ATRIANS
Active material: nelarabin
When ATH: L01BB07
CCF: Anticancer drug. Antimetaʙolit
ICD-10 codes (testimony): C91.0
When CSF: 22.02.02
Manufacturer: GlaxoSmithKline Trading Company (Russia)
PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING
Solution for infusion clear, colorless, without visible mechanical inclusions.
| 1 ml | 1 fl. | |
| nelarabin | 5 mg | 250 mg |
Excipients: sodium chloride, hydrochloric acid, Sodium hydroxide, water d / and.
50 ml – bottles (6) – packs cardboard.
Pharmacological action
Anticancer drug. Antimetaʙolit. Nelarabin is prolekarstvom 9-β-D-arabinofuranozilguanina (ARA-g), analogue dezoksiguanozina. Under the influence of adenozindezaminaza nelarabin quickly morphs into ARA-g, and then, as a result fosfaurilirovania formed his 5-monophosphate and hereafter – ARA-GTP (ARA-GTP). As a result of the accumulation of ARA-GTP in blast cells in leukemia it competitive is embedded in the DNA chain, What causes inhibition of DNA synthesis and, Consequently, the death of cells. In vitro it was shown, that T-cells are more sensitive to the cytotoxic effects of nelarabina compared to b-cells.
Pharmacokinetics
Absorption
Cmax ARA-g in the blood plasma is achieved at the end of infusions of nelarabina and an average above, than Cmax nelarabina, that implies fast and intensive transformation of prodrug in medicine. After a two-hour infusions in a dose of nelarabina 1500 mg / m2 adult patients the mean values of Cmax nelarabina and ARA-g were 13.9 Xylose and 115 mmol, respectively.
AUC nelarabina and ARA-g were 13.5 μmol/h 571 μmol/h, respectively, after infusion 1500 mg / m2. Intracellular Cmax for ARA-GTP is achieved through 3-25 h on the first day of a course of treatment. The average intracellular Cmax and ARA-GTP AUC were 95.6 Xylose and 2214 μmol/h for a specified dose.
Distribution
Nelarabin and ARA-g are characterized by a large Vd. Vd in equilibrium in adults and children was, respectively, 115 l/m2 and 89.4 l/m2. In Кажущийсяd ARA-g is 44.8 l/m2 and 32.1 l/m2 in adults and children, respectively.
Linking nelarabina and ARA-g with blood plasma proteins is negligible and is less than 25%, for both components, it does not depend on the concentrations in the range of 600 mmol. No cumulation nor nelarabina, No ARA-g, incl. in the scheme introduction “1, 3, 5 day”.
Intracellular ARA-GTP concentrations limfoblastah were determined for an extended period after infusion nelarabina. Marked accumulation of ARA-GTP inside cages infuziah repeated schema nelarabina “1, 3, 5” with increasing values of Cmax и AUC(0-t) on the third day of treatment at 50% and 30%, respectively, compared with similar figures for the first day of the course.
Metabolism
The main route of biotransformation of nelarabina is o-demethylation with formation of adenozindezaminazoj ARA-g, next metaboliziruûŝegosâ to guanine. Besides, nelarabin partially hydrolyzed to metilguanina, which then undergoes o-demetilirovaniu with formation of guanine. The next step is N-guanine deamination with formation of Xanthine and its oxidation to uric acid.
Deduction
Nelarabin and ARA-g fast are derived from blood plasma, T1/2 is, respectively, 30 Mines and 3 h after infusions in the dose 1500 mg / m2.
The average clearance nelarabina when administered in doses from 104 to 2900 mg/m2 in adults and children was, respectively, 138 l / h / m2 and 125 l / h / m2 in a day 1. The apparent clearance of ARA-g was comparable in both age groups and is 9.5 l / h / m2 adults and 10.8 l / h / m2 children per day 1.
Nelarabin and ARA-g displays partial kidneys. The average number of, display the news, is for nelarabina and ARA-g, respectively, 5.3% and 23.2% from the imposed dose within 24 h after infusions of nelarabina per day 1. Kidney klirens averages 16.4 l/h for nelarabina and 4.9 l / – for ARA-g.
Pharmacokinetics in special clinical situations
Basic pharmacokinetic parameters in children are similar to those in adults.
No differences in the basic parameters of Pharmacokinetic in elderly patients.
In clinical studies included patients with KK more 80 ml / min, with mild impairment of renal function (CC 50-80 ml / min) and moderate degree (CC less than 50 ml / min) degrees. Average apparent clearance of ARA-g 7% lower in patients with moderate kidney dysfunction. Differences in the efficacy and safety of the drug is not observed.
For patients with impaired liver no data.
Clinical effectiveness and safety
Nelarabin showed clinical efficacy in adult and child's recommended dose in patients in two independent clinical studies – CALGB 19801 and COG R9673. In adults with acute lymphoblastic t-Lymphocytic Leukemia or t-Lymphoma after two or more courses of induction monotherapy nelarabinom resulted in complete remission (AVE) in 18% cases (DI 95%: 6-37%) When the duration of complete remission from 15 to 195+ weeks; survival through 1 year amounted to 29%, that confirms the clinical efficacy of the drug in this group of patients, previously conducted intensive treatment. Equal values were obtained in children and patients over 21 years with recurrent or refrakternym acute lymphoblastic t-Lymphocytic Leukemia or t-Lymphoma after two or more induction courses (Group 02): monotherapy nelarabinom caused a complete remission in 13% cases (DI 95%: 4-27%) When the length of PR from 4.7 to 36.4 weeks; survival through 1 year amounted to 14%.
In some patients after two or more courses of ineffective induction, in the period reached amid alone nelarabinom complete remission was made blood stem cell transplantation. At the time of the transplant complete remission duration was 1.6-9.3 the week in children and 6.3-195.4+ weeks in adults. PGAA2001 study data about restore blood indicators were obtained from 21 from 27 patients, After nelarabinom therapy was performed by hematopoietic stem cell transplantation. Of these, 20 patients (95%) It was confirmed by the restoration of the level of neutrophils. PGAA2002 study on the restoration of the data obtained from hematology 6 from 7 patients, After nelarabinom therapy was performed by hematopoietic stem cell transplantation. In 3 of them (50%) noted restoration of the level of neutrophils.
From refractory patients, After the ineffective course of induction, nelarabinom therapy provided an impressive frequency of complete remission – 18% in adults and children after two or more prior induction courses and 44% in children after one leading up to the induction course. In addition to patients, attained complete remission, one adult patient and three children with refrakternym disease was achieved complete remission when optional parameters normalization.
Testimony
In patients with refrakternym to chemotherapy or recurrent disease:
— T-cell acute lymphoblastic leukemia;
— T-lymphoblast cell lymphoma.
Dosage regimen
The course of treatment nelarabinom may only be carried out by a specialist, with experience in the use of anticancer drugs.
The product is intended for in/infusion in nerazvedennom form.
To Adult (16 and older) The recommended dose is 1500 mg / m2 I /, during 2 no, in the days of 1, 3 and 5 every 21 day.
To children (to 16 years) The recommended dose is 650 mg / m2, I /, during 1 no, consistently 5 days (days 1-5) every 21 day.
Insufficient data to generate concrete recommendations on correction mode when violations renal function (CC less than 50 ml / min). Given the partial kidney excretion, requires careful monitoring of the patient's clinical condition.
Insufficient data to generate concrete recommendations on correction mode for patients with impaired liver function.
Application of nelarabina should be discontinued at the first sign of neurotoxicity 2 severity and above on toxicity criteria of the National Cancer Institute. Increase intervals between dosing can be considered as an alternative to the development of other toxic manifestation, including hematologic toxicity.
Side effect
Safety nelarabina was estimated for the general population of patients, included in clinical research. The overall safety assessment carried out for 103 adults and 84 children, included in the controlled clinical studies. Most private undesirable phenomena: fatiguability, gastrointestinal disorders, violation of hematopoiesis, disorders of the respiratory system and increased body temperature. Neurotoxicity dozozavisima.
The incidence of adverse events was classified as follows:: Often (≥1/10), often (≥ 1/100, <1/10), sometimes (≥1/1000, <1/100), rarely (≥1/10 000, <1 /1000), rarely (<1/10 000), including individual cases.
Infections and infestations: Often – infection, including sepsis, bacteremia, pneumonia, fungal infections. There are anecdotal reports on the development of fatal opportunistic infections. One case of adult progressive multifocal lejkoèncefalopatii, confirmed by biopsy.
Neoplasms (benign and malignant, including cysts and polyps): often in adults – tumor lysis syndrome.
Metabolism: Often – kaliopenia (children); often – kaliopenia (adults), hypocalcemia, gipomagniemiya, gipoglikemiâ (children), anorexia (adults), increasing the concentration of creatinine in the blood.
From the hematopoietic system: Often – febrile neutropenia (adults), neutropenia, leukopenia (children), thrombocytopenia, anemia; often – febrile neutropenia (children), leukopenia (adults).
Cardio-vascular system: often in adults – decrease in blood pressure.
The respiratory system: very often in adults – breathlessness, cough; often – pleural effusion, whistling rales
From the digestive system: very often in adults – diarrhea, nausea, vomiting, constipation; often in adults – stomatitis, stomach ache, children – diarrhea, stomatitis, nausea, vomiting, constipation.
Liver and biliary tract: very often in children – increase in liver transaminases; often – giperʙiliruʙinemija, adult – increasing the concentration of AST.
On the part of the musculoskeletal system: very often in adults – myalgia; often in adults – muscular weakness, back pain, arthralgia, pain in the limbs, children – arthralgia, pain in the limbs.
From the body as a whole: very often in adults – swelling, peripheral edema, fever, pain, fatiguability, asthenia; often in adults – gait disturbance, children – fever, pain, fatiguability, asthenia.
For part of the view: often in adults – blurred vision.
From the nervous system: very often in adults – dizziness, decreased sensitivity, paresthesia, drowsiness, Peripheral neurological disorders (motor and sensory), headache, children – Peripheral neurological disorders (motor and sensory), headache; often in adults – confusion, amnesia, dysgeusia, violation of body balance control, blurred vision, convulsions (including convulsions, status epilepticus, great epileptic attack), ataxia, tremor, children – drowsiness, decreased sensitivity, paresthesia, convulsions (including convulsions, status epilepticus, great epileptic attack), tremor, ataxia, confusion; rarely – demyelination, ascending peripheral neuropathy, similar manifestations with Guillain-Barre syndrome. Registered one case fatal epileptic patient's status in children
Contraindications
- Hypersensitivity to any component of the drug.
Pregnancy and lactation
Data on the use of drugs in pregnancy and lactation (breast-feeding) no.
Nelarabin has a genotoksičeskoe effect on mammalian cells.
Women and men during nelarabinom therapy and for at least 3 months after the need to use reliable methods of contraception.
Cautions
Nelarabin is an active, echocg. Application is possible only under the supervision of a physician, experienced with cytostatics.
There must be strict monitoring of the condition of the patient of the risk neirotoksicskih reactions. Neurotoxicity is the dozolimitiruûŝim factor. Application of nelarabina should be discontinued at the first sign of neurotoxicity 2 severity and above on toxicity criteria of the National Cancer Institute.
Risk of development may be considered reactions neirotoksicskih patients, receiving or previously receiving chemotherapy or intratekalno kraniospinal′noe irradiation.
Insufficient data on the application of nelarabina in elderly patients (65 and older). Maybe, patients 65 years of age and older are also at high risk for the development of the drug effects neirotoksicskih.
In patients with the risk that the tumor Lysis in/rehydration in accordance with accepted standards to prevent gieperriquemii. Consideration should be given to the need for simultaneous appointment allopourinola.
Not recommended for immunization of live vaccines in patients with reduced immune status due to the risk of infection.
Requires constant monitoring of blood formula, including content of platelets, due to the potential toxicity of Hematology.
Effects on ability to drive vehicles and management mechanisms
Because nelarabin causes drowsiness, continuing for a few days after infusion, account should be taken of the General clinical condition of the patient and the possible development of adverse events in assessing ability to driving and working with machinery, requiring responsiveness.
Overdose
There is no specific antidote.
Symptoms: suspected drug overdose is accompanied by symptoms of severe neurotoxicity, mielosupressiei and may have fatal consequences.
Treatment: symptomatic therapy. Hemodialysis is not effective.
Drug Interactions
30-minute infusion 30 mg / m2 Fludarabine for 4 hours before the introduction of the nelarabina does not affect the farmakokinetiku nelarabina, ARA-g and ARA-GTP.
Nelarabin and ARA-g were not substrates or inhibitors of glycoprotein p and does not inhibit the activity of isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 и CYP3A4. Besides, linking nelarabina and ARA-g with human blood plasma proteins is weak (less 25%) and does not depend on the concentration of. Thus, This mechanism cannot sufficiently provide for possible drug interactions.
Pentostatin (dezoksikoformicin) is a potent inhibitor of adenozindezaminaza (HELL). In vitro cytotoxicity studies revealed increasing concentrations of nelarabina, the overwhelming growth of cells (IC50), in proportion to the concentration of inhibitors of HELL. Reviewed by ADA inhibitors do not affect the value of IC50 ARA-g. According to the results of in vitro studies using other inhibitors of HELL, efficacy may be reduced in the presence of nelarabina pentostatina. The simultaneous use of nelarabina and inhibitors of HELL is not recommended.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be kept out of reach of children at a temperature of no higher than 30° c. Shelf life – 3 year.
At temperatures above 30° c the solution is stable for 8 no.
