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Zovirax

Препарат Зовиракс. Glaxo Operetaions UK Limited (Глаксо Оперейшнс ЮК Лимитед) Великобритания

Producer: Glaxo Operetaions UK Limited (Glakso Opereyshns YuK Limited) Great Britain

Code of automatic telephone exchange: J05AB01

Release form: Firm dosage forms. Lyophilisate for solution for injections.

Indications to use: Herpes infection (Herpes). Cytomegaloviral infection.

General characteristics. Structure:

Lyophilisate for preparation of solution for infusions in the form of powder of white or almost white color, hydroscopic or the caked weight (porous flat cake).

Active ingredient: acyclovir of 250 mg

Excipients: sodium hydroxide.

Pharmacological properties:

Antiviral drug, synthetic analog of a purine nucleoside which possesses ability to inhibit in vitro and in vivo replication of the Herpes simplex viruses of type 1 and 2, the Varicella zoster virus, Epstein-Burra's (EBV) virus and a cytomegalovirus (CMV). In culture of cells the acyclovir has the most expressed antiviral activity concerning Herpes simplex of type 1, further in decreasing order of activity follow: Herpes simplex of type 2, Varicella zoster, EBV and CMV.

Action of an acyclovir on viruses has high-selective character. The acyclovir is not substrate for enzyme of a thymidinekinase of not infected cells therefore it малотоксичен for cells of mammals. The thymidinekinase of the cells infected with the Herpes simplex viruses of type 1 and 2, Varicella zoster, EBV and CMV turns an acyclovir in an acyclovir monophosphate - an analog of a nucleoside which then consistently turns into diphosphate and triphosphate under the influence of cellular enzymes. Inclusion of an acyclovir of triphosphate in a chain of virus DNA and the subsequent break of a chain block further replication of virus DNA.

At patients with the expressed immunodeficiency long or repeated courses of therapy by an acyclovir can lead to formation of resistant strains and therefore further treatment by an acyclovir can be inefficient. At the majority of the allocated strains with a hyposensitivity to an acyclovir rather low maintenance of a virus thymidinekinase, disturbance of structure of a virus thymidinekinase or DNA polymerase was noted. Impact of an acyclovir on strains of the Herpes simplex in vitro virus can also lead to formation of strains, less sensitive to it. Correlation between sensitivity of virus strains of Herpes simplex to an acyclovir in vitro and clinical performance of drug is not established.

It was shown what in/in administration of Zovirax in high doses reduces the frequency of occurrence and detain development of a Cytomegaloviral infection. If after such infusional therapy to carry out treatment by an acyclovir for intake in high doses within 6 months, then mortality and frequency of development of a viremiya decreases.

Pharmacokinetics. Distribution

Adults have average Cmax of an acyclovir in 1 h after infusion in a dose of 2.5 mg/kg, 5 mg/kg, 10 mg/kg and 15 mg/kg made 22.7 µmol (5.1 mkg/ml), 43.6 µmol (9.8 mkg/ml), 92 µmol (20.7 mkg/ml) and 105 µmol (23.6 mkg/ml) respectively. Cmin of drug in plasma in 7 h after infusion equaled respectively 2.2 µmol (0.5 mkg/ml), 3.1 µmol (0.7 mkg/ml), 10.2 µmol (2.3 mkg/ml) and 8.8 µmol (2.0 mkg/ml).

Concentration of an acyclovir in cerebrospinal fluid makes about 50% of its plasma concentration.

The acyclovir in insignificant degree contacts proteins of a blood plasma (9-33%).

Removal

At adults later in/in introductions of an acyclovir of T1/2 makes about 2.9 h of plasma. The most part of drug is removed by kidneys in not changed look. The renal clearance of an acyclovir considerably exceeds clearance of creatinine that demonstrates removal of an acyclovir by means of not only glomerular filtering, but also canalicular secretion. The main metabolite of an acyclovir is the 9-карбоксиметокси-methylguanine to which share in urine about 10-15% of the entered drug dose fall.

At purpose of an acyclovir in 1 h after reception of 1 g of a probenetsid of T1/2 of an acyclovir and AUC increased by 18 and 40% respectively.

Pharmacokinetics in special clinical cases

At children 1 years the size Cmax and Cmin corresponding that at adults are more senior it was observed at administration of Zovirax in a dose of 250 mg/sq.m instead of 5 mg/kg (a dose for adults) and in a dose of 500 mg/sq.m instead of 10 mg/kg (a dose for adults).

At newborns (from 0 to 3 months) by which the acyclovir was entered in the form of infusion lasting more than 1 h each 8 h Cmax made 61.2 µmol (13.8 mkg/ml), a Cmin was equal to 10.1 µmol (2.3 mkg/ml), and T1/2 is 3.8 h.

At elderly people the clearance of an acyclovir decreases in parallel with reduction of clearance of creatinine with age, however T1/2 of an acyclovir changes slightly.

At patients with a chronic renal failure of T1/2 of an acyclovir averaged 19.5 h, and when carrying out a hemodialysis of T1/2 averaged 5.7 h, concentration of an acyclovir in plasma decreased approximately by 60%.

Indications to use:

— treatment of the infections caused by the Herpes simplex virus of type 1 and 2;

— prevention of the infections caused by the Herpes simplex virus of type 1 and 2 at patients with an immunodeficiency;

— treatment of the infections caused by the Varicella zoster virus;

— treatment of the infections caused by the Herpes simplex virus of type 1 and 2 in newborns;

— prevention of a Cytomegaloviral infection at recipients of transplants of marrow.

Route of administration and doses:

Drug is intended for in/in infusional introductions.

The adult for treatment of the infections caused by the Herpes simplex viruses (except for herpetic encephalitis) and Varicella zoster, drug each 8 h appoint in a dose 5 mg/kg of body weight.

For treatment of the infections caused by the Varicella zoster virus, and herpetic encephalitis at patients with an immunodeficiency each 8 h (carry out to infusions in a dose 10 mg/kg of body weight at normal function of kidneys).

For prevention of a Cytomegaloviral infection at transplantation of marrow drug is used in a dose 500 mg/sq.m of a body surface of 3 times / with an interval of 8 h. Treatment duration — of 5 days before transplantation and up to 30 days after transplantation.

At patients with obesity the same doses are recommended that patients have c normal body weight.

At appointment in/in Zovirax infusions patients with a renal failure should correct the dosing mode according to decrease in clearance of creatinine.

Clearance of creatinine                                        the Recommended doses
25-50                             ml/min. 5-10 mg/kg or 500 mg/sq.m each 12 h
10-25                             ml/min. 5-10 mg/kg or 500 mg/sq.m each 24 h

0 (anury) - 10 ml/min. At continuous out-patient peritoneal
dialysis: 2.5-5 mg/kg or 250 mg/sq.m each 24 h

At a hemodialysis: 2.5-5 mg/kg or 250 mg/sq.m each 24 h and after dialysis.

To children aged from 3 months up to 12 years of a dose of Zovirax for in/in infusion are established depending on body surface area.

At newborns the mode of dosing is set depending on body weight; at the infections caused by the Herpes simplex virus of type 1 and 2, the recommended dose makes 10 mg/kg each 8 h. Duration of treatment of herpetic encephalitis and the infections caused by the Herpes simplex virus at newborns usually makes 10 days.

At the infections caused by the Herpes simplex viruses (except herpetic encephalitis) and Varicella zoster, the drug each 8 h administer in a dose 250 mg/sq.m.

For the treatment of herpetic encephalitis and infections caused by the Varicella zoster virus at children with an immunodeficiency drug each 8 h (appoint in a dose 500 mg/sq.m at normal function of kidneys).

Limited data allow to assume that for prevention of a Cytomegaloviral infection at children 2 years which underwent transplantation of marrow are more senior, Zovirax can be entered in the doses recommended for adults.

Dose adjustment according to degree of a renal failure is required from children with reduced function of kidneys.

At patients of advanced age with reduced clearance of creatinine it is necessary to consider a question of a dose decline.

The course of treatment Zovirax in a look in/in infusions usually makes 5 days, but can change depending on a condition of the patient and the response to therapy.

Duration of preventive use of Zovirax in a look in/in infusions is defined by duration of the period of existence of risk of infection.

Rules of preparation and administration of solution

The recommended dose of Zovirax should be entered in the form of slow into infusions during 1 h.

The following volumes of water for injections or solution of sodium of chloride for injections (0.9%) for Zovirax solution preparation with contents in 1 ml of the received solution of 25 mg of an acyclovir are used.

Zovirax dose in 1 ampoule (mg)                    solution Volume for cultivation (ml)
                                                                                      125 5
                                                                                      250 10
                                                                                     500 20

The recommended solution volume for cultivation needs to be added to an ampoule with powder of Zovirax and to shake up carefully until ampoule contents completely are not dissolved.

The solution of Zovirax received after cultivation can be entered by means of the special infusional pump regulating drug rate of administering. Other way of introduction is possible, at the same time the prepared solution of Zovirax is diluted before obtaining the concentration of an acyclovir which is not exceeding 5 mg/ml (0.5%). For this purpose it is necessary to add the prepared solution to the chosen infusion solution which is recommended below, and it is good to shake up for full mixing of solutions.

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

For adults it is recommended to use infusion solutions in packagings on 100 ml even if it will give concentration of an acyclovir significantly lower than 0.5%. Thus, infusion solution of 100 ml can be used for introduction of any dose of an acyclovir between 250 mg and 500 mg (10 and 20 ml of divorced solution). For doses between 500 mg and 1000 mg of an acyclovir the second infusion solution of this volume has to be used.

Zovirax for in/in infusions is compatible to the following infusion solutions and remains at cultivation by them stable during 12 h at the room temperature (from 15 ° to 25 °C): 0.45% and 0.9% chloride sodium solutions for in/in infusions; 0.18% solution of sodium of chloride and 4% glucose solution for in/in infusions; 0.45% solution of sodium of chloride and 2.5% glucose solution for in/in infusions; Hartman's solution.

As the composition of solutions included no antibacterial preservative, dissolution and cultivation have to be carried out completely in aseptic conditions just before administration of drug.

Unused solution is destroyed.

At opacification of solution or loss of crystals it should be destroyed.

Features of use:

At the patients with herpetic encephalitis receiving Zovirax in high doses it is necessary to control function of kidneys (especially at dehydration or at an initial renal failure).

With care and under control of function of kidneys it is necessary to apply Zovirax along with the drugs breaking function of kidneys (for example, cyclosporine, такролимус).

The prepared solution of Zovirax has рН =11 therefore it cannot be applied inside.

Side effects:

From the alimentary system: nausea, vomiting, reversible increase in level of bilirubin and activity of liver enzymes; very seldom – hepatitis, jaundice.

From system of a hemopoiesis: anemia, leukopenia and thrombocytopenia.

From an urinary system: seldom - increase in level of urea and creatinine in blood that is connected with the size Cmax and a condition of a water balance of the patient. To avoid the similar phenomena, it is necessary to administer the drug in the form of slow infusion during 1 h and to support a water balance of patients. The symptoms of a renal failure which arose against the background of therapy by Zovirax usually quickly are stopped at a regidratation of patients and/or reduction of a dose of drug or its cancellation. Progressing to an acute renal failure happens in exceptional cases.

From TsNS: reversible neurologic disturbances, such as confusion of consciousness, a hallucination, excitement, a tremor, drowsiness, psychosis, spasms and a coma (usually at predisposed patients).

Allergic reactions: rash, photosensitization, urticaria, itch, fever; seldom - an asthma, a Quincke's disease, an anaphylaxis.

Local reactions: the heavy inflammatory reactions leading to a necrosis were observed at Zovirax solution hit under skin.

Interaction with other medicines:

Clinically significant interactions of Zovirax with other medicines were not noted.

Blockers of calcium channels and Cimetidinum increase AUC of an acyclovir and reduce its renal clearance (correction of the mode of dosing of Zovirax is not required).

At simultaneous use of Zovirax with the drugs which are removed by active canalicular secretion increase in concentration of active agents or their metabolites in plasma is possible (care at purpose of such combinations is necessary).

The combined use of an acyclovir and mikofenolat of a mofenil, the immunosuppressant which is applied at organ transplantation leads to increase in an indicator of AUC of an acyclovir and inactive metabolite of a mikofenolat of a mofenil.

Contraindications:

— hypersensitivity to an acyclovir or a valatsiklovir.

With care it is necessary to apply at dehydration, a renal failure, neurologic disturbances, and also during development of reactions to cytotoxic drugs at them in introduction (and at instructions on such reactions in the anamnesis).

Drug ZOVIRAKS® use lyophilisate at pregnancy and feeding by a breast

Purpose of Zovirax at pregnancy and in the period of a lactation (breastfeeding) demands care and it is possible only after assessment of estimated advantage for mother and potential risk for a fruit and the child.

Increase in number of inborn defects at children whose mothers received Zovirax during pregnancy, in comparison with the general population is not revealed.

At use of Zovirax in the form of lyophilisate in the period of a lactation (breastfeeding) it is necessary to consider that after Zovirax reception inside in a dose of 200 mg the 5th time / acyclovir was defined in breast milk in the concentration making 0.6-4.1% of plasma concentration. At such concentration in breast milk the children who are on breastfeeding can receive an acyclovir in a dose to 0.3 mg/kg /

Use at renal failures
At appointment in/in Zovirax infusions patients with a renal failure should correct the dosing mode according to decrease in clearance of creatinine.

Clearance of creatinine                                          the Recommended doses
25-50                                     ml/min. 5-10 mg/kg or 500 mg/sq.m each 12 h
10-25                                     ml/min. 5-10 mg/kg or 500 mg/sq.m each 24 h
0 (anury) - 10 ml/min.               At continuous out-patient peritoneal
                                                  dialysis: 2.5-5 mg/kg or 250 mg/sq.m each 24 h

At a hemodialysis: 2.5-5 mg/kg or 250 mg/sq.m each 24 h and after dialysis.

Use for elderly patients
At patients of advanced age with reduced clearance of creatinine it is necessary to consider a question of a dose decline.

Use for children
To children aged from 3 months up to 12 years of a dose of Zovirax for in/in infusion are established depending on body surface area.

Overdose:

Symptoms: increase in level of serumal creatinine, blood urea nitrogen, renal failure. Neurologic symptoms include confusion of consciousness, a hallucination, excitement, spasms and a coma.

Treatment: carry out symptomatic therapy. Carrying out a hemodialysis is shown.