Atriance^® (Solution) Instructions for Use

Marketing Authorization Holder

Sandoz, d.d. (Slovenia)

Manufactured By

Fareva Unterach, GmbH (Austria)

Or

Glaxo Operations UK Limited (United Kingdom)

Quality Control Release

Glaxo Operations UK, Limited (United Kingdom)

Or

NOVARTIS FARMACEUTICA, S.A. (Spain)

ATC Code

L01BB07 (Nelarabine)

Active Substance

Nelarabine (Rec.INN registered by WHO)

Dosage Form

Atriance®

Solution for infusion 5 mg/1 ml: 50 ml vial, 1 or 6 pcs.

Dosage Form, Packaging, and Composition

Solution for infusion clear, colorless.

Excipients: sodium chloride – 4.5 mg, 0.1 M hydrochloric acid solution or 0.1 M sodium hydroxide solution – to adjust pH to 5.5-6.5 (average pH 6.0), water for injections – up to 1 ml.

50 ml – glass vials (1) – cardboard packs.
50 ml – glass vials (6) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agents; antimetabolites; purine analogues

Pharmacological Action

Antitumor drug, antimetabolite. Nelarabine is a prodrug of 9-β-D-arabinofuranosylguanine (ara-G), a deoxyguanosine analogue. Under the action of adenosine deaminase, Nelarabine is rapidly transformed into ara-G, and then, as a result of phosphorylation, its 5-monophosphate and then ara-guanosine triphosphate (ara-GTP) are formed. As a result of the accumulation of ara-GTP in blast cells in leukemia, it is competitively incorporated into the DNA chain, which causes suppression of DNA synthesis and, consequently, cell death. In vitro, T-cells were shown to be more sensitive to the cytotoxic effects of nelarabine compared to B-cells.

Clinical efficacy and safety

Nelarabine demonstrated clinical efficacy at the recommended adult and pediatric dose in patients in two independent clinical studies – CALGB 19801 and COG P9673. In adults with T-cell acute lymphoblastic leukemia or T-lymphoma after two or more induction courses, nelarabine monotherapy led to complete remission in 18% of cases (95% CI: 6-37%) with a duration of complete remission from 15 to 195+ weeks; one-year survival was 29%, confirming the clinical efficacy of the drug in this group of patients who had previously received intensive treatment. Similar rates were obtained in children and patients aged 21 years and younger with relapsed or refractory T-cell acute lymphoblastic leukemia or T-lymphoma after two or more induction courses (group 02): nelarabine monotherapy induced complete remission in 13% of cases (95% CI: 4-27%) with a duration of complete remission from 4.7 to 36.4 weeks; one-year survival was 14%.

In some patients after two or more ineffective induction courses, hematopoietic stem cell transplantation was performed during the complete remission achieved with nelarabine monotherapy. At the time of transplantation, the duration of complete remission was 1.6-9.3 weeks in children and 6.3-195.4+ weeks in adults. In study PGAA2001, hematological recovery data were obtained for 21 out of 27 patients who underwent hematopoietic stem cell transplantation after nelarabine therapy. Of these, 20 patients (95%) had confirmed neutrophil recovery. In study PGAA2002, hematological recovery data were obtained for 6 out of 7 patients who underwent hematopoietic stem cell transplantation after nelarabine therapy. Neutrophil recovery was noted in 3 of them (50%).

In refractory patients, after an ineffective induction course, nelarabine therapy provided an impressive complete remission rate – 18% in adults and children after two or more prior induction courses and 44% in children after one prior induction course. In addition to patients who achieved complete remission, one adult patient and three children with refractory disease achieved complete remission without mandatory normalization of hematological parameters.

Pharmacokinetics

Absorption

C_max of ara-G in plasma is reached at the end of the nelarabine infusion and is on average higher than the C_max of nelarabine, suggesting rapid and intensive transformation of the prodrug into the drug. After a two-hour infusion of nelarabine at a dose of 1500 mg/m² in adult patients, the mean C_max values for nelarabine and ara-G were 13.9 µmol and 115 µmol, respectively.

AUC of nelarabine and ara-G averaged 13.5 µmol/h and 571 µmol/h, respectively, after infusion of 1500 mg/m². Intracellular C_max for ara-GTP is reached in 3-25 h on the first day of course treatment. Mean intracellular C_max and AUC values for ara-GTP were 95.6 µmol and 2214 µmol/h for the specified dose.

Distribution

Nelarabine and ara-G are characterized by a large V_d. The V_d at steady state in adults and children was 115 L/m² and 89.4 L/m², respectively. The apparent V_d of ara-G is 44.8 L/m² and 32.1 L/m² in adults and children, respectively.

The binding of nelarabine and ara-G to plasma proteins is insignificant and is less than 25% for both components; it is independent of concentration in the range up to 600 µmol. No accumulation of either nelarabine or ara-G was noted, including with the “days 1, 3, 5” administration schedule.

Intracellular concentrations of ara-GTP in lymphoblasts were determined for a prolonged period after nelarabine infusion. Accumulation of ara-GTP inside cells was noted with repeated nelarabine infusions according to the “1, 3, 5” schedule with an increase in C_max and AUC_(0-t) values on the third day of treatment by 50% and 30%, respectively, compared to similar indicators for the first day of the course.

Metabolism

The main pathway of nelarabine biotransformation is O-demethylation by adenosine deaminase to form ara-G, which is then metabolized to guanine. In addition, Nelarabine is partially hydrolyzed to methylguanine, which then undergoes O-demethylation to form guanine. At the next stage, N-deamination of guanine occurs with the formation of xanthine and its oxidation to uric acid.

Excretion

Nelarabine and ara-G are rapidly eliminated from plasma, T_1/2 is 30 min and 3 h, respectively, after infusion at a dose of 1500 mg/m².

The mean clearance of nelarabine when administered at doses from 104 to 2900 mg/m² in adults and children was 138 L/h/m² and 125 L/h/m² on day 1, respectively. The apparent clearance of ara-G is comparable in both age groups and is 9.5 L/h/m² in adults and 10.8 L/h/m² in children on day 1.

Nelarabine and ara-G are partially excreted by the kidneys. The mean amount excreted by the kidneys for nelarabine and ara-G is 5.3% and 23.2% of the administered dose, respectively, within 24 hours after nelarabine infusions on day 1. Renal clearance averages 16.4 L/h for nelarabine and 4.9 L/h for ara-G.

Pharmacokinetics in special clinical cases

The main pharmacokinetic parameters in children are similar to those in adults.

There are no differences in the main pharmacokinetic parameters in elderly patients.

The clinical studies included patients with CrCl greater than 80 ml/min, with mild renal impairment (CrCl 50-80 ml/min) and moderate renal impairment (CrCl less than 50 ml/min). The mean apparent clearance of ara-G is 7% lower in patients with moderate renal impairment. No differences in the efficacy and safety of the drug were noted.

There are no data for patients with hepatic impairment.

Indications

In patients with chemotherapy-refractory or relapsed disease

• T-cell acute lymphoblastic leukemia;
• T-cell lymphoblastic lymphoma.

ICD codes

Dosage Regimen

A course of treatment with nelarabine can only be carried out by a specialist with experience in the use of antitumor drugs.

The drug is intended for intravenous infusion undiluted.

For adults (16 years and older) the recommended dose is 1500 mg/m² IV over 2 hours on days 1, 3 and 5 every 21 days.

For children (under 16 years) the recommended dose is 650 mg/m² IV over 1 hour for 5 consecutive days (days 1-5) every 21 days.

Insufficient data to form specific recommendations for dosage regimen adjustment in renal impairment (CrCl less than 50 ml/min). Given partial renal excretion, careful monitoring of the patient’s clinical condition is required.

Insufficient data to form specific recommendations for dosage regimen adjustment for patients with hepatic impairment.

Nelarabine administration should be discontinued at the first signs of neurotoxicity of grade 2 severity and higher according to the National Cancer Institute toxicity criteria. Increasing the intervals between doses may be considered as an alternative in the development of other toxic manifestations, including hematological toxicity.

Adverse Reactions

The safety of nelarabine was assessed for the general population of patients included in clinical studies. The overall safety assessment was conducted for 103 adults and 84 children included in controlled clinical studies. Most frequently fatigue, gastrointestinal disorders, hematopoietic disorders, respiratory system disorders and increased body temperature. Neurotoxicity is dose-dependent.

Definition of frequency of adverse reactions: very common (≥1/10), common (≥ 1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10 000, <1/1000), very rare (<1/10 000, including isolated cases).

Infections and infestations: very common – infections, including sepsis, bacteremia, pneumonia, fungal infections. There are isolated reports of fatal opportunistic infections. One case of progressive multifocal leukoencephalopathy confirmed by biopsy was reported in an adult.

Neoplasms (benign and malignant, including cysts and polyps): common in adults – tumor lysis syndrome.

Metabolism and nutrition disorders very common – hypokalemia (children); common – hypokalemia (adults), hypocalcemia, hypomagnesemia, hypoglycemia (children), anorexia (adults), increased blood creatinine concentration.

Blood and lymphatic system disorders very common – febrile neutropenia (adults), neutropenia, leukopenia (children), thrombocytopenia, anemia; common – febrile neutropenia (children), leukopenia (adults).

Cardiac disorders common in adults – decreased BP.

Respiratory, thoracic and mediastinal disorders very common in adults – dyspnea, cough; common – pleural effusion, wheezing.

Gastrointestinal disorders very common in adults – diarrhea, nausea, vomiting, constipation; common in adults – stomatitis, abdominal pain, in children – diarrhea, stomatitis, nausea, vomiting, constipation.

Hepatobiliary disorders: very common in children – increased activity of hepatic transaminases; common – hyperbilirubinemia, in adults – increased AST concentration.

Musculoskeletal and connective tissue disorders very common in adults – myalgia; common in adults – muscle weakness, back pain, arthralgia, limb pain, in children – arthralgia, limb pain.

Eye disorders: common in adults – decreased visual acuity.

Nervous system disorders: very common in adults – dizziness, hypoesthesia, paresthesia, somnolence, peripheral neurological disorders (motor and sensory), headache, in children – peripheral neurological disorders (motor and sensory), headache; common in adults – confusion, amnesia, taste perversion, impaired balance control, blurred vision, seizures (including convulsions, status epilepticus, grand mal seizure), ataxia, tremor, in children – somnolence, hypoesthesia, paresthesia, seizures (including convulsions, status epilepticus, grand mal seizure), tremor, ataxia, confusion; very rare – demyelination, ascending peripheral neuropathy similar in manifestations to Guillain-Barré syndrome. One case of fatal status epilepticus was reported in a pediatric patient.

General disorders and administration site conditions: very common in adults – edema, peripheral edema, increased body temperature, pain, fatigue, asthenia; common in adults – gait disturbance, in children – increased body temperature, pain, fatigue, asthenia.

Contraindications

• Hypersensitivity to the components of the drug.

Use in Pregnancy and Lactation

There are no data on the use of the drug during pregnancy and lactation (breastfeeding).

Nelarabine has a genotoxic effect on mammalian cells.

Women and men during nelarabine therapy and for at least 3 months after its completion must use reliable methods of contraception.

Use in Hepatic Impairment

Insufficient data to form specific recommendations for dosage regimen adjustment for patients with hepatic impairment.

Use in Renal Impairment

Insufficient data to form specific recommendations for dosage regimen adjustment in renal impairment (CrCl less than 50 ml/min). Given partial renal excretion, careful monitoring of the patient’s clinical condition is required.

Pediatric Use

For children (under 16 years) the recommended dose is 650 mg/m², IV, over 1 hour, for 5 consecutive days (days 1-5) every 21 days.

Geriatric Use

Insufficient data on the use of nelarabine in elderly patients (65 years and older). It is possible that patients aged 65 years and older are also at increased risk of developing neurotoxic effects of the drug.

Special Precautions

Nelarabine is an active cytostatic agent. The use of the drug is possible only under the supervision of a physician with experience in working with cytostatics.

Strict monitoring of the patient’s condition is necessary due to the risk of developing neurotoxic reactions. Neurotoxicity is a dose-limiting factor. Nelarabine administration should be discontinued at the first signs of neurotoxicity of grade 2 severity and higher according to the National Cancer Institute toxicity criteria.

Patients receiving or having previously received intrathecal chemotherapy or craniospinal irradiation may be at risk for developing neurotoxic reactions.

Insufficient data on the use of nelarabine in elderly patients (65 years and older). It is possible that patients aged 65 years and older are also at increased risk of developing neurotoxic effects of the drug.

In patients at risk of tumor lysis, intravenous rehydration should be performed in accordance with accepted standards to prevent hyperuricemia. The need for simultaneous administration of allopurinol should be considered.

Immunization with live vaccines is not recommended in patients with reduced immune status due to the risk of developing infection.

Constant monitoring of blood counts, including platelet count, is required due to the possible hematological toxicity of the drug.

Effect on ability to drive vehicles and operate machinery

Since Nelarabine causes drowsiness that persists for several days after infusions, the patient’s overall clinical condition and the possible development of adverse events should be taken into account when assessing the ability to drive a car and operate machinery requiring quick reactions.

Overdose

Symptoms presumably, drug overdose is accompanied by symptoms of severe neurotoxicity, myelosuppression and may have fatal consequences.

Treatment: symptomatic therapy is carried out. Hemodialysis is not effective. There is no specific antidote.

Drug Interactions

A 30-minute infusion of 30 mg/m² fludarabine 4 hours before nelarabine administration did not affect the pharmacokinetics of nelarabine, ara-G and ara-GTP.

Nelarabine and ara-G are not substrates or inhibitors of P-glycoprotein and do not inhibit the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isoenzymes. In addition, the binding of nelarabine and ara-G to human plasma proteins is weak (less than 25%) and concentration-independent. Thus, this mechanism cannot sufficiently ensure possible drug interactions.

Pentostatin (deoxycoformycin) is a potent inhibitor of adenosine deaminase (ADA). In in vitro cytotoxicity studies, an increase in the concentration of nelarabine that inhibits cell growth (IC₅₀) was detected, proportional to the increase in the concentration of ADA inhibitors. The studied ADA inhibitors did not affect the IC₅₀ value of ara-G. According to the results of in vitro studies using other ADA inhibitors, the efficacy of nelarabine may decrease in the presence of pentostatin. Concomitant use of nelarabine and ADA inhibitors is not recommended.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.