Arranon Side Effects

Generic Name: nelarabine

Please note - some side effects for Arranon may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Arranon - for the Consumer

Arranon

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Arranon:

Blurred vision; constipation; cough; diarrhea; dizziness; drowsiness; headache; loss of appetite; muscle, joint, or back pain; nausea; stomach pain; stuffy nose; tiredness; trouble sleeping; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Arranon:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; coma; confusion; depression; fast heartbeat; fever, chills, or sore throat; loss of coordination; memory loss; mental or mood changes; numbness, burning, prickling, or tingling of the skin, hands, or feet; paralysis; seizures; severe drowsiness; shortness of breath; stomach swelling; swelling or the hands, feet, or legs; unusual bruising or bleeding; weakness; wheezing.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Arranon Side Effects - for the Professional

Arranon

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

• Neurologic [see Boxed Warning and 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 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.

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) 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

System Organ Class    Preferred Term	Percentage of Patients (N = 103)
	Toxicity Grade
	Grade 3 %	Grade 4 and 5a %	All Grades %
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
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 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

Nervous System Disorders    Preferred Term	Percentage of Patients (N =103)
	Grade 1 %	Grade 2 %	Grade 3 %	Grade 4 %	All Grades %
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 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

System Organ Class    Preferred Term	Percentage of Patients (N = 84)
	Toxicity Grade
	Grade 3 %	Grade 4 and 5a %	All Grades %
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
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 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

Nervous System Disorders    Preferred Term	Percentage of Patients (N = 84)
	Grade 1 %	Grade 2 %	Grade 3 %	Grade 4 and 5a %	All Grades %
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.

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Side Effects by Body System - for Healthcare Professionals

Hematologic

Hematologic side effects including anemia (99%), thrombocytopenia (86%), neutropenia (81%), and febrile neutropenia (12%) have been reported. A case of biopsy confirmed multifocal leukoencephalopathy has also been reported.

Nervous system

Nervous system side effects (64%) have been reported including somnolence (23%), dizziness (21%), peripheral neurologic disorders (21%), hypoesthesia (17%), headache (15%), paresthesia (15%), ataxia (9%), depressed level of consciousness (6%), tremor (5%), amnesia (3%), dysgeusia (3%), balance disorder (2%), and sensory loss (2%). Neurologic disorders have included peripheral sensory neuropathy (13%), peripheral motor neuropathy (7%), peripheral neuropathy (5%), neuropathy (4%), demyelination, and ascending peripheral neuropathies similar in appearance to Guillain-Barre syndrome.

Other

There were four reported additional fatalities unrelated to treatment with nelarabine.

Other side effects have included reports of sometimes fatal opportunistic infections in patients receiving nelarabine. A fatal case of cerebral hemorrhage/coma/leukoencephalopathy which was thought to be related to treatment with nelarabine has also been reported.

Gastrointestinal

Gastrointestinal side effects including nausea (41%), diarrhea (22%), vomiting (22%), constipation (21%), abdominal pain (9%), anorexia (9%), stomatitis (8%), and abdominal distention (6%) have been reported.

General

General side effects including fatigue (50%), pyrexia (23%), asthenia (17%), peripheral edema (15%), edema (11%), pain (11%), infection (9%), rigors (8%), dehydration (7%), abnormal gait (6%), chest pain (5%), and noncardiac chest pain (5%) have been reported.

Respiratory

Respiratory side effects including cough (25%), dyspnea (20%), pleural effusion (10%), epistaxis (8%), pneumonia (8%), exertional dyspnea (7%), sinusitis (7%), and wheezing (5%) have been reported.

Hepatic

Hepatic side effects including increased AST (6%) have been reported.

Metabolic

Metabolic side effects including hyperglycemia (6%) and tumor lysis syndrome have been reported.

Musculoskeletal

Musculoskeletal side effects including myalgia (13%), arthralgia (9%), back pain (8%), muscular weakness (8%), and pain in extremity (7%) have been reported.

Psychiatric

Psychiatric side effects including confusional state (8%), insomnia (7%), and depression (6%) have been reported.

Cardiovascular

Cardiovascular side effects including sinus tachycardia (8%) and hypotension (8%) have been reported.

Dermatologic

Dermatologic side effects including petechiae (12%) have been reported.

Ocular

Ocular side effects including blurred vision (4%) has been reported.

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