Атрианс

General characteristics. Structure:

Active ingredient: неларабин 5 mg

Excipients: sodium chloride - 4.5 mg, 0.1 M solution of Acidum hydrochloricum or 0.1 M solution of sodium of hydroxide - for bringing PH value to level 5.5-6.5 (average PH value 6.0), water for and - to 1 ml.

50 ml - bottles glass (6) - packs cardboard.

Pharmacological properties:

Antineoplastic drug, antimetabolite. Nelarabin is pro-medicine 9-β-D-arabinofuranozilguanina (are-g), a deoxyguanosine analog. Under the influence of an adenosinedeaminase неларабин it is quickly transformed in are-g, and then, as a result of phosphorylation 5 monophosphate and - the macaw-guanozintrifosfat are formed further it (ara-GTF). As a result of accumulation ara-GTF in blast cells at a leukosis it is competitively built in DNA chain that causes suppression of synthesis of DNA and, therefore, death of a cell. In vitro was shown that T-cells are more sensitive to cytotoxic effects of a nelarabin in comparison with V-cells.

Clinical performance and safety

Nelarabin showed clinical performance in the recommended adult and children's dose at patients in two independent clinical trials - CALGB 19801 and COG P9673. At adults with an acute T-cellular lymphoblastoid leukosis or the T-lymphoma after two and more courses of induction monotherapy nelarabiny led to full remission in 18% of cases (DI of 95%: 6-37%) lasting full remission from 15 to 195 + weeks; survival in 1 year made 29% that confirms clinical performance of drug in this group of patients to whom intensive treatment was carried out earlier. Close indicators were received at children and patients 21 years with a recurrent or refractory acute T-cellular lymphoblastoid leukosis or the T-lymphoma after two and more courses of induction are not more senior (group 02): monotherapy nelarabiny caused full remission in 13% of cases (DI of 95%: 4-27%) from 4.7 to 36.4 weeks lasting full remission; survival in 1 year made 14%.

At some patients after two and more courses of inefficient induction, during the full remission reached against the background of monotherapy nelarabiny transplantation of stem cells of blood was made. At the time of transplantation duration of full remission made 1.6-9.3 weeks at children and 6.3-195.4+ weeks at adults. In the research PGAA2001 data on recovery of hematologic indicators were obtained at 21 of 27 patients who after therapy nelarabiny carried out transplantation of haematopoietic stem cells. From them at 20 patients (95%) recovery of level of neutrophils was confirmed. In the research PGAA2002 data on recovery of hematologic indicators are obtained at 6 of 7 patients who after therapy nelarabiny carried out transplantation of haematopoietic stem cells. At 3 of them (50%) recovery of level of neutrophils is noted.

At refractory patients, after an inefficient course of induction, therapy nelarabiny provided the impressive frequency of full remission - adults and children have 18% after two and more previous courses of induction and 44% is at children after one previous induction course. In addition to the patients who reached full remission at one adult patient and at three children with the refractory course of a disease full remission at optional normalization of hematologic parameters was reached.

 

Pharmacokinetics. Absorption

Cmax of are-g in a blood plasma is reached on the end of infusion of a nelarabin and on average above, than Cmax of a nelarabin that assumes bystry and intensive transformation of pro-medicine in medicine. After two-hour infusions of a nelarabin in a dose of 1500 mg/sq.m by the adult patient average Cmax values of a nelarabin and are-g made 13.9 µmol and 115 µmol, respectively.

AUC of a nelarabin and are-g averaged 13.5 µmol/h and 571 µmol/h, respectively, after infusion of 1500 mg/sq.m. Intracellular Cmax for ara-GTF is reached in 3-25 h for the first days of course treatment. Average intracellular Cmax and AUC values ara-GTF made 95.6 µmol and 2214 µmol/h for the specified dose.

Distribution

Nelarabin and are-g are characterized by big Vd. Vd in an equilibrium state at adults and children made, respectively, 115 l/sq.m and 89.4 l/sq.m. The seeming Vd of are-g makes 44.8 l/sq.m and 32.1 l/sq.m at adults and children, respectively.

Binding of a nelarabin and are-g with proteins of a blood plasma slightly also makes less than 25%, for both components it does not depend on concentration in the range up to 600 µmol. Cumulation of either a nelarabin, or are-g is noted, including at the scheme of introduction "1, 3, 5 days".

Intracellular concentration ara-GTF in lymphoblasts were defined during the long period after infusion of a nelarabin. Cumulation ara-GTF in cells is noted at repeated infusions of a nelarabin according to the scheme "1, 3, 5" with increase in Cmax and AUC(0-t) values for the third day of treatment for 50% and 30% respectively, in comparison with similar indicators for the first day of a course.

Metabolism

The main way of biotransformation of a nelarabin is O-demethylation by an adenosinedeaminase with formation of the are-g which further is metabolized to guanine. Besides, неларабин it is partially hydrolyzed to a methylguanine which then is exposed to O-demethylation with formation of guanine. At the following stage there is a N-deamination of guanine to formation of xanthine and its oxidation to uric acid.

Removal

Nelarabin and are-g are quickly brought out of a blood plasma, T1/2 makes, respectively, 30 min. and 3 h after infusion in a dose of 1500 mg/sq.m.

The average clearance of a nelarabin at introduction in doses from 104 to 2900 mg/sq.m at adults and children made respectively 138 l/h/sq.m and 125 l/h/sq.m a day 1. The seeming clearance of are-g is comparable in both age groups and makes 9.5 l/h/sq.m at adults and children have 10.8 l/h/sq.m in day 1.

Nelarabin and are-g are removed partially by kidneys. The average quantity removed by kidneys makes for a nelarabin and are-g, respectively, 5.3% and 23.2% of the entered dose during 24 h after infusions of a nelarabin in day 1. The renal clearance averages 16.4 l/h for a nelarabin and 4.9 l/h - for are-g.

Pharmacokinetics in special clinical cases

The key pharmacokinetic parameters at children are similar to those at adults.

There are no differences in the key pharmacokinetic parameters at elderly patients.

Clinical trials joined patients with KK more than 80 ml/min., with a renal failure of easy degree (KK of 50-80 ml/min.) and moderate degree (KK less than 50 ml/min.) degrees. The average seeming clearance of are-g is 7% lower at patients with moderate renal failures. Distinctions in efficiency and safety of drug are noted.

For patients with an abnormal liver function there are no data.

Indications to use:

At patients with refractory to chemotherapy or a recurrent disease:

— T-cellular acute lymphoblastoid leukosis;

— T-cellular lymphoblastoid lymphoma.

Route of administration and doses:

Nelarabiny it can be treated only with the specialist having experience in use of antineoplastic drugs.

Drug is intended for in/in infusions in not divorced look.

For adults (16 years are also more senior) the recommended dose makes 1500 mg/sq.m in/in, during 2 h, a days 1, 3 and 5 each 21 day.

For children (up to 16 years) the recommended dose makes 650 mg/sq.m in/in, during 1 h, consistently 5 days (days 1-5) each 21 day.

There are not enough specific recommendations about correction of the mode of dosing made for formation at renal failures (KK less than 50 ml/min.). Considering partial removal by kidneys, careful observation of a clinical condition of the patient is required.

There are not enough specific recommendations about correction of the mode of dosing for patients made for formation with abnormal liver functions.

Use of a nelarabin has to be stopped at the first signs of a neurotoxicity 2 severity above by criteria of toxicity of National Institute of Cancer. Increase in intervals between dosing can be considered an alternative at development of other toxic manifestations, including hematologic toxicity.

Features of use:

Nelarabin is an active tsitostatik. Use of drug is possible only under control of the doctor having experience with cytostatics.

Strict monitoring of a condition of the patient because of risk of development of neurotoxic reactions is necessary. The neurotoxicity is a dozolimitiruyushchy factor. Use of a nelarabin has to be stopped at the first signs of a neurotoxicity 2 severity above by criteria of toxicity of National Institute of Cancer.

The patients who are receiving or earlier receiving chemotherapy intratekalno or craniospinal radiation can treat risk group of development of neurotoxic reactions.

There are not enough data on use of a nelarabin for elderly patients (65 years are also more senior). It is possible that patients of 65 years also are more senior also treat group of the increased risk on development of neurotoxic effects of drug.

At patients with risk of a lysis of a tumor carrying out in/in a regidratation according to the accepted standards for prevention of a hyperuricemia is recommended. It is necessary to consider need of co-administration of Allopyrinolum.

Immunization by live vaccines at patients with the reduced immune status because of danger of development of an infection is not recommended.

Continuous monitoring of a blood count, including the maintenance of thrombocytes, because of possible hematologic toxicity of drug is required.

Influence on ability to driving of motor transport and to control of mechanisms

As неларабин causes the drowsiness proceeding within several days after infusions it is necessary to consider the general clinical condition of the patient and possible development of the undesirable phenomena at assessment of ability to driving and the work with mechanisms demanding speed of reaction.

Side effects:

Safety of a nelarabin was estimated for the general population of the patients included in clinical trials. The general assessment of safety was carried out for 103 adults and 84 children included in controlled clinical trials. Most often: fatigue, gastrointestinal disorders, disturbances of a blood formation, disturbance from respiratory system and fervescence. Neurotoxicity of a dozozavisim.

Determination of frequency of side reactions: very often (≥1/10), it is frequent (≥ 1/100, <1/10), infrequently (≥1/1000, <1/100), is rare (≥1/10 000, <1/1000), is very rare (<1/10 000, including separate cases).

Infections and invasions: very often - infections, including sepsis, bacteremia, pneumonia, fungal infections. There are separate messages on development of fatal opportunistic infections. One case of development in the adult of the progressing multifocal leukoencephalopathy confirmed with a biopsy is registered.

New growths (high-quality and malignant, including cysts and polyps): often at adults - a syndrome of a lysis of a tumor.

From a metabolism: very often - a hypopotassemia (children); often - a hypopotassemia (adults), a hypocalcemia, a hypomagnesiemia, a hypoglycemia (children), anorexia (adults), increase in concentration of creatinine in blood.

From system of a hemopoiesis: very often - a febrile neutropenia (adults), a neutropenia, a leukopenia (children), thrombocytopenia, anemia; often - a febrile neutropenia (children), a leukopenia (adults).

From cardiovascular system: often at adults - decrease in the ABP.

From respiratory system: very often at adults - short wind, cough; often - a pleural exudate, the whistling rattles.

From the alimentary system: very often at adults - diarrhea, nausea, vomiting, a lock; often adults - stomatitis, abdominal pains, at children have a diarrhea, stomatitis, nausea, vomiting, a lock.

From a liver and biliary tract: very often at children - increase in activity of hepatic transaminases; often - the hyperbilirubinemia, at adults is increase in concentration of nuclear heating plant.

From a musculoskeletal system: very often at adults - a mialgiya; often adults - muscular weakness, dorsodynias, an arthralgia, extremity pains, at children have an arthralgia, extremity pains.

From an organ of sight: often at adults - decrease in visual acuity.

From a nervous system: very often adults - dizziness, decrease in sensitivity, paresthesia, drowsiness, peripheral neurologic disturbances (motor and touch), a headache, at children have peripheral neurologic disturbances (motor and touch), a headache; often adults - confusion of consciousness, amnesia, a food faddism, disturbance of control of balance of a body, a zatumanennost of sight, a spasm (including convulsions, the epileptic status, a big epileptic attack), an ataxy, a tremor, at children have a drowsiness, decrease in sensitivity, paresthesia, spasm (including convulsions, the epileptic status, a big epileptic attack), a tremor, an ataxy, confusion of consciousness; very seldom - demyelination, the ascending peripheral neuropathy similar on manifestations to a syndrome to Giyena-Barra. One case of the fatal epileptic status at the patient of children's age is registered.

From an organism in general: very often at adults - hypostases, peripheral hypostases, fervescence, pains, fatigue, an adynamy; often adults - gait disturbance, at children have a fervescence, pains, fatigue, an adynamy.

Interaction with other medicines:

30-minute infusion of 30 mg/sq.m of a fludarabin for 4 h before introduction of a nelarabin did not influence pharmacokinetics of a nelarabin, are-g and ara-GTF.

Nelarabin and are-g are not substrates or inhibitors of a P-glycoprotein and do not suppress activity of isoenzymes of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Besides, binding of a nelarabin and are-g with proteins of a blood plasma of the person is weak (less than 25%) and does not depend on concentration. Thus, this mechanism cannot provide possible medicinal interaction adequately.

Pentostatin (дезоксикоформицин) is powerful inhibitor of an adenosinedeaminase (HELL). In researches of cytotoxicity in vitro increase in the concentration of a nelarabin suppressing growth of cells (IC50) in proportion to increase in concentration of inhibitors of HELL was revealed. The studied inhibitors of HELL did not influence IC50 value of are-g. According to results of the researches in vitro with use of other inhibitors of HELL, efficiency of a nelarabin can decrease in the presence of a pentostatin. Simultaneous use of a nelarabin and inhibitors of HELL is not recommended.

Contraindications:

— hypersensitivity to drug components.

 

Use of drug ATRIANS at pregnancy and feeding by a breast

There are no data on use of drug at pregnancy and in the period of a lactation (breastfeeding).

Nelarabin has genotoksichesky effect on cells of mammals.

Women and men during therapy nelarabiny and, at least, within 3 months after its termination need to use reliable methods of contraception.

 

Use at abnormal liver functions

There are not enough specific recommendations about correction of the mode of dosing for patients made for formation with abnormal liver functions.

 

Use at renal failures

There are not enough specific recommendations about correction of the mode of dosing made for formation at renal failures (KK less than 50 ml/min.). Considering partial removal by kidneys, careful observation of a clinical condition of the patient is required.

 

Use for elderly patients

There are not enough data on use of a nelarabin for elderly patients (65 years are also more senior). It is possible that patients of 65 years also are more senior also treat group of the increased risk on development of neurotoxic effects of drug.

 

Use for children

For children (up to 16 years) the recommended dose makes 650 mg/sq.m, in/in, during 1 h, 5 days (days 1-5) each 21 day are consecutive.

Overdose:

Symptoms: presumably, the overdose of drug is followed by symptoms of a heavy neurotoxicity, a miyelosupressiya and can have fatal effects.

Treatment: carry out symptomatic therapy. The hemodialysis is not effective. The specific antidote does not exist.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature not above 30 °C. A period of validity - 3 years.

At a temperature above 30 °C solution is stable during 8 h.

Issue conditions:

According to the recipe

Packaging:

• solution for инф. 5 mg / 1 ml: фл. 50 ml 6 - LSR-009514/08, 28.11.08. Validity period рег. уд. it is not limited. VED.