Tsimeven

General characteristics. Structure:

Active ingredient: 500 mg of a gantsiklovir in the form of sodium salt.

Antiviral medicine, with the expressed activity against a cytomegalovirus of the person (TsMV).

Pharmacological properties:

Pharmacodynamics. Gantsiklovir represents a synthetic analog 2 deoxyguanosines which suppresses reproduction of viruses of herpes both in vitro, and in vivo. It is active concerning a cytomegalovirus of the person (TsMV), viruses of a herpes simplex of the 1st and 2nd type (Herpes simplex 1 and 2), a virus of herpes of the person 6, 7 and 8 type, Epstein-Barre's virus, a virus of chicken pox (Varicella zoster) and a virus of hepatitis B. Clinical trials were limited to assessment of efficiency of drug at the patients infected with a cytomegalovirus.

In TsMV-the infected cells ганцикловир it is phosphorylated under the influence of a virus protein kinase with formation of a gantsiklovirmonofosfat in the beginning. Further phosphorylation happens under the influence of several cellular kinases therefore it is formed ганцикловиртрифосфат which then is exposed to slow intracellular metabolism. It is shown that this metabolism comes in the cells infected with TsMV of the person and a virus of a herpes simplex thus after disappearance of a gantsiklovir from extracellular liquid the period of intracellular semi-removal of drug makes, respectively, 18 and 6-24 hours. As phosphorylation of a gantsiklovir more depends on action of a virus kinase, it occurs preferential in the infected cells.

Virusostatichesky action of a gantsiklovir is caused by suppression of synthesis of virus DNA in the way: (1) competitive inhibition of embedding of a dezoksiguanozintrifosfat in DNA under the influence of a DNA polymerase; (2) inclusions of the gantsiklovirtrifosfat in virus DNA leading to the termination of lengthening of virus DNA or its very limited lengthening. The typical minimum concentration of drug in blood causing the inhibiting antiviral effect concerning TsMV, equal 50% of maximum (IC50) certain in vitro, is in the range from 0.14 microns (0.04 mkg/ml) to 14 microns (3.5 mkg/ml).

Virus resistance. Modern definition of resistance of TsMV to a gantsiklovir is based on definition of in vitro: the median of IC50 exceeds 1.5 mkg/ml (6.0 microns). Resistance of TsMV to a gantsiklovir develops seldom (about 1%). Resistance was noted at the patients with AIDS and TsMV a retinitis who never were receiving ганцикловир. In the first 6 months of treatment of TsMV of a retinitis Tsimeven (in infusions or in capsules) virus resistance is defined by drug at 3-8% of patients. Stability of a virus was noted also at patients, is long receiving therapy by drug Tsimeven in infusions concerning retinitis TsMV. The main mechanism of resistance of TsMV to a gantsiklovir – decline in the ability to form active triphosphate. The steady viruses containing mutations in UL97 TsMV gene which is responsible for phosphorylation of a gantsiklovir were described. Also the mutations in a gene of a virus DNA polymerase defining virus resistance to a gantsiklovir are described, and viruses with this mutation can be steady and to other drugs operating on TsMV.

Pharmacokinetics. Absorption. After infusion of a gantsiklovir in a dose of 5 mg/kg within 1 hour of HIV - and TsMV-to the infected patients or adult sick AIDS the total area under a curve "concentration time" (AUC0-24) fluctuates from 21.4±3.1 to 26.0±6.06 mkg x hour/ml. The maximum concentration of drug in plasma (Cmax) was in range from 7.59±3.21 and 8.27±1.02 up to 9.03±1.42 mkg/ml.

Distribution. The volume of distribution of a gantsiklovir after intravenous administration correlates with body weight and at achievement of equilibrium concentration makes 0.5-0.8 l/kg. Concentration of drug in cerebrospinal fluid in 0.25-5.67 hours after intravenous administration of a gantsiklovir in a dose of 2.5 mg/kg in each 8 or 12 hours makes 24-67% of concentration in plasma and is equal to 0.50-0.68 mkg/ml. Communication with proteins of plasma - 1-2%.

Metabolism and removal. After intravenous administration in doses from 1.6 to 5.0 mg/kg the kinetics of a gantsiklovir has linear character. The main way of removal - renal excretion of not changed drug by glomerular filtering and canalicular secretion. With normal function of kidneys of 89.6±5.0% of intravenously entered dose ганцикловир it is found in patients in urine in not changed look. At persons with normal function of kidneys the system clearance is in range from 2.64±0.38 to 4.52±2.79 ml/min., and renal clearance – from 2.57±0.69 to 3.48±0.68 ml/min. that corresponds to 90-101% of the entered gantsiklovir. The elimination half-life at persons without renal failure fluctuates from 2.73±1.29 to 3.98±1.78 hours.

Pharmacokinetics at special groups of patients. Diseases of kidneys. The hemodialysis reduces concentration of a gantsiklovir in plasma after intravenous and peroral administration in doses of 1.25-5.0 mg/kg approximately by 50%.

When using the discontinuous scheme of a hemodialysis indicators of clearance of a gantsiklovir make from 42 to 92 ml/min., a drug elimination half-life during dialysis - 3.3-4.5 hours. At continuous dialysis the clearance of a gantsiklovir was lower (4.0-29.6 ml/min.), but during the period before the following administration of drug from an organism the bigger percent of the accepted dose was removed. At a discontinuous hemodialysis the fraction of the gantsiklovir removed for one session of a hemodialysis makes from 50% to 63%.

Elderly patients. At persons 65 years are more senior than researches it was not carried out.

Indications to use:

Treatment life-threatening or to sight of manifest TsMV of an infection at persons with immunodeficiencies, including AIDS. Prevention of manifest TsMV of an infection at patients after organ transplantation.

Route of administration and doses:

Maintenance therapy: on 5 mg/kg by intravenous infusion within 1 hour, daily for 7 days a week or on 6 mg/kg of body weight daily for 5 days a week.

As ганцикловир gets divorced not bacteriostatic sterile water, for reduction of risk of bacterial contamination infusion solution needs to be used within 24 hours after preparation.

Features of use:

Pregnancy and period of feeding by a breast. Category C drug (on FDA classification – U.S. Food and Drug Administration).

During treatment gantsikloviry it is necessary to recommend to women of childbearing age to use reliable methods of contraception. Men are recommended to use a barrier method of contraception during treatment and not less than 90 days after its termination.

In researches on animals teratogenecity of drug is revealed. Safety of a gantsiklovir at pregnancy at the person is not established. Pregnant women should avoid purpose of drug if only the potential advantage for mother does not exceed possible risk for a fruit.

Peri-and post-natal development after influence of a gantsiklovir was not studied, however it is impossible to exclude that ганцикловир can be removed with milk and cause serious undesirable reactions in the baby. Nursing mothers have to be instructed about need to stop feeding by a breast at administration of drug Tsimeven.

Gantsiklovir possesses potential teratogenic and cancerogenic action, can cause inborn malformations and malignant new growths. Gantsiklovir can oppress temporarily or with firmness a spermatogenesis.

At the patients accepting ганцикловир cases of a heavy leukopenia, a neutropenia, anemia, thrombocytopenia, a pancytopenia, a miyelosupressiya and aplastic anemia were observed. It is not necessary to begin treatment gantsikloviry if the absolute number of neutrophils is less than 500 cells in 1 мкл or number of thrombocytes less than 25000 cells in 1 мкл or hemoglobin less than 8 g/dl (see the sections "Special Instructions on Dosing" and "Side effect").

During treatment it is recommended to monitorirovat number of uniform elements of blood, including number of thrombocytes. At patients with a heavy leukopenia, a neutropenia, anemia and/or thrombocytopenia it is recommended to carry out treatment by hemopoietic growth factors and/or to temporarily interrupt therapy with drug (see the sections "Special Instructions on Dosing" and "Pharmacokinetics at Special Groups of Patients").

At a renal failure it is recommended to carry out dose adjustment of drug depending on clearance of creatinine (see the sections "Special Instructions on Dosing" and "Pharmacokinetics at Special Groups of Patients").

The patients accepting ганцикловир can have convulsive attacks, drowsiness, dizziness, an ataxy, confusion of consciousness and/or a lump.

At the patients accepting imipenem/tsilastatin and ганцикловир development of spasms therefore ганцикловир it is not necessary to appoint along with imipenemom/tsilastatiny is described if only potential advantages of therapy do not exceed possible risk (see the section "Interaction with Other Medicines").

As ганцикловир, and a zidovudine can cause a neutropenia and anemia therefore some patients can not transfer a concomitant use of these drugs in the standard recommended doses (see the section "Interaction with Other Medicines").

At a concomitant use of a gantsiklovir plasma concentration of a didanozin therefore such patients should be observed carefully regarding the phenomena of toxicity of a didanozin can increase (see the section "Interaction with Other Medicines").

The concomitant use of a gantsiklovir and the drugs having myelosuppressive or nefrotoksichny effects can lead to development of the additive toxicity (see the section "Interaction with Other Medicines").

Influence on ability to driving of vehicles and work with cars and mechanisms. The patients accepting ганцикловир can have convulsive attacks, drowsiness, dizziness, an ataxy, confusion of consciousness. Similar symptoms can influence performance of the types of activity requiring special attention including ability to driving of vehicles and work with cars and mechanisms. At development of these symptoms patients should refuse driving of vehicles and work with cars and mechanisms.

Side effects:

HIV-positive patients. The clinical undesirable phenomena which were noted at ≥2% of the patients who were intravenously receiving ганцикловир irrespective of their relationship of cause and effect using drug and severity:
from system of blood and lymphatic system: neutropenia, anemia, thrombocytopenia, leukopenia, lymphadenopathy;

from the alimentary system: diarrhea, abdominal pain, dysphagy, gullet candidiasis;

from the central and peripheral nervous system: hypesthesia, condition of alarm;

from skin and a hypodermic fatty tissue: itch;

from respiratory system: cough, pneumocystic pneumonia, cough with a phlegm, developments of stagnation in paranasal sinuses;

from laboratory indicators: increase in activity of an alkaline phosphatase in blood, a giperkreatininemiya;

from a musculoskeletal system: arthralgias;

others: fever, candidiasis, infections in an injection site, sepsis, including secondary sepsis, anorexia, the infection caused by Mycobacterium avium complex, pain of various localization, including thorax pain, bacteremia, an inflammation in an injection site.

Patients after transplantation. The clinical undesirable phenomena which were noted at ≥5% of the patients who were intravenously receiving ганцикловир for treatment or prevention of manifest TsMV of an infection after transplantation of marrow irrespective of their relationship of cause and effect using drug and severity:
from system of blood and bodies of a hemopoiesis: pancytopenia, leukopenia;

from bodies of the alimentary system: diarrhea, nausea, dyspepsia, abdominal distention;

laboratory indicators: increase in concentration of creatinine, activity of "hepatic" transaminases, hypomagnesiemia, hypocalcemia, hypopotassemia;

from a nervous system: headache, tremor, confusion of consciousness;

from skin and a hypodermic fatty tissue: exfoliative dermatitis;

from respiratory system: rhinitis, short wind;

from cardiovascular system: tachycardia, lowering of arterial pressure;

from urinogenital system: hamaturia;

from sense bodys: hematopsia;

from a musculoskeletal system: mialgiya;

others: damage of mucous membranes, fever, shiver, sepsis, anorexia, face edema.

The clinical undesirable phenomena which were noted at ≥5% of the patients receiving intravenously ганцикловир after heart transplantation irrespective of relationship of cause and effect using drug or gravity:
from a metabolism and food: hypostases (9%);

from the central and peripheral nervous system: headache (18%), confusion of consciousness (5%), peripheral neuropathy (7%);

from respiratory system: pleural exudate (5%);

from cardiovascular system: increase in arterial pressure (20%);

from urinogenital system: deterioration in function of kidneys (14%), renal failure (12%);

others: infections (18%).

Because of high bioavailability of intravenously entered gantsiklovir it is impossible to exclude that at intravenous administration of drug the same undesirable phenomena, as well as in researches with oral administration of a gantsiklovir can be noted.

For a total characteristic of a profile of safety of intravenously entered gantsiklovir the corresponding undesirable phenomena revealed with a bigger frequency at oral administration of a gantsiklovir at HIV - infected or patients after organ transplantation, irrespective of degree of their weight and relationship of cause and effect using drug are included below. Some undesirable phenomena at oral administration of a gantsiklovir can be connected with this way of administration of drug:
from system of blood and lymphatic system: leukocytosis;

from the alimentary system: lock, cholangitis, meteorism, vomiting;

from cardiovascular system: vazodilatation (decrease in the ABP, erubescence of the person);

from the central and peripheral nervous system: depression, dizziness, sleeplessness;

from a liver and biliary tract: cholestatic jaundice;

from skin and a hypodermic fatty tissue: sweating strengthening;

from sense bodys: amblyopia, taste disturbances;

from a metabolism and food: diabetes mellitus, hyponatremia, hypoproteinemia, decrease in body weight;

others: ascites, adynamy, bleedings, bacterial, fungal and viral infections, indisposition.

Other undesirable phenomena. The significant undesirable phenomena which were not stated above since inclusions (less than 2%) did not meet criteria are included below:
from system of blood and lymphatic system: aplastic anemia, miyelosupressiya, eosinophilia; potentially life-threatening bleedings against the background of thrombocytopenia; the episodes of infections caused by oppression of marrow and immune system (local and system infections and sepsis);

from the alimentary system: gastrointestinal bleedings, eructation, incontience calla, stomacace, pancreatitis, glossitis;

from the central and peripheral nervous system: excitement, spasms, hallucinations, psychosis, disorder of thinking, "dreadful" dreams, an ataxy, a coma, dryness in a mouth, euphoria, nervousness, drowsiness;
from skin and a hypodermic fatty tissue: dermatitis, acne, alopecia, herpes simplex, urticaria;

from sense bodys: amotio of a retina, a vision disorder, a blindness, decrease in hearing, pain in an eyeglobe, glaucoma, destruction of a vitreous;

from laboratory indicators: increase in activity of a kreatinfosfokinaza and lactate dehydrogenase in blood, a hypoglycemia;

from urinogenital system: the speeded-up urination;

from cardiovascular system: arrhythmia (including, ventricular), thrombophlebitis of deep veins, migraine, phlebitis;

from a musculoskeletal system: myasthenic syndrome;

others: a cachexia, dehydration, weakness, thrombosis in the place of an injection, abscess in the place of an injection, hypostasis in the place of an injection, pain in the place of an injection, hemorrhage in the place of an injection, an indisposition, reactions of a photosensitization.

Experience of post-registration use of drug. The undesirable phenomena, according to spontaneous messages at use of a gantsiklovir for HIV - the infected patients and other patients with the weakened immunity (for example, after transplantation) for whom it is impossible to exclude relationship of cause and effect using drug: an anaphylaxis, decrease in fertility at men.

For the rest the undesirable phenomena described at post-registration use of drug are similar to those which were noted in clinical trials.

Interaction with other medicines:

Interaction at intravenous administration of a gantsiklovir. Extent of linkng of a gantsiklovir with proteins of plasma makes only 1-2% therefore the interactions caused by replacement of drugs from places of communication with proteins of plasma should not be expected.

Didanozin: it is established that at simultaneous use of a didanozin and intravenous or peroral administration of a gantsiklovir of concentration of a didanozin in plasma with firmness raise. At intravenous administration of a gantsiklovir in doses of 5-10 mg/kg in days of AUC the didanozina increased by 38-67%. This increase cannot be explained with change of canalicular secretion of drug as the percent of removal of a didanozin increased. This increase in AUC can be caused or the increased bioavailability, or reduction of speed of metabolism. Clinically significant changes of concentration of a gantsiklovir at the same time were not. However, taking into account increase in plasma concentration of a didanozin in the presence of a gantsiklovir, patients should be observed carefully regarding toxicity of a didanozin.

Imipenem/tsilastatin: at the patients who were at the same time receiving ганцикловир and imipenem/tsilastatin spasms were observed. It is necessary to appoint this drug in a combination with drug Tsimeven only if possible advantages exceed risk.

Mikofenolata mofetit (MMF): co-administration of these drugs which are potentially competing at canalicular secretion can lead to increase in concentration of a gantsiklovir and phenolic glucuronide of mikofenolny acid. Essential change of pharmacokinetics of mikofenolovy acid is not expected, it is not required to adjust a dose of a mikofenolat of a mofetil. At patients with a renal failure who at the same time receive ганцикловир and MMF, it is necessary to observe recommendations about dosing of a gantsiklovir and to make careful observation.

Interaction at oral administration of a gantsiklovir. Probenetsid. At a concomitant use of a probenetsid and a peroral gantsiklovir reduction of renal clearance of a gantsiklovir (20%) was observed that led to statistically significant increase in its exposure (40%). These changes are explained by the competition for canalicular secretion. It is necessary to watch carefully a condition of the patients accepting пробенецид and Tsimeven because of possible emergence of symptoms of toxicity of a gantsiklovir.

Zidovudine. The concomitant use of a zidovudine and a peroral gantsiklovir brought to small (17%), but to statistically significant increase in AUC of a zidovudine. Also the tendency to reduction of concentration of a gantsiklovir (statistically insignificant values) was observed. Considering that as ганцикловир, and a zidovudine can cause a neutropenia and anemia, the intolerance of a concomitant use of these drugs in the standard recommended doses at some patients is possible (see the section "Special Instructions").

Zaltsitabin. The concomitant use of a zaltsitabin and a peroral gantsiklovir increased AUC0-8 of the last by 13%. Statistically significant changes of other pharmacokinetic parameters are not revealed. Besides, despite small increase in a constant of speed of elimination, clinically significant changes in pharmacokinetics of a zaltsitabin were not observed.

Stavudin. At simultaneous use of a stavudin and peroral gantsiklovir statistically significant changes of pharmacokinetic parameters were not observed.

Trimethoprimum. At simultaneous use of Trimethoprimum and peroral gantsiklovir statistically significant reduction of renal clearance of a gantsiklovir by 16.3% was observed that was associated with statistically significant reduction of final speed of elimination and increase in an elimination half-life by 15%. However, it is improbable that these changes have clinical value as AUC0-8 and Cmax did not change. The only statistically significant change in Trimethoprimum pharmacokinetics at a concomitant use with a peroral gantsiklovir was increase in Cmin. It is also improbable that this change is clinically significant. Dose adjustment is not required.

Cyclosporine. When comparing residual concentration of cyclosporine of data on influence of a gantsiklovir on pharmacokinetics of cyclosporine it is not revealed. However after the beginning of therapy gantsikloviry increase in the maximum value of creatinine of blood serum was observed.

Other possible medicinal interactions. Strengthening of toxicity at purpose of a gantsiklovir along with other drugs possessing myelosuppressive action or breaking function of kidneys is possible (such as: dapsone, pentamidine, флуцитозин, Vincristinum, vinblastine, adriamycin, Amphotericinum In, nukleozidny analogs and a hydroxycarbamide). Therefore, it is necessary to appoint these drugs along with gantsikloviry only if potential advantages exceed possible risk (see the section "Special Instructions").

Contraindications:

Hypersensitivity to a gantsiklovir, a valgantsiklovir or any other component of drug.

Because of similarity of chemical structure of a gantsiklovir, an acyclovir and a valatsiklovir between these drugs reactions of cross hypersensitivity are possible.

The absolute number of neutrophils is less than 500 cells in 1 мкл or number of thrombocytes less than 25000 cells in 1 мкл or the level of hemoglobin is less than 8 g/dl.

Children's age up to 12 years.

Overdose:

Overdose of intravenously entered gantsiklovir. At overdose in certain cases no undesirable phenomena arose. At most of patients it was noted one or several of the following undesirable phenomena.

Hematologic toxicity: pancytopenia, miyelosupressiya, marrow aplasia, leukopenia, neutropenia, granulocytopenia.

Hepatotoxic: hepatitis, abnormal liver function.

Nephrotoxicity: increase of a hamaturia at the patient with already available damage of kidneys, an acute renal failure, increase in concentration of creatinine.

Gastrointestinal toxicity: abdominal pains, diarrhea, vomiting.

Neurotoxicity: generalized tremor, spasms.

Besides, to one adult patient the excess volume of solution of a gantsiklovir for intravenous administration then it developed temporary loss of sight and occlusion of the central artery of a retina owing to increase in the intraocular pressure caused by the entered liquid volume was intravitrealno entered.

In plasma at drug overdose Tsimeven it is possible to apply a hemodialysis and hydration to decrease in concentration of a gantsiklovir (see the section "Pharmacokinetics at Special Groups of Patients"). At patients with a heavy leukopenia, a neutropenia, anemia and/or thrombocytopenia it is recommended to carry out treatment by hemopoietic growth factors.

Storage conditions:

Period of validity 3 years. Not to use after the period of validity specified on packaging. At a temperature not over 30º C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for infusions, 500 mg. On 500 mg of a gantsiklovir in the bottle from colourless glass of a hydrolytic class 1 (EF) with a capacity of 10 ml corked by a cover from butyl rubber, which is pressed out by an aluminum cap and closed by a plastic cover. Each bottle together with the application instruction is placed in a cardboard pack.