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A - Drug Name

nelarabine

SYNONYM(S):   506U78; GW506U78

COMMON TRADE NAME(S):   Atriance® (Novartis)

 
B - Mechanism of Action and Pharmacokinetics

Nelarabine is a pro-drug of the deoxyguanosine analogue ara-G that is demethylated by adenosine deaminase to ara-G, then phosphorylated to the active moiety ara-GTP, which is incorported into the DNA of leukemic cells resulting in cytotoxic effects.



Absorption

Nelarabine is rapidly and extensively converted to ara-G.

Peak plasma levels Cmax 3-25 hours following 1500 mg/m2 infused over 2 hours

Distribution

Nelarabine and ara-G are extensively distributed.

PPB < 25%
Cross blood brain barrier? yes
Metabolism
Main enzymes involved O-demethylation by adenosine deaminase to ara-G, followed by hydrolysis to guanine.
Active metabolites yes
Inactive metabolites yes
Elimination

Mean clearance of nelarabine is 30% higher in pediatric compared to adult patients; clearance of ara-G is similar for both.

Half-life nelarabine: 30 minutes; ara-G: 2-3 hours
Urine mean urinary excretion: nelarabine, 5%; ara-G: 23% of administered dose
 
C - Indications and Status
Health Canada Conditional Approvals
(pending the result of studies to verify the drug’s clinical benefit. Patients should be advised of the nature of the marketing authorization granted.)

For the treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.

Note:

Conditional approval was based on improvements in complete response; no survival benefit has been demonstrated.



 
D - Adverse Effects

Emetogenic Potential:  

Minimal

Extravasation Potential:   None

The following adverse effects were reported mainly in adult patients. (DeAngelo 2007)

 

 

 

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Hypotension (8%) E
Gastrointestinal Abdominal pain (9%) E
Anorexia (9%) E
Constipation (21%) E
Diarrhea (22%) E
Mucositis (8%) E
Nausea, vomiting (41%) (severe - 1%) I  E
General Edema (15%) E
Fatigue (50%) E
Hematological Myelosuppression ± infection, bleeding (79%) (severe neutropenia, including opportunistic infections and PML) E
Hepatobiliary ↑ LFTs (6%) (1% severe) E
Metabolic / Endocrine Hyperglycemia (6%) E
Musculoskeletal Musculoskeletal pain (13%) E
Rhabdomyolysis (also increased CPK; rare) E
Nervous System Ataxia (9%) E
Confusion (8%) E
Dizziness (21%) E
Hallucinations (1%) E
Headache (15%) E
Insomnia (7%) E
Leukoencephalopathy (rare) E
Myelitis (transverse - rare) E
Neuropathy (21%) (may be severe, including cranial - rare) E
Seizure (rare) E
Somnolence (23%) E
Ophthalmic Blurred vision (4%) (also reduced vision; blindness - rare) E
Respiratory Cough, dyspnea (25%) E
Pleural effusion (10%) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects in adults include myelosuppression ± infection, bleeding, fatigue, nausea, vomiting, cough, dyspnea, somnolence, diarrhea, constipation, dizziness, neuropathy and edema.

The most common side effects in pediatric patients were myelosuppression +/- infection, bleeding, headache, increased transaminase and bilirubin, decreased serum potassium and albumin and vomiting. Severe neurological events, including seizures were also reported in pediatric patients.

Patients at risk of tumour lysis syndrome (i.e. high tumour burden) should have appropriate prophylaxis and be monitored closely.

Neurotoxicity is dose-limiting and may be irreversible. Risk of severe neurotoxicity (including fatalities) is higher with intrathecal chemotherapy or  craniospinal irradiation. Signs and symptoms include somnolence, confusion, altered level of consiousness, seizures, ataxia, paresthesias and hypothesia. Severe effects may include coma, status epilepticus, myelopathy, craniospinal demyelination or ascending neuropathy resembling Guillain-Barre syndrome. Discontinue nelarabine for grade 2 or higher neurotoxicity.

Acute hepatic failure, including fatalities has been reported.

 
E - Dosing

Refer to protocol by which patient is being treated. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.

Prophylaxis for tumour lysis syndrome is recommended.



Adults:

Intravenous: 1500 mg/m² over 2 hours Days 1, 3 and 5 every 3 weeks

See Children dosage description section below for recommended pediatric dose.


Dosage with Toxicity:

Refer to the protocol by which the patient is being treated for dose modification guidelines. The following are suggested modifications.

 

 

 

Toxicity / Grade
Action
Platelets < 100 x 109/L and/or ANC < 1.5 x 109/L OR Febrile neutropenia
Hold until recovery
Grade 3 non-hematologic toxicity (NOT including neurotoxicity)
Hold until recovery
Grade 4 non-hematologic toxicity OR
Grade 2 or greater neurotoxicity OR rhabdomyolysis, drug-related increases in CPK
Discontinue

 



Dosage with Hepatic Impairment:

No dosage adjustment is recommended for hepatic impairment. Patients with severe hepatic impairment should be monitored closely for toxicities.



Dosage with Renal Impairment:

Nelarabine and ara-G are partially renally excreted.  No dosage adjustment is recommended for CrCl ≥ 50 ml/min. No dosing data available for  CrCl < 50 ml/min; monitor these patients closely as there may be an increased risk of adverse effects.



Dosage in the elderly:

No dosage adjustment is recommended in the elderly; however, these patients may have reduced renal function (see dosage with renal impairment). Patients over age 65 had increased rates of neurologic adverse effects.



Dosage based on gender:

A pharmacokinetic study found that AUC was 2-3 fold greater in average adult females compared to average adult males. No safety or efficacy differences were observed in clinical trials.



Dosage based on ethnicity:

The effect of race on pharmacokinetics has not been evaluated.



Children:

650 mg/m2/day IV over 1 hour on days 1 to 5 every 3 weeks*

*The optimal dosing regimen for patients aged 16 to 21 has not been established

See dosage with toxicity, hepatic and renal impairment sections for dose adjustment recommendations where applicable.



 
F - Administration Guidelines
  • Should not be diluted prior to administration 
  • Stable in PVC infusion bags and glass containers up to 8 hours at 30oC
  • Visually inspect for particulates and discolouration prior to administration
  • Store vials at 25oC with excursions permitted between 15-30oC

     

 
G - Special Precautions
Contraindications:

  • Patients who have a hypersensitivity to this drug or any of its components
  • Concurrent intrathecal chemotherapy or craniospinal radiation

Other Warnings/Precautions:

  • Patients who have had prior intrathecal chemotherapy, craniospinal irradiation, or who have CNS disease may be at increased risk of severe neurologic adverse effects
  • Use caution with driving or using machinery as drowsiness or dizziness may occur with treatment
  • Avoid live vaccines, since they may result in serious or fatal infections in immunocompromised patients


Other Drug Properties:

  • Carcinogenicity: Unknown

Pregnancy and Lactation:
  • Mutagenicity: Yes
  • Genotoxicity: Yes
  • Teratogenicity: Yes
  • Fetotoxicity: Yes

    Nelarabine is not recommended for use in pregnancy. Highly effective contraception (< 1% failure rate) should be used by both sexes during treatment, and for at least 6 months after the last dose.

  • Excretion into breast milk: Unknown

    Breastfeeding is not recommended.

  • Fertility effects: Unknown
 
H - Interactions

No formal drug interaction studies have been performed. Nelarabine does not appear to inhibit CYP-P450 isoenzymes.

AGENT EFFECT MECHANISM MANAGEMENT
adenosine deaminase inhibitors (pentostatin) ↓ nelarabine concentration and/or efficacy ↓ conversion of nelarabine pro-drug to active form (in vitro) Avoid
Intrathecal chemotherapy (e.g. methotrexate) reports of fatal neurotoxicity Additive Avoid
 
I - Recommended Clinical Monitoring
Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline and before each cycle
Liver and renal function tests Baseline and before each cycle

Clinical toxicity assessment for neurotoxicity, infections and bleeding, GI, musculoskeletal and respiratory effects

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
K - References

Berg SL, Blaney SM, Devidas M, et al.; Children's Oncology Group. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol. 2005 May 20;23(15):3376-82.

DeAngelo DJ, Yu D, Johnson JL, et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood. 2007 Jun 15;109(12):5136-42.

McEvoy GK, ed in chief. AHFS: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2013: 1136-37.

Product Monograph: Atriance® (nelarabine). GlaxoSmithKline Inc., June 2015.

Schiff D, Wen PY, van den Bent MJ, et al.  Neurological adverse effects caused by cytotoxic and targeted therapies.  Nat Rev Clin Oncol 2009 Oct;6(10):596-603.


October 2017 updated neurotoxicity in adverse effects description, precautions and interactions sections

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

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