal to AUC with intravenous administration (iv) of acyclovir in a dose of 5 mg every 8 hours. After a single dose of 250-2000 mg valacyclovir, the maximum concentration (C_max) of acyclovir in healthy volunteers with normal renal function is on average 10-37 μmol / l (2.2-8.3 μg / ml), the time to reach C_mOh averages 1-2 hours._mOhvalacyclovir in plasma is only 4% of the concentration of acyclovir and is achieved on average 30-100 minutes after taking the drug; after 3 h level C_max remains the same or decreases. Valaciclovir and acyclovir have similar pharmacokinetic parameters after a single and repeated administration.

Distribution

The degree of binding of acyclovir to plasma proteins is very low - 15%. Acyclovir is well distributed in the tissues and body fluids, including the brain, kidneys, lungs, liver, intraocular fluid, lacrimal fluid, intestines, muscles, spleen, uterus, mucous membrane and vaginal secretion, semen, amniotic fluid, cerebrospinal fluid (CSF) (50% of the concentration in the plasma), a liquid of herpetic vesicles. The highest concentrations are created in the kidneys, liver and intestines.Penetrates through the placenta and into breast milk.

Excretion

In patients with normal renal function, the half-life period (T_1/2) of acyclovir is approximately 3 hours, with the terminal stage of renal failure - 14 hours. Valaciclovir is excreted in the urine, mainly in the form of acyclovir (more than 80% of the dose) and its metabolite 9-carboxymethoxymethylguanine, less than 1% of the drug is unchanged.

Pharmacokinetics in special clinical cases

The pharmacokinetics of valaciclovir and acyclovir after oral administration of valaciclovir are largely unaffected in patients infected with HBV and HSV.

In late pregnancy, a steady daily rate AUC after receiving Valaciclovir 1000 mg was more approximately 2 times than that when taking acyclovir in a dose of 1200 mg / day.

In patients with HIV infection after single or repeated oral administration of valacyclovir in a dose of 1000 mg and 2000 mg, the distribution and pharmacokinetic characteristics of acyclovir remain unchanged in comparison with healthy individuals.

In transplant recipients of organs receiving valaciclovir in a dose of 2000 mg 4 times a day, FROM_max Acyclovir is equal to or greater than that of healthy volunteers who received the same dose of the drug with the same kidney function in both groups. However, the daily indicators AUC healthy volunteers are much higher.

Indications:

Adults:

- treatment of herpes zoster caused by a virus Herpes zoster (reduces the intensity and duration of pain caused by herpes zoster, including acute and postherpetic neuralgia);

- treatment of infections of the skin and mucous membranes caused by the virus Herpes simplex type 1 and 2 (including newly diagnosed and recurrent genital herpes), treatment of labial herpes;

- prevention (suppression) of recurrences of infections of the skin and mucous membranes caused by the virus Herpes simplex type 1 and 2, including genital herpes;

- valacyclovir can reduce the infection of genital herpes with a healthy partner, if taken as a suppressive therapy in combination with safe sex.

Adults and adolescents aged 12 years and over:

- prevention of cytomegalovirus (CMV) infection, as well as reactions of acute graft rejection (in patients with kidney transplants), opportunistic infections and other herpes of viral infections (HSV, VZV) after organ transplantation.

Contraindications:

- Hypersensitivity to valaciclovir, acyclovir or any other component included in the preparation;

- children under 12 years of age when preventing cytomegalovirus infection;

- children under 18 for all other indications.

Carefully:PIn clinically expressed forms of HIV infection (including the content of Cd4⁺ lymphocytes less than 100 / μl), hepatic / renal failure, pregnancy and lactation, simultaneous use of nephrotoxic drugs.

Pregnancy and lactation:

There are limited data on the use of valacyclovir during pregnancy. Use during pregnancy is only possible if the intended benefit to the mother exceeds the potential risk to the fetus.

Lactation

Acyclovir, the main metabolite of valacyclovir, is excreted in breast milk. After oral administration of valaciclovir in a dose of 500 mg, the maximum concentration (FROM_max) of acyclovir in breast milk was 0.5-2.3 times (mean 1.4) higher than the corresponding serum aciclovir plasma concentrations in the mother. The ratio of the area levels under the concentration-time curve (AUC) of acyclovir in the mother's milk and maternal blood plasma 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 μM). When a valaciclovir mother is taken inside at a dose of 500 mg twice a day, the child will undergo the same effect of acyclovir as if taking it inside at a dose of about 0.61 mg / kg / day. The half-life (T_1/2) of acyclovir from breast milk is the same as from plasma of blood. Valaciclovir in unmodified form was not determined in the plasma of the mother, breast milk or in the urine of the child.

It should be used with caution valaciclovir mother during breastfeeding.

Dosing and Administration:

Treatment of herpes zoster (Herpes Zoster)

Adults: treatment is recommended to begin as soon as possible and not later than 3 days after the first signs of the disease appear at 1000 mg (4 tablets of 250 mg or 2 tablets of 500 mg) 3 times a day for 7 days.

Treatment of infections, caused by HSV

Adults: valaciclovir is prescribed in a dose of 500 mg 2 times a day for 5 days.

In more severe cases of debut treatment should be started as soon as possible, and its duration should be increased from 5 to 10 days.

In case of relapse, treatment should last 3 or 5 days.With relapses of HSV, the administration of the drug in the prodromal period or immediately after the appearance of the first symptoms of the disease is ideal.

As an alternative for treatment labial herpes effective administration of valaciclovir in a dose of 2 g 2 times a day. The second dose should be taken after approximately 12 hours (but not earlier than 6 hours) after taking the first dose. With this dosing regime, the duration of treatment should not exceed 1 day. Therapy should be started when the earliest symptoms appear labial herpes (ie tingling, itching, burning).

Prevention (suppression) of recurrences of infection caused by HSV

Adults: in patients with preserved immunity the recommended dose is 500 mg once a day.

In patients with immunodeficiency, the recommended dose is 500 mg twice a day.

Prophylaxis of transmission of genital herpes to a healthy partner

To infected immunocompetent persons with relapses no more than 9 times a year, the recommended dose of the drug is 500 mg once a day for a year or more every day.

Data on the prevention of infection in other populations of patients are absent.

Prevention of cytomegalovirus infection (CMV) after transplantation

Adults and teenagers from 12 years and older: the recommended dose is 2 g 4 times a day, prescribed as soon as possible after transplantation.

The dose should be reduced depending on the creatinine clearance (CK). The duration of treatment is 90 days, but in patients with high-risk treatment can be extended.

Special patient groups

Patients with impaired renal function

Treatment of shingles and infections caused by HSV, prevention (suppression) of recurrences of infection caused by HSV, prevention of transmission of genital herpes to a healthy partner

The dose of the drug is recommended to be reduced in patients with a significant decrease in kidney function. Such patients need to maintain adequate hydration.

The experience of using the drug in children with CC values less than 50 ml / min / 1.73 m² no.

Table 1.

Indications	Creatinine clearance (CK), ml / min	Dose of the drug
Shingles (Herpes zoster)	15-30	1 g 2 times a day
Shingles (Herpes zoster)	Less than 15	1 g 2 times a day
Treatment of infection caused by HSV (according to the scheme of 500 mg 2 times a day)	Less than 15	500 mg once a day
Treatment of labial herpes (according to the scheme 2 g 2 times a day for one day)	31-49	1 g twice for 1 day
	15-30	500 mg twice for 1 day
	Less than 15	500 mg once
Prevention (suppression) pecentnersof infections caused by HSV:
- Patients with normal immunity;	Less than 15	250 mg once a day
- Patients with reduced immunity:	Less than 15	500 mg once a day
- reduced risk of transmission of genital herpes	Less than 15	250 mg once a day

Patients on hemodialysis are recommended to prescribe valaciclovir the day of hemodialysis immediately after the end of the hemodialysis session at the same dose as patients with QC less than 15 ml / min.

Prevention of cytomegalovirus infection (CMB) after transplantation

The mode of prescribing the drug in patients with impaired renal function should be established in accordance with Table 2 below.

Table 2.

Creatinine clearance (CK), ml / min	Dose of the drug
75 and more	2 g 4 times a day
50 to less than 75	1.5 g 4 times a day
25 to less than 50	1.5 g 3 times a day
10 to less than 25	1.5 g 2 times a day
Less than 10 or dialysis *	1.5 g 1 once a day

* In patients on hemodialysis, the drug should be prescribed after the end of the hemodialysis session.

Frequent control of QC is necessary, especially during a period when there is a rapid change in kidney function (for example, immediately after kidney transplantation or transplant engraftment).In this case, the dose of valaciclovir should be adjusted in accordance with the QA indices.

Patients with impaired hepatic function

In adults with a mild or moderate degree of liver function disorder, while maintaining the synthetic function, dose adjustment is not required.

Pharmacokinetic data in adult patients with severe impairment of liver function (decompensated cirrhosis), with a violation of the synthetic function of the liver and the presence of port-caval anastomoses also do not indicate the need to adjust the dose of the drug, but the clinical experience for this pathology is limited.

Children under the age of 12 years

There is no data on the use of the drug in children.

Elderly patients

There is no need for correction of the dosing regimen for elderly patients, provided there are no serious violations of kidney function (see doses in renal failure). It is necessary to maintain an adequate water-electrolyte balance.

Side effects:

According to the World Health Organization (WHO), unwanted effects are classified according to their frequency of development as follows: very often (≥1 / 10),often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1,000 to <1/100), rarely (from ≥1 / 10,000 to <1 / 1,000), very rarely (<1 / 10,000) ; frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Clinical studies of valacyclovir

Disorders from the central nervous system

Often: headache.

Disorders from the gastrointestinal tract

often: nausea.

Postpartum application of valaciclovir

Infectious and parasitic diseases

frequency is unknown: respiratory tract infections.

Violations of the blood and lymphatic system

infrequently: leukopenia, thrombocytopenia. Mainly leukopenia was registered in patients with reduced immunity;

frequency is unknown: neutropenia, aplastic anemia, leukoplastic vasculitis, thrombocytopenic purpura, decrease hemoglobin.

Immune system disorders

rarely: anaphylaxis.

Disorders from the central nervous system

often: dizziness;

infrequently: confusion, hallucinations, decreased mental abilities, tremor, agitation;

rarely: oppression of consciousness, ataxia, dysarthria, seizures, psychotic symptoms, encephalopathy, coma, delirium;

rarely: mania, depression, agitation, tremor.

Neurological disorders, sometimes severe, can be a manifestation of encephalopathy and include confusion, agitation, convulsions, hallucinations, coma. These reactions are reversible and are usually observed in patients with impaired renal function or against a background of other predisposing conditions. In patients with a transplanted organ receiving valaciclovir in high doses (8 g per day) for the prevention of cytomegalovirus infection, neurologic reactions develop more often than in patients receiving lower doses for other indications.

Disturbances on the part of the organ of sight

frequency is unknown: impaired vision.

Heart Disease

frequency is unknown: tachycardia.

Vascular disorders

frequency is unknown: increase in blood pressure.

Disturbances from the respiratory system, organs of the chest and the mediastinum

infrequently: dyspnea;

frequency is unknown: nasopharyngitis, rhinorrhea.

Disorders from the gastrointestinal tract

often: vomiting, diarrhea;

infrequently: feeling of discomfort in the abdomen.

Disorders from the liver and biliary tract

infrequently: reversible increase in functional liver tests (incl.bilirubin, hepatic transaminases), which are sometimes regarded as manifestations of hepatitis.

Disturbances from the skin and subcutaneous tissue

often: Rash, including photosensitivity, itching;

infrequently: hives;

rarely: angioedema.

frequency is unknown: erythema multiforme.

Narushfrom the musculoskeletal and connective tissues

frequency is unknown: arthralgia.

Disorders from the urinary system

infrequently: renal colic, hematuria (often associated with other impaired renal function);

rarely: renal impairment, acute renal failure (especially in elderly patients or in patients with impaired renal function receiving doses higher than those recommended);

frequency is unknown: hypercreatininaemia.

Renal colic can be associated with kidney failure. The cases of intratubular deposition of acyclovir crystals in the kidneys are recorded. Fluid intake should be adequate during the treatment.

Violations of the genitals and mammary gland

frequency unknown: dysmenorrhea.

General disorders and reactions at the site of administration

frequency is unknown: fatigue, fever, dehydration.

Other: in patients with severe impairment of immunity, especially in the late stage of HIV infection, receiving valaciclovir in high doses (8 g per day) for a long period of time, there were cases of renal failure, microangiopathic hemolytic anemia, and thrombocytopenia (sometimes in combination). Similar adverse reactions were reported in patients with similar underlying or concomitant diseases who did not receive valaciclovir.

Overdose:

Symptoms: with an overdose of valacyclovir, it is possible to develop acute renal failure and neurologic symptoms, incl. confused consciousness, hallucinations, agitation, decreased consciousness and coma. Nausea and vomiting may also develop.

It is necessary to pay special attention to the possible unintentional overdose of the drug. Many of the cases of overdose occurred in elderly patients and in patients with renal insufficiency who received a repeated overdose due to the lack of the required dose reduction.

Treatment: patients should be under careful medical supervision to identify signs of toxic effects.Hemodialysis significantly increases the excretion of acyclovir from the blood plasma and can be considered a method of choice in managing patients with an overdose of valaciclovir.

Interaction:

Clinically significant drug interactions were not established. Acyclovir is mainly excreted in the urine unchanged as a result of active tubular secretion. After administration of valaciclovir in a dose of 1 g cimetidine and probenecid, reducing tubular secretion, increase AUC acyclovir and reduce its renal clearance by 45 and 25%, respectively. However, dose adjustment of valacyclovir is not required, acyclovir has a wide therapeutic index.

It is necessary to use caution valaciclovir in higher doses (4 g per day) concomitantly with medications (including tenofovir), which compete with acyclovir for the pathway of elimination, because there is a risk of an increase in plasma levels of one or both drugs or their metabolites. An increase was noted AUC acyclovir and an inactive metabolite of mycophenolate mofetil (an immunosuppressant used in transplantation) with the simultaneous use of these drugs.

Care must also be taken (monitoring of kidney function) when the drug is combined in higher doses (4 mg in knocking and higher) with drugs that affect other kidney functions (for example, ciclosporin, tacrolimus).

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

Special instructions:

Patients with a risk of dehydration, especially the elderly, during treatment with valaciclovir, it is necessary to ensure adequate fluid replenishment.

There are no data on the use of valaciclovir in high doses (4000 mg per day or more) in patients with liver disease.

Studies on valacyclovir in patients with liver transplantation have not been carried out, and therefore caution should be used to prescribe valaciclovir in a daily dose of 4000 mg and above listed categories of patients.

Acyclovir is excreted by renal secretion, so the dose of valacyclovir in patients with renal insufficiency should be reduced.

Older patients are characterized by a decrease in kidney function, therefore, for this group of patients, the need to reduce the dose of valaciclovir should be considered. Both elderly patients and patients with impaired renal function are at high risk of developing adverse neurological reactions, and the development of these reactions should be clearly monitored in these patient groups. In the cases described, these reactions were generally reversible and passed after the drug was discontinued.

In patients after transplantation who have an increased risk of developing CMV infection (for example, if the donor has a positive CMV status and the CMV recipient is negative, or when using induction therapy with anti-thymocyte globulin), the use of valaciclovir It is permissible only in case when for safety reasons it is impossible to prescribe valganciclovir or ganciclovir.

High doses of valaciclovir, necessary for the prevention of CMV infection, can cause more frequent side effects,including the disruption of the CNS, which were detected when lower doses were used for other indications. It is necessary to monitor the change in renal function, with a dose of valacyclovir to be adjusted in accordance with the QC values (see section "Method of administration and dose").

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 complete cure. During valaciclovir therapy, the patient should take measures to ensure the safety of the partner during sexual intercourse.

Special precautions for the destruction of unused medicinal product

There is no need for special precautions when destroying an unused Valmik® preparation.

Effect on the ability to drive transp. cf. and fur:

During the treatment with Valmik®, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated 250 mg, 500 mg.

Packaging:

For 10 or 14 tablets in PVC / PE / PVDC / Al blister.

For 1, 2 or 3 blisters, along with instructions for medical use, are placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children!

Shelf life:

2 years.

Do not use the product after the expiry date printed on the package!

Terms of leave from pharmacies:On prescription

Registration number:LP-003163

Date of registration:31.08.2015

Expiration Date:31.08.2020

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

SANDOZ PRIVATE, Limited India

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp19.01.2017

Illustrated instructions

Instructions

Valmic® (Valmik®)