Arranon (Page 3 of 5)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ARRANON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and Infestations: Fatal opportunistic infections

Metabolism and Nutrition Disorders: Tumor lysis syndrome

Nervous System Disorders: Demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome

Musculoskeletal and Connective Disorders: Rhabdomyolysis, blood creatine phosphokinase increased

7 DRUG INTERACTIONS

Administration of ARRANON in combination with adenosine deaminase (ADA) inhibitors, such as pentostatin, is not recommended [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action and findings in animal studies, ARRANON can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited available data with ARRANON use in pregnant women are insufficient to determine a drug-associated risk for major birth defects, miscarriage or adverse maternal, or fetal outcomes. There are risks to the pregnant woman associated with untreated leukemia or lymphoma (see Clinical Considerations). In animal reproduction studies, intravenous administration of nelarabine to pregnant rabbits during the period of organogenesis resulted in teratogenicity at maternal doses below the recommended human adult dose of 1500 mg/m2 /day (see Data). Advise pregnant women of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-fetal Risk

There are risks to the mother from untreated leukemia or lymphoma, including anemia, thrombocytopenia, and death.

Data

Animal Data

In an embryo-fetal development study in which pregnant rabbits were administered daily doses of nelarabine during organogenesis, increased incidences of fetal malformations, anomalies, and variations were observed at doses greater than or equal to 360 mg/m2 /day (8-hour IV infusion; approximately 25% of the recommended human adult dose compared on a mg/m2 basis), which was the lowest dose tested. Cleft palate was seen in rabbits given 3600 mg/m2 /day (approximately 2-fold the adult dose), absent pollices (digits) in rabbits given greater than or equal to 1200 mg/m2 /day (approximately 75% of the recommended adult dose), while absent gall bladder, absent accessory lung lobes, fused or extra sternebrae, and delayed ossification was seen at all doses. Maternal body weight gain and fetal body weights were reduced in rabbits given 3600 mg/m2 /day (approximately 2-fold the adult dose), but could not account for the increased incidence of malformations seen at this or lower administered doses.

8.2 Lactation

Risk Summary

There are no data on the presence of nelarabine or ara-G in human or animal milk, the effect on the breastfed child, or the effect on milk production. Because of the potential for serious adverse reactions in the breastfed child from ARRANON, such as severe neurological reactions, advise women not to breastfeed during treatment with ARRANON.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

ARRANON can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Verify the pregnancy status of females of reproductive potential prior to starting treatment with ARRANON.

Contraception

Females

ARRANON can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)]. Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with ARRANON.

Males

Because of the potential for genotoxicity, advise males (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with ARRANON and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of ARRANON for relapsed or refractory T-ALL and T-LBL has been established in pediatric patients age 1 year and older. The effectiveness of ARRANON in pediatric patients is supported by one single-arm clinical trial, and safety has been asssessed in 165 pediatric patients age 1 year and older across multiple Phase I and Phase II trials. The trial establishing efficacy included 84 patients age 21 years and younger, who had relapsed or refractory T-ALL or T-LBL. The most frequent adverse reactions of any grade occurring on treatment in this study were hematologic laboratory abnormalities. Hematologic toxicity observed in the pediatric population was higher than that seen in the adult population [see Dosage and Administration (2.1), Adverse Reactions (6.1), Clinical Studies (14.2)].

Nervous system adverse reactions have been reported for 42% of pediatric patients across the Phase I and Phase II trials. The incidence of nervous system adverse reactions was less in the pediatric population than that seen in adult patients with relapsed/refractory T-ALL/T-LBL [see Adverse Reactions (6.1)].

In a phase III study of ARRANON in combination with multi-agent chemotherapy as first-line therapy, there were 411 patients with T-ALL or T-LBL treated with ARRANON. The safety profile in the 357 patients age 1 to 16 years was consistent with that seen in older patients in the study [see Adverse Reactions (6.1)].

Due to lack of long-term follow up data, a determination of the impact of ARRANON on the growth and pubertal development of pediatric patients cannot be made.

8.5 Geriatric Use

Clinical studies of ARRANON did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. In an exploratory analysis, increasing age, especially age 65 years and older, appeared to be associated with increased rates of neurologic adverse reactions. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection [see Use in Specific Populations (8.6)].

8.6 Renal Impairment

Ara-G clearance decreased as renal function decreased [see Clinical Pharmacology (12.3)]. Because the risk of adverse reactions to this drug may be greater in patients with moderate (CLCr 30 to 50 mL/min) or severe (CLCr less than 30 mL/min) renal impairment, these patients should be closely monitored for toxicities when treated with ARRANON [ see Dosage and Administration (2.3 ) ].

8.7 Hepatic Impairment

The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated. Because the risk of adverse reactions to this drug may be greater in patients with severe hepatic impairment (total bilirubin greater than 3 times upper limit of normal), these patients should be closely monitored for toxicities when treated with ARRANON.

10 OVERDOSAGE

There is no known antidote for overdoses of ARRANON. It is anticipated that overdosage would result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression, and potentially death. In the event of overdose, supportive care consistent with good clinical practice should be provided.

At a dose of 2200 mg/m2 given on Days 1, 3, and 5 every 21 days, 2 patients developed a significant Grade 3 ascending sensory neuropathy. Magnetic resonance imaging evaluations of the 2 patients demonstrated findings consistent with a demyelinating process in the cervical spine.

11 DESCRIPTION

ARRANON (nelarabine) is a prodrug of the cytotoxic deoxyguanosine analogue, 9-β-D -arabinofuranosylguanine (ara-G).

The chemical name for nelarabine is 2-amino-9-β-D -arabinofuranosyl-6-methoxy-9H -purine. It has the molecular formula C11 H15 N5 O5 and a molecular weight of 297.27. Nelarabine has the following structural formula:

The following structural formula for nelarabine is 2-amino-9-b-D-arabinofuranosyl-6-methoxy-9H-purine. It has the molecular formula C11H15N5O5 and a molecular weight of 297.27.

Nelarabine is slightly soluble to soluble in water and melts with decomposition between 209ºC and 217ºC.

ARRANON Injection is supplied as a clear, colorless, sterile solution in glass single-dose vials. Each vial contains 250 mg of nelarabine (5 mg nelarabine per mL) and the inactive ingredient sodium chloride (4.5 mg per mL) in 50 mL Water for Injection, USP. ARRANON is intended for intravenous infusion.

Hydrochloric acid and sodium hydroxide may have been used to adjust the pH. The solution pH ranges from 5.0 to 7.0.

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