Arranon

Name: Arranon

Warnings

Included as part of the PRECAUTIONS section.

Uses of Arranon

Arranon is a prescription anti-cancer medicine used to treat adults and children who have:

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

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Side Effects of Arranon

Arranon may cause serious nervous system problems. See “Arranon Precautions”.

Common side effect of Arranon include:

  • 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.

Arranon Interactions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take pentostatin (Nipent).

This is not a complete list of Arranon drug interactions. Ask your doctor or pharmacist for more information.

 

Pregnancy & Lactation

Pregnancy Category: D

Lactation: do not nurse

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

What happens if I miss a dose?

Call your doctor for instructions if you miss an appointment for your nelarabine injection.

Arranon Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

  • Appropriate measures (e.g., administration of IV fluids, allopurinol, and alkalinization of urine) should be taken to prevent hyperuricemia of tumor lysis syndrome.1 (See Tumor Lysis Syndrome under Cautions.)

Administration

IV Administration

Administer by IV infusion.1

Nelarabine injection should not be diluted prior to administration.1

Withdraw appropriate dose from the required number of vials and transfer into empty PVC infusion bags or glass containers prior to administration.1

Rate of Administration

Adults: Administer by IV infusion over 2 hours.1

Pediatric patients: Administer by IV infusion over 1 hour.1

Dosage

Pediatric Patients

Acute Lymphocytic Leukemia Relapsed or Refractory T-cell ALL or T-cell Lymphoblastic Lymphoma IV

650 mg/m2 daily for 5 consecutive days; repeat every 21 days.1 2

Optimal duration of treatment not established.1 In clinical studies, treatment was continued until evidence of disease progression, unacceptable toxicity, bone marrow transplantation, or lack of clinical benefit was observed.1

Adults

Acute Lymphocytic Leukemia Relapsed or Refractory T-cell ALL or T-cell Lymphoblastic Lymphoma IV

1500 mg/m2 on days 1, 3, and 5; repeat every 21 days.1 2

Optimal duration of treatment not established.1 In clinical studies, treatment was continued until evidence of disease progression, unacceptable toxicity, bone marrow transplantation, or lack of clinical benefit was observed.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1

Renal Impairment

No dosage adjustment required in patients with mild renal impairment (Clcr ≥50 mL/minute); not studied in patients with moderate to severe renal impairment.1

Geriatric Patients

No specific dosage recommendations at this time.1

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Arranon or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Arranon. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Dosage forms and strengths

250 mg/50 mL (5 mg/mL) vial

Warnings and precautions

      Neurologic Adverse Reactions

Neurotoxicity is the dose-limiting toxicity of nelarabine. Patients undergoing therapy with Arranon should be closely observed for signs and symptoms of neurologic toxicity [see Boxed Warning, Dosage and Administration (2.2)]. Common signs and symptoms of nelarabine-related neurotoxicity include somnolence, confusion, convulsions, ataxia, paresthesias, and hypoesthesia. Severe neurologic toxicity can manifest as coma, status epilepticus, craniospinal demyelination, or ascending neuropathy similar in presentation to Guillain-Barré syndrome.

Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risk for neurologic adverse events.

      Hematologic Adverse Reactions

Leukopenia, thrombocytopenia, anemia, and neutropenia, including febrile neutropenia, have been associated with nelarabine therapy. Complete blood counts including platelets should be monitored regularly [see Dosage and Administration (2.2), Adverse Reactions (6.1)].

      Pregnancy

Pregnancy Category D

Arranon can cause fetal harm when administered to a pregnant woman.

Nelarabine administered during the period of organogenesis caused increased incidences of fetal malformations, anomalies, and variations in rabbits (see Use in Specific Populations (8.1)].

There are no adequate and well-controlled studies of Arranon in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with Arranon.

      Hyperuricemia

Patients receiving Arranon should receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumor lysis syndrome. Consideration should be given to the use of allopurinol in patients at risk of hyperuricemia [see Dosage and Administration (2.4)].

      Vaccinations

Administration of live vaccines to immunocompromised patients should be avoided.

Adverse reactions

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

  • Neurologic [see Boxed Warning, Warnings and Precautions (5.1)]
  • Hematologic [see Warnings and Precautions (5.2)]
  • Hyperuricemia [see Warnings and Precautions (5.4)]

      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 with 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.

Adults: 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) trial and an adult chronic lymphocytic leukemia trial.

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
Percentage of Patients (N = 103)
Toxicity Grade
System Organ Class Grade 3 Grade 4 and 5a All Grades
Preferred Term % % %
Blood and Lymphatic System Disorders
      Anemia 20 14 99
      Thrombocytopenia 37 22 86
      Neutropenia 14 49 81
      Febrile neutropenia 9 1 12
Cardiac Disorders
      Sinus tachycardia 1 0 8
Gastrointestinal Disorders
      Nausea 0 0 41
      Diarrhea 1 0 22
      Vomiting 1 0 22
      Constipation 1 0 21
      Abdominal pain 1 0 9
      Stomatitis 1 0 8
      Abdominal distension 0 0 6
General Disorders and Administration Site Conditions
      Fatigue 10 2 50
      Pyrexia 5 0 23
      Asthenia 0 1 17
      Edema, peripheral 0 0 15
      Edema 0 0 11
      Pain 3 0 11
      Rigors 0 0 8
      Gait, abnormal 0 0 6
      Chest pain 0 0 5
      Non-cardiac chest pain 0 1 5
Infections
      Infection 2 1 9
      Pneumonia 4 1 8
      Sinusitis 1 0 7
Hepatobiliary Disorders
      AST increased 1 1 6
Metabolism and Nutrition Disorders
      Anorexia 0 0 9
      Dehydration 3 1 7
      Hyperglycemia 1 0 6
Musculoskeletal and Connective Tissue Disorders
      Myalgia 1 0 13
      Arthralgia 1 0 9
      Back pain 0 0 8
      Muscular weakness 5 0 8
      Pain in extremity 1 0 7
Nervous System Disorders (see Table 2)
Psychiatric Disorders
      Confusional state 2 0 8
      Insomnia 0 0 7
      Depression 1 0 6
Respiratory, Thoracic, and Mediastinal Disorders
      Cough 0 0 25
      Dyspnea 4 2 20
      Pleural effusion 5 1 10
      Epistaxis 0 0 8
      Dyspnea, exertional 0 0 7
      Wheezing 0 0 5
Vascular Disorders
      Petechiae 2 0 12
      Hypotension 1 1 8

a       Five patients had a fatal adverse reaction. Fatal adverse reactions included hypotension (n = 1), respiratory arrest (n = 1), pleural effusion/pneumothorax (n = 1), pneumonia (n = 1), and cerebral hemorrhage/coma/leukoencephalopathy (n = 1).

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 trials. 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
Percentage of Patients (N =103)
Nervous System Disorders Grade 1 Grade 2 Grade 3 Grade 4 All Grades
Preferred Term % % % % %
Somnolence 20 3 0 0 23
Dizziness 14 8 0 0 21
Peripheral neurologic disorders, any adverse reaction 8 12 2 0 21
      Neuropathy 0 4 0 0 4
      Peripheral neuropathy 2 2 1 0 5
      Peripheral motor neuropathy 3 3 1 0 7
      Peripheral sensory neuropathy 7 6 0 0 13
Hypoesthesia 5 10 2 0 17
Headache 11 3 1 0 15
Paresthesia 11 4 0 0 15
Ataxia 1 6 2 0 9
Depressed level of consciousness 4 1 0 1 6
Tremor 2 3 0 0 5
Amnesia 2 1 0 0 3
Dysgeusia 2 1 0 0 3
Balance disorder 1 1 0 0 2
Sensory loss 0 2 0 0 2

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%).

Pediatrics: 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 trial.

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
Percentage of Patients (N = 84)
Toxicity Grade
System Organ Class Grade 3 Grade 4 and 5a All Grades
Preferred Term % % %
Blood and Lymphatic System Disorders
      Anemia 45 10 95
      Neutropenia 17 62 94
      Thrombocytopenia 27 32 88
      Leukopenia 14 7 38
Hepatobiliary Disorders
      Transaminases increased 4 0 12
      Blood albumin decreased 5 1 10
      Blood bilirubin increased 7 2 10
Metabolic/Laboratory
      Blood potassium decreased 4 2 11
      Blood calcium decreased 1 1 8
      Blood creatinine increased 0 0 6
      Blood glucose decreased 4 0 6
      Blood magnesium decreased 2 0 6
Nervous System Disorders (see Table 4)
Gastrointestinal Disorders
      Vomiting 0 0 10
General Disorders & Administration Site Conditions
      Asthenia 1 0 6
Infections & Infestations
      Infection 2 1 5

a       Three patients had a fatal adverse reaction. Fatal adverse reactions included neutropenia and pyrexia (n = 1), status epilepticus/seizure (n = 1), and fungal pneumonia (n = 1).

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 trials. 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
Percentage of Patients (N = 84)
Nervous System Disorders Grade 1 Grade 2 Grade 3 Grade 4 and 5a All Grades
Preferred Term % % % % %
Headache 8 2 4 2 17
Peripheral neurologic disorders, any adverse reaction 1 4 7 0 12
      Peripheral neuropathy 0 4 2 0 6
      Peripheral motor neuropathy 1 0 2 0 4
      Peripheral sensory neuropathy 0 0 6 0 6
Somnolence 1 4 1 1 7
Hypoesthesia 1 1 4 0 6
Seizures 0 0 0 6 6
      Convulsions 0 0 0 3 4
      Grand mal convulsions 0 0 0 1 1
      Status epilepticus 0 0 0 1 1
Motor dysfunction 1 1 1 0 4
Nervous system disorder 1 2 0 0 4
Paresthesia 0 2 1 0 4
Tremor 1 2 0 0 4
Ataxia 1 0 1 0 2

a       One (1) patient had a fatal neurologic adverse reaction, status epilepticus.

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-Barré syndrome.

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

References

  1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.
  2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
  3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
  4. Polovich M, White JM, Kelleher LO (eds.) 2005. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. (2nd ed) Pittsburgh, PA: Oncology Nursing Society.

What is the most important information i should know about nelarabine (arranon)?

Nelarabine may cause serious side effects of the central nervous system, such as problems with balance, coordination, or fine motor skills. These symptoms may not go away even after you stop receiving nelarabine. Talk with your doctor if you have concerns about any possible long-term side effects.

Do not use nelarabine if you are pregnant. It could harm the unborn baby.

You should not breast-feed while you are using nelarabine.

Before you receive nelarabine, tell your doctor if you have liver or kidney disease, a nerve disorder, a history of chemotherapy or radiation treatment of your head, neck, or spinal cord.

Nelarabine can lower blood cells that help your body fight infections and help your blood to clot. Your blood may need to be tested often. Avoid being near people who are sick or have infections. Avoid activities that may increase your risk of bleeding injury. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while you are being treated with nelarabine.

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

How is Arranon given?

Arranon is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Arranon must be given slowly, and the IV infusion can take up to 2 hours to complete.

This medication is usually given every day or every other day for 5 days in a row every 3 weeks. Your treatment schedule may be different. Follow your doctor's instructions.

Arranon can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your nervous system and kidney function may also need to be tested. Your cancer treatments may be delayed based on the results of these tests. Visit your doctor regularly.

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