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

Note: The quantity claimed sodium hydroxide is usually sufficient to produce a pH of 10.7-11.7 in the prepared product solution; the amount added can vary between 41.25 and 48.75 mg.

Description:Lyophilized powder or lyophilized mass of white or almost white color.

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

S.01.A.D Antiviral drugs

Pharmacodynamics:

Mechanism of action

Acyclovir is a synthetic analogue of a purine nucleoside, which has the ability to inhibit in vitro and in vivo herpes simplex viruses, including herpes simplex virus (HSV) type 1 and type 2, varicella zoster virus and herpes zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In cell culture acyclovir has the most pronounced antiviral activity against HSV-1, then in order of decreasing activity follows: HSV-2, VZV (varicella-zoster virus, Varicella zoster virus), EBV and CMV.

The effect of acyclovir on herpes viruses (HSV-1, HSV-2, VZV, EBV, CMV) is highly selective. Acyclovir is not a substrate for the enzyme thymidine kinase of uninfected cells, therefore acyclovir low toxicity for cells of mammals. Thymidine kinase of cells infected with HSV, VDV, EBV and CMV viruses converts acyclovir in acyclovir monophosphate - an analogue of a nucleoside, which is then subsequently converted into a diphosphate and triphosphate under the action of cellular enzymes. Inclusion of acyclovir triphosphate in the chain of viral DNA and subsequent chain termination block further replication of the viral DNA.

In patients with severe immunodeficiency, prolonged or repeated courses of therapy with acyclovir may lead to the emergence of resistant strains, so further treatment with acyclovir may not be effective. In most isolated strains with reduced sensitivity to acyclovir, a relatively low content of viral thymidine kinase was observed, a disruption in the structure of viral thymidine kinase or DNA polymerase. The effect of acyclovir on strains of the herpes simplex virus (HSV) in vitro can also lead to the formation of less sensitive strains. There was no correlation between the sensitivity of strains of the herpes simplex virus (HSV) to acyclovir in vitro and clinical efficacy of the drug

It was shown that high doses of Zovirax preparation, lyophilizate for the preparation of a solution for infusions, reduce the frequency of occurrence and delay the development of CMV infection. If, after high-dose Zovirax infusion therapy, Zovirax is administered for oral administration at high doses for 6 months, the mortality and frequency of viremia develop.

Pharmacokinetics:

Suction

In adults, the maximum equilibrium concentrations (C_ssmax) Acyclovir after a one-hour infusion at a dose of 2.5 mg / kg, 5 mg / kg, 10 mg / kg and 15 mg / kg was 22.7 μmol / L (5.1 μg / ml); 43.6 μmol / L (9.8 μg / ml); 92 μmol / l (20.7 μg / ml) and 105 μmol / l (23.6 μg / ml), respectively. Minimum equilibrium drug concentrations in plasma (C_ssmin) 7 hours after the infusion, respectively, equaled 2.2 μmol / l (0.5 μg / ml); 3.1 μmol / l (0.7 μg / ml); 10.2 μmol / L (2.3 μg / ml) and 8.8 μmol / L (2.0 μg / ml). In children older than 1 year, comparable C_ssmax and C_ssminwere observed when administered at a dose of 250 mg / m² is equivalent to 5 mg / kg (dose for adults) and at a dose of 500 mg / m² is equivalent to 10 mg / kg (adult dose). In newborns (from 0 to 3 months), which acyclovir was administered as an infusion at a dose of 10 mg / kg for more than one hour every 8 hours, C_ssmax was 61.2 μmol / L (13.8 μg / ml), and C_ssmin - 10.1 μmol / L (2.3 μg / ml).

Distribution

The concentration of acyclovir in the cerebrospinal fluid is approximately 50% of its concentration in the plasma.

With blood plasma proteins acyclovir is bound to an insignificant degree (9-33%), therefore, drug interactions due to displacement from the sites of binding to plasma proteins are unlikely.

Excretion

In adults, after intravenous administration of acyclovir, the half-life of plasma is about 2.9 hours. Most of the drug is excreted by the kidneys unchanged. Renal clearance of acyclovir significantly exceeds the creatinine clearance, which indicates the excretion of acyclovir by not only glomerular filtration, but also tubular secretion. The main metabolite of acyclovir is 9-carboxymethoxy-methylguanine, which accounts for about 10-15% of the administered dose in urine. In the appointment of acyclovir 1 h after receiving 1 g of probenecid, the half-life of acyclovir and AUC (the area under the concentration-time curve) increased by 18 and 40%, respectively.

Special patient groups

In elderly people the clearance of acyclovir decreases with age in parallel with a decrease in the clearance of creatinine, but the half-life of acyclovir varies insignificantly.

In patients with chronic renal insufficiency, the half-life of acyclovir averaged 19.5 hours, with hemodialysis the mean half-life of acyclovir was 5.7 hours, and the concentration of acyclovir in plasma decreased by approximately 60%.

Indications:

- Treatment of infections caused by the herpes simplex virus (HSV);

- prevention of infections caused by the herpes simplex virus (HSV), in patients with immunodeficiency;

- treatment of infections caused by varicella zoster virus (VZV, Varicella zoster virus), including varicella zoster and herpes zoster herpes;

- treatment of infections caused by the herpes simplex virus (HSV) in newborns;

- prevention of cytomegalovirus infection (CMV) in recipients of bone marrow transplants.

Contraindications:

Hypersensitivity to acyclovir or valacyclovir.

Carefully:

1 With dehydration, renal failure, neurological disorders, during the development of reactions to cytotoxic drugs (with their intravenous administration) and in the presence of those in the anamnesis, during pregnancy and lactation.

2 It should be combined Zovirax, lyophilizate for the preparation of a solution for infusions, (it is necessary to monitor the kidney function) with drugs that disrupt the function of the kidneys (for example, ciclosporin, tacrolimus).

Pregnancy and lactation:

Fertility

There is no evidence of the effect of acyclovir on female fertility. In studies on 20 male patients with a normal number of spermatozoa,that the use of acyclovir in oral form in a dose of up to 1 g per day for 6 months had no clinical effect on the number, mobility or morphology of spermatozoa.

Pregnancy

Post-registration results showed that when using acyclovir during pregnancy, there was no increase in the number of birth defects in newborns compared to the general population, and any birth defects did not show a relationship with the use of acyclovir. However, caution should be exercised when using Zovirax in women during pregnancy and assess the estimated benefit for mother and possible risk to the fetus.

Breastfeeding period

After taking the drug Zovirax inside at a dose of 200 mg 5 times a day acyclovir was determined in breast milk at concentrations ranging from 60% to 410% of plasma concentrations. At such concentrations in breast milk, breastfed infants may receive acyclovir in a dose up to 0.3 mg / kg / day. Given this fact, caution should be exercised when using Zovirax in lactating women.

Dosing and Administration:

Treatment of infections caused by the herpes simplex virus (HSV)

The course of treatment with Zovirax, a lyophilizate for the preparation of a solution for infusions, is usually 5 days, but it may vary depending on the patient's condition and response to therapy.

The duration of treatment of herpetic encephalitis is usually 10 days.

Adults

For obese patients, the dose should be calculated based on the ideal body weight, not the actual body weight of the patient.

Patients with HSV infection (other than herpetic encephalitis) are prescribed Zovirax, a lyophilizate for the preparation of a solution for infusions, at a dose of 5 mg / kg of body weight every 8 hours.

Patients with an infection of herpetic encephalitis are prescribed Zovirax, lyophilizate for the preparation of a solution for infusions, at a dose of 10 mg / kg of body weight every 8 hours with normal kidney function.

Children

Calculation of doses of Zovirax preparation, lyophilizate for the preparation of a solution for infusions, in children aged from 3 months to 12 years is carried out depending on the surface area of the body.

Patients of childhood with infection caused by the HSV virus (other than herpetic encephalitis),prescribe the drug Zovirax, lyophilizate for the preparation of a solution for infusions, at a dose of 250 mg / m body surface every 8 hours. Patients of childhood with infection of herpetic encephalitis are prescribed Zovirax, lyophilizate for the preparation of a solution for infusions, at a dose of 500 mg / m body surface every 8 hours with normal kidney function.

Children with reduced renal function require a dose adjustment in accordance with the degree of renal failure.

Newborns

In newborn doses are calculated depending on the body weight.

Newborns with an infection caused by the HSV virus are recommended to take a dose of 10 mg / kg body weight every 8 hours. The duration of treatment for HSV infections in newborns is usually 10 days.

Elderly patients

The possibility renal failure in elderly patients, the dose should be adjusted according to the degree of renal failure (see subsection "Patients with renal insufficiency").

Required ensure the maintenance adequate water balance.

Patients with renal insufficiency

Zovirax preparation, lyophilizate for solution for infusion, should be administered with caution in patients with renal insufficiency. It is necessary to ensure the maintenance of adequate water balance.

Table 1 shows the following dose adjustment scheme depending on the degree of decrease in creatinine clearance:

Table 1.

Clearance creatinine	Doses
25-50 ml / min	5-10 mg / kg every 12 hours
10-25 ml / min	5-10 mg / kg every 24 hours
0 (anuria) - 10 ml / min	In patients on continuous ambulatory peritoneal dialysis: 2.5-5 mg / kg every 24 hours. In patients, of the on hemodialysis: 2.5-5 mg / kg every 24 hours and after dialysis.

Prevention of infections caused by the herpes simplex virus (HSV), in patients with immunodeficiency

The duration of preventive use of the Zovirax preparation, lyophilizate for the preparation of a solution for infusions, is determined the duration of the period of the risk of infection.

Adults

For obese patients, the dose should be calculated based on the ideal body weight, not the actual body weight of the patient.

Treatment regimens are preserved both in the treatment of infections caused by herpes simplex virus (HSV).

Children

Treatment regimens are preserved both in the treatment of infections caused by herpes simplex virus (HSV).

Children with reduced renal function require a dose adjustment in accordance with the degree of renal failure.

Elderly patients

It is necessary to take into account the possibility of renal failure in elderly patients, the doses should be adjusted in accordance with the degree of renal failure (see subsection "Patients with renal insufficiency").

It is necessary to ensure the maintenance of an adequate water balance.

Patients with renal insufficiency

Zovirax preparation, lyophilizate for the preparation of a solution for infusion, should be administered with caution in patients with renal insufficiency. It is necessary to ensure the maintenance of an adequate water balance.

Doses should be adjusted in accordance with Table 1.

Treatment of infections caused by varicella zoster virus (VZV, Varicella zoster virus)

The course of treatment with Zovirax, a lyophilizate for the preparation of a solution for infusions, is usually 5 days, but it may vary depending on the patient's condition and response to therapy.

Adults

For patients with obesity, the dose should be calculated from the ideal mass

body, and not from the actual body weight of the patient.

Patients with an infection caused by the varicella zoster virus and herpes zoster (VZV) are prescribed Zovirax, a lyophilizate for the preparation of a solution for infusions, at a dose of 5 mg / kg body weight every 8 hours.

Patients with weakened immunity with infection caused by the virus of varicella and herpes zoster (VZV) are prescribed Zovirax, lyophilizate for the preparation of a solution for infusions, at a dose of 10 mg / kg of body weight every 8 hours with normal kidney function.

Children

Patients of childhood with infection caused by the virus of varicella and herpes zoster (VZV) are prescribed Zovirax preparation, lyophilizate for solution for infusion, at a dose of 250 mg / m² body surface every 8 hours.Patients of childhood with weakened immunity with infection caused by the virus of varicella and herpes zoster (VZV), prescribe the drug Zovirax, lyophilizate for the preparation of a solution for infusions, in a dose

500 mg / m² body surface every 8 hours with normal kidney function.

Children with reduced renal function require a dose adjustment in accordance with the degree of renal failure.

Elderly patients

It is necessary to ensure the maintenance of an adequate water balance.

Patients with renal insufficiency

Doses should be adjusted in accordance with Table 1.

Prevention of cytomegalovirus infection (CMV) in recipients of bone marrow transplants

The duration of preventive use of the Zovirax preparation, lyophilizate for the preparation of a solution for infusions, is determined by the duration of the period of the risk of infection.

Adults

For obese patients, the dose should be calculated based on the ideal body weight, not the actual body weight of the patient.

For the prevention of cytomegalovirus infection (CMV) in recipients of bone marrow transplants, prescribe Zovirax, lyophilizate for the preparation of a solution for infusions, at a dose of 500 mg / m body surface intravenously 3 times a day at an interval of 8 hours. Duration of treatment from 5 days to transplantation and up to 30 days after transplantation.

Children

Limited data suggest that in children older than 2 years who underwent bone marrow transplantation, the dose given for adults can be used to prevent CMV infection.

Children with reduced renal function require dose adjustment in accordance with the degree of renal functioninsufficiency.

Elderly patients

It is necessary to take into account the possibility of renal failure in patients the dose should be adjusted in accordance with the degree of renal failure (see subsection "Patients with renal insufficiency").

It is necessary to ensure the maintenance of an adequate water balance.

Patients with renal insufficiency

Doses in patients with renal insufficiency should be calculated according to Table 2.

Table 2.

Clearance creatinine

Doses

25-50 ml / min

500 mg / m every 12 hours

10-25 ml / min

500 mg / m every 24 hours

0 (anuria) - 10 ml / min

In patients, of the on continuous ambulatory peritoneal dialysis: 250 mg / m² every 24 hours.

In patients, of the on hemodialysis: 250 mg / m every 24 hours and after dialysis and after dialysis.

PREPARATION OF THE SOLUTION AND METHOD OF INTRODUCTION

The recommended dose of Zovirax should be given as a slow intravenous infusion for 1 hour.

10 ml of dilution solution (water for injection or solution of sodium chloride for injection (0.9%)) are used to prepare a solution of Zovirax preparation containing 1 mg of the resulting solution of 25 mg of acyclovir.

The recommended volume of dilution solution must be added to the powder bottle of Zovirax preparation, gently shake until the contents of the vial completely dissolve.

After dilution, the solution of Zovirax can be administered as an intravenous infusion with the help of a special infusion pump that regulates the rate of administration of the drug.

Another way of infusion administration is possible when the prepared solution of Zovirax is diluted further to obtain an acyclovir concentration not exceeding 5 mg / ml (0.5%).

To do this, add the prepared solution to the selected infusion solution, which is recommended below, and shake well until the solutions are completely mixed.

For children and newborns who need to enter minimal infusion volumes, it is recommended to add 4 ml of the prepared solution of Zovirax (100 mg of acyclovir) to 20 ml of the solvent.

For adults, it is recommended to use infusion solutions in

100 ml, even if it gives a concentration of acyclovir significantly below 0.5 %. Thus, one 100 ml infusion solution can be used for any dose of acyclovir between 250 mg and 500 mg (10 and 20 ml diluted solution). For doses between 500 and 1000 mg of acyclovir, another solution for infusion of this volume (100 ml) should be used.

Zovirax, a lyophilizate for the preparation of a solution for infusions, is compatible with the following infusion solutions and remains diluted with them for 12 hours at room temperature (15 ° C to 25 ° C):

1 Sodium chloride for intravenous infusions (0.45% and 0.9%)

2 Sodium chloride (0.18%) and glucose (4%) for intravenous infusions

3 Sodium chloride (0.45%) and glucose (2.5%) for intravenous infusions

4 Hartmann's solution

When preparing Zovirax solution for infusions, as indicated above, the concentration of acyclovir is not more than 0.5%.

Dissolution and dilution should be carried out completely in aseptic conditions immediately prior to administration of the preparation. Unused solution is disposed of. If the solution is cloudy or the crystals fall out, it must be destroyed.

Side effects:

The incidence of adverse events described below is approximately estimated.

For most adverse events, there is no data to accurately estimate the frequency.

The adverse events presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. Frequency of occurrence is defined as follows: very often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1 000 and <1/100), rarely (> 1/10 000 and <1/1 000), very rarely (<1/10 000).

Frequency of occurrence of undesirable phenomena

Violations of the blood and lymphatic system

Infrequently: decrease in the content of blood elements (anemia, thrombocytopenia, leukopenia).

Immune system disorders

Rarely: anaphylaxis.

Disturbances from the nervous system

Rarely: headache, dizziness, agitation, confusion, tremor, ataxia, dysarthria, hallucinations, psychotic symptoms, convulsions, drowsiness, encephalopathy, coma.

The above phenomena were usually observed in patients with impaired renal function and other predisposing factors and, as a rule, were reversible.

Vascular disorders

Often: phlebitis.

Disturbances from the respiratory system, chest and mediastinal organs

Rarely: dyspnea.

Disorders from the gastrointestinal tract

Often: nausea, vomiting.

Rarely: diarrhea, abdominal pain.

Disturbances from the liver and bile ducts

Often: reversible increase in the activity of liver enzymes.

Rarely: reversible increase in bilirubin concentration, jaundice, hepatitis.

Disturbances from the skin and subcutaneous tissues

Often: itching, urticaria, rash (including photosensitization).

Rarely: angioedema.

Disorders from the kidneys and urinary tract

Often: increase in the concentration of urea and creatinine in the blood.

A rapid increase in the concentration of urea and creatinine in the blood is presumably associated with a peak concentration of acyclovir in the blood plasma and the state of water-salt metabolism of the body. To avoid these phenomena, you should prescribe a slow infusion for 1 hour.

Very rarely: renal dysfunction, acute renal failure, pain in the projection of the kidneys.

Pain in the projection of the kidneys can be associated with impaired renal function. It is necessary to ensure adequate maintenance of water-salt metabolism of the body. Renal failure,which develops during the period of treatment with Zovirax, lyophilizate for the preparation of a solution for infusions, is usually quickly stopped when patients dehydrate and / or reduce the dose of the drug or cancel it. Progression to acute renal failure occurs in extremely rare cases.

General disorders and disorders at the site of administration

Very rarely: general weakness, fever, local inflammatory reactions.

With the random introduction of acyclovir into the extracellular space with intravenous infusion, severe local inflammatory reactions have been identified, which can lead to destructive skin changes.

Overdose:

Symptoms

Overdoses of Zovirax preparation, lyophilizate for solution for infusion, cause an increase in the serum creatinine concentration, blood urea nitrogen and subsequent renal failure. Neurological symptoms include confusion, hallucinations, agitation, convulsions and coma.

Treatment

Patients should be monitored for the timely detection of signs of an overdose. Hemodialysis significantly increases the excretion of acyclovir from the blood,therefore it is indicated in case of an overdose of acyclovir.

Interaction:

No clinically significant interactions were observed with Zovirax. Acyclovir is excreted unchanged through the kidneys through active tubular secretion. All drugs with a similar elimination route can increase the plasma concentration of acyclovir. Thus, probenecid and cimetidine increase the AUC of acyclovir and reduce its renal clearance. However, dose adjustment is not required due to a wide range of therapeutic doses of acyclovir.

In patients receiving Zovirax preparation, a lyophilizate for the preparation of a solution for infusions, care must be taken when using drugs competing for the elimination pathway due to the potential increase in plasma concentrations of one, both drugs or their metabolites. The combined use of acyclovir and mycophenolate mofetil (an immunosuppressive drug) used in organ transplantation leads to an increase in the AUC for acyclovir and the inactive metabolite of mycophenolate mofetil.

It is also necessary to observe (with monitoring changes in kidney function) with intravenous infusions of acyclovir withother drugs that affect other aspects of renal physiology (for example, ciclosporin, tacrolimus).

Special instructions:

Use in patients with renal insufficiency and elderly patients

Acyclovir is excreted through the kidneys, so patients with renal insufficiency should be administered a reduced dose of the drug. In elderly patients, kidney function may be reduced, so the need to reduce the dose should be evaluated. As for elderly patients, and for patients with renal insufficiency, the risk of developing unwanted reactions from the central nervous system is increased, so these patients should be under close medical supervision to detect symptoms in time. According to recorded reports of these adverse events, they are usually reversible and stop after the drug is discontinued.

In patients receiving higher doses of the Zovirax preparation, lyophilizate for the preparation of a solution for infusions, (for example, in herpetic encephalitis), renal function should be closely monitored,especially on the background of dehydration or already existing renal failure.

The prepared solution of the Zovirax preparation has a pH of about 11.0, so it can not be used orally.

Prolonged or repeated treatment with Zovirax in immunocompromised patients may lead to the appearance of strains of the virus with reduced sensitivity, which may not respond to the continuation of therapy with acyclovir. If the response to treatment with acyclovir in patients with immunodeficiency is absent, and this is clinically confirmed, then another therapy should be considered.

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

The Zovirax preparation, a lyophilizate for the preparation of a solution for infusions, is intended for use only in hospital settings, so there is no evidence of the effect of the drug on the ability to drive and / or other mechanisms.

Form release / dosage:Lyophilizate for the preparation of a solution for infusions 250 mg.

Packaging:250 mg of acyclovir in a neutral glass bottle (type I), sealed with a plug of synthetic rubber, crimped with an aluminum cap with a plastic snap-on lid.5 vials with instructions for medical use in a pack of cardboard with an integrated cardboard separator.

Storage conditions:

List B.

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015101 / 02

Date of registration:29.12.2008

The owner of the registration certificate:GlaxoSmithKline Trading, ZAO GlaxoSmithKline Trading, ZAO Russia

Manufacturer: & nbsp

GlaxoSmithKline Manufacturing, S.p.A. Italy

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp21.02.2014

Illustrated instructions

Instructions

Zovirax ® (Zovirax®)