Nelarabine

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Neurologic [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
• Hematologic [see WARNINGS AND PRECAUTIONS]
• Hyperuricemia [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

ARRANON was studied in 459 patients in Phase I and Phase II clinical trials.

The safety profile of ARRANON is based on data from 103 adult patients treated with the recommended dose and schedule in 2 studies: an adult T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) study and an adult chronic lymphocytic leukemia study.

The most common adverse reactions in adults, regardless of causality, were fatigue; gastrointestinal (GI) disorders (nausea, diarrhea, vomiting, and constipation); hematologic disorders (anemia, neutropenia, and thrombocytopenia); respiratory disorders (cough and dyspnea); nervous system disorders (somnolence and dizziness); and pyrexia.

The most common adverse reactions in adults, by System Organ Class, regardless of causality, including severe or life threatening adverse reactions (NCI Common Toxicity Criteria grade 3 or grade 4) and fatal adverse reactions (grade 5) are shown in Table 1.

Table 1: Most Commonly Reported ( > 5% Overall) Adverse Reactions Regardless of Causality in Adult Patients Treated with 1,500 mg/m²  of ARRANON Administered Intravenously Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days

Other Adverse Events: Blurred vision was also reported in 4% of adult patients.

There was a single report of biopsy confirmed progressive multifocal leukoencephalopathy in the adult patient population.

Neurologic Adverse Reactions: Nervous system adverse reactions, regardless of drug relationship, were reported for 76% of adult patients across the Phase I and Phase II studies. The most common neurologic adverse reactions ( > 2%) in adult patients, regardless of causality, including all grades (NCI Common Toxicity Criteria) are shown in Table 2.

Table 2: Neurologic Adverse Reactions ( > 2%) Regardless of Causality in Adult Patients Treated with 1,500 mg/m²  of ARRANON Administered Intravenously Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days

One patient had a fatal neurologic adverse reaction, cerebral hemorrhage/coma/leukoencephalopathy.

Most nervous system adverse reactions in the adult patients were evaluated as grade 1 or 2. The additional grade 3 adverse reactions in adult patients, regardless of causality, were aphasia, convulsion, hemiparesis, and loss of consciousness, each reported in 1 patient (1%). The additional grade 4 adverse reactions, regardless of causality, were cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy, each reported in one patient (1%).

The other neurologic adverse reactions, regardless of causality, reported as grade 1, 2, or unknown in adult patients were abnormal coordination, burning sensation, disturbance in attention, dysarthria, hyporeflexia, neuropathic pain, nystagmus, peroneal nerve palsy, sciatica, sensory disturbance, sinus headache, and speech disorder, each reported in one patient (1%).

The safety profile for children is based on data from 84 pediatric patients treated with the recommended dose and schedule in a T-cell acute lymphoblastic leukemia (T- ALL)/T-cell lymphoblastic lymphoma (T-LBL) treatment study.

The most common adverse reactions in pediatric patients, regardless of causality, were hematologic disorders (anemia, leukopenia, neutropenia, and thrombocytopenia). Of the non- hematologic adverse reactions in pediatric patients, the most frequent adverse reactions reported were headache, increased transaminase levels, decreased blood potassium, decreased blood albumin, increased blood bilirubin, and vomiting.

The most common adverse reactions in pediatric patients, by System Organ Class, regardless of causality, including severe or life threatening adverse reactions (NCI Common Toxicity Criteria grade 3 or grade 4) and fatal adverse reactions (grade 5) are shown in Table 3.

Table 3: Most Commonly Reported ( > 5% Overall) Adverse Reactions Regardless of Causality in Pediatric Patients Treated with 650 mg/m²  of ARRANON Administered Intravenously Over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days

Neurologic Adverse Reactions: Nervous system adverse reactions, regardless of drug relationship, were reported for 42% of pediatric patients across the Phase I and Phase II studies. The most common neurologic adverse reactions ( > 2%) in pediatric patients, regardless of causality, including all grades (NCI Common Toxicity Criteria) are shown in Table 4.

Table 4: Neurologic Adverse Reactions ( > 2%) Regardless of Causality in Pediatric Patients Treated with 650 mg/m²  of ARRANON Administered Intravenously Over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days

The other grade 3 neurologic adverse reaction in pediatric patients, regardless of causality, was hypertonia reported in 1 patient (1%). The additional grade 4 neurologic adverse reactions, regardless of causality, were 3rd nerve paralysis, and 6th nerve paralysis, each reported in 1 patient (1%).

The other neurologic adverse reactions, regardless of causality, reported as grade 1, 2, or unknown in pediatric patients were dysarthria, encephalopathy, hydrocephalus, hyporeflexia, lethargy, mental impairment, paralysis, and sensory loss, each reported in 1 patient (1%).

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-Barre syndrome.

Musculoskeletal and Connective Disorders: Rhabdomyolysis, blood creatine phosphokinase increased.

ARRANON®Â 
(AIR-ra-non)
Nelarabine Injection

Read the Patient Information that comes with ARRANON before you or your child start treatment with ARRANON. Read the information you get each time before each treatment with ARRANON. There may be new information. This information does not take the place of talking with the doctor about your or your child's medical condition or treatment. Talk to your or your child's doctor, if you have any questions.

What is the most important information I should know about ARRANON?

ARRANON may cause serious nervous system problems including:

• extreme sleepiness
• seizures
• coma
• numbness and tingling in the hands, fingers, feet, or toes (peripheral neuropathy)
• weakness and paralysis

Call the doctor right away if you or your child has the following symptoms:

• seizures
• numbness and tingling in the hands, fingers, feet, or toes
• problems with fine motor skills such as buttoning clothes
• unsteadiness while walking
• increased tripping while walking
• weakness when getting out of a chair or walking up stairs

These symptoms may not go away even when treatment with ARRANON is stopped.

What is ARRANON?

ARRANON is an anti-cancer medicine used to treat adults and children who have:

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

What should you tell the doctor before you or your child starts ARRANON?

Tell the doctor about all health conditions you or your child have, including if you or your child:

• have any nervous system problems.
• have kidney problems.
• are breast-feeding or plan to breast-feed. It is not known whether ARRANON passes through breast milk. You should not breast-feed during treatment with ARRANON.
• are pregnant or plan to become pregnant. ARRANON may harm an unborn baby. You should use effective birth control to avoid getting pregnant. Talk with your doctor about your choices.

Tell the doctor about all the medicines you or your child take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

How is ARRANON given?

ARRANON is an intravenous medicine. This means it is given through a tube in your vein.

What should you or your child avoid during treatment with ARRANON?

• You or your child should not drive or operate dangerous machines. ARRANON may cause sleepiness.
• You or your child should not receive vaccines made with live germs during treatment with ARRANON.

What are the possible side effects of ARRANON?

ARRANON may cause serious nervous system problems. See “What is the most important information I should know about ARRANON?”

ARRANON may also cause:

• decreased blood counts such as low red blood cells, low white blood cells, and low platelets. Blood tests should be done regularly to check blood counts. Call the doctor right away if you or your child:
  • is more tired than usual, pale, or has trouble breathing
  • has a fever or other signs of an infection
  • bruises easy or has any unusual bleeding
• stomach area problems such as nausea, vomiting, diarrhea, and constipation
• headache
• sleepiness
• blurry eyesight

Call your doctor right away if you experience unexplained muscle pain, tenderness, or weakness while taking ARRANON. This is because on rare occasions, muscle problems can be serious.

These are not all the side effects associated with ARRANON. Ask your doctor or pharmacist for more information.

General Advice about ARRANON

This leaflet summarizes important information about ARRANON. If you have questions or problems, talk with your or your child's doctor. You can ask your doctor or pharmacist for information about ARRANON that is written for healthcare providers or it is available at  www.GSK.com.

Nelarabine may be found in some form under the following brand names:

• Arranon

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. You should use effective birth control to avoid getting pregnant. Talk with your doctor about your choices.

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

• 2-Amino-6-Methoxypurine Arabinoside
• 506U78
• GW506U78

There are no contraindications listed in the US labeling.

Canadian labeling: Hypersensitivity to nelarabine or any component of the formulation.

Refer to adult dosing.

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl <50 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling, (although ARA-G clearance is decreased as renal function declines, data is insufficient for a dosing recommendation); monitor closely.

Adequate IV hydration recommended to prevent tumor lysis syndrome; allopurinol may be used if hyperuricemia is anticipated.

IV:

Children: Infuse over 1 hour daily for 5 consecutive days

Adults: Infuse over 2 hours on days 1, 3, and 5

Severe neurologic reactions have been reported with the use of nelarabine. These reactions have included the following: altered mental states, including severe somnolence; CNS effects, including convulsions; and peripheral neuropathy, ranging from numbness and paresthesias to motor weakness and paralysis. There have also been reports of reactions associated with demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.

Full recovery from these reactions has not always occurred with cessation of therapy with nelarabine. Close monitoring for neurologic reactions is strongly recommended; discontinue nelarabine for neurologic reactions of National Cancer Institute (NCI) Common Toxicity Criteria grade 2 or greater.