ADVERSE REACTIONS
ARRANON was studied in 459 patients in Phase I and Phase II clinical trials. The safety profile for the recommended dosages of ARRANON is based on data from 103 adult patients enrolled and treated in the CALGB 19801 and an adult chronic lymphocytic leukemia study (PGAA2003) who were treated with the recommended dose and schedule. The safety profile for children is based on data from 84 pediatric patients enrolled and treated in the COG P9673 study who were treated with the recommended dose and schedule.
The most common adverse events in pediatric patients, regardless of causality, were hematologic disorders (anemia, leukopenia, neutropenia, and thrombocytopenia). Of the non-hematologic adverse events in pediatric patients, the most frequent events reported were headache, increased transaminase levels, decreased blood potassium, decreased blood albumin, increased blood bilirubin, and vomiting.
The most common adverse events 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 events by System Organ Class, regardless of causality, including severe or life threatening events (NCI Common Toxicity Criteria grade 3 or grade 4) and fatal events (grade 5) are shown in Table 4 for pediatric patients and Table 5 for adult patients.
Table 4. Most Commonly Reported (≥5% Overall) Adverse Events 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: 650 mg/m 2 ; N = 84
|
Toxicity Grade
|
Grade 3
%
|
Grade 4+
%
|
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 (see Table 6)
|
Gastrointestinal Disorders
|
Vomiting
|
0
|
0
|
10
|
General Disorders & Administration Site Conditions
|
Asthenia
|
1
|
0
|
6
|
Infections& Infestations
|
Infection
|
2
|
1
|
5
|
Grade 4+ = Grade 4 and Grade 5
Three (3) patients had a fatal event. Fatal events included neutropenia and pyrexia (n = 1), status epilepticus/seizure (n = 1), and fungal pneumonia (n = 1). The status epilepticus was thought to be related to treatment with ARRANON. All other fatal events were unrelated to treatment with ARRANON.
Table 5. Most Commonly Reported (≥5% Overall) Adverse Events 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+
%
|
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 (see Table 7)
|
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
|
Grade 4+ = Grade 4 and Grade 5
Five (5) patients had a fatal event. Fatal events included hypotension (n = 1), respiratory arrest (n = 1), pleural effusion/pneumothorax (n = 1), pneumonia (n = 1), and cerebral hemorrhage/coma/leukoencephalopathy (n = 1). The cerebral hemorrhage/coma/leukoencephalopathy was thought to be related to treatment with ARRANON. All other fatal events were unrelated to treatment with ARRANON.
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.
There have been reports of sometimes fatal opportunistic infections in patients receiving ARRANON.
Neurologic Adverse Events
Nervous system events, regardless of drug relationship, were reported for 64% of patients across the Phase I and Phase II studies.
Pediatric
The most common neurologic adverse events (≥2%), regardless of causality, including all grades (NCI Common Toxicity Criteria) are shown in Table 6 for pediatric patients.
Table 6. Neurologic Adverse Events (≥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+
%
|
All Grades
%
|
Headache
|
8
|
2
|
4
|
2
|
17
|
Peripheral neurologic disorders, any event
|
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
|
Grade 4+ = Grade 4 and Grade 5
One (1) patient had a fatal neurologic event, status epilepticus. This event was thought to be related to treatment with ARRANON.
The other grade 3 event in pediatric patients, regardless of causality, was hypertonia reported in 1 patient (1%). The additional grade 4+ events, regardless of causality, were 3rd nerve paralysis, and 6th nerve paralysis, each reported in 1 patient (1%).
The other neurologic adverse events, 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%).
Adults
The most common neurologic adverse events (≥2%), regardless of causality, including all grades (NCI Common Toxicity Criteria) are shown in Table 7 for adult patients.
Table 7. Neurologic Adverse Events (≥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 event
|
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 (1) patient had a fatal neurologic event, cerebral hemorrhage/coma/leukoencephalopathy. This event was thought to be related to treatment with ARRANON.
Most nervous system events in the adult patients were evaluated as grade 1 or 2. The additional grade 3 events in adult patients, regardless of causality, were aphasia, convulsion, hemiparesis, and loss of consciousness, each reported in 1 patient (1%). The additional grade 4 events, regardless of causality, were cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy, each reported in one patient (1%).
The other neurologic adverse events, 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%).
Other Neurologic Events
There have also been reports of events associated with demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.
Adverse Reactions from Other Clinical Programs
In addition to the safety data from the pivotal clinical trials, tumor lysis syndrome has been observed (see PRECAUTIONS, General).
|
REPORTS OF SUSPECTED ARRANON SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Arranon. The information is not vetted and should not be considered as verified clinical evidence.
Possible Arranon side effects / adverse reactions in 16 year old male
Reported by a physician from Japan on 2011-12-14
Patient: 16 year old male
Reactions: Muscle Atrophy, Dyspnoea, Monoplegia, Muscular Weakness, Decreased Vibratory Sense, Hypoaesthesia, Fall, Nerve Conduction Studies Abnormal, Respiratory Arrest, Areflexia, Nervous System Disorder, Nuclear Magnetic Resonance Imaging Abnormal
Suspect drug(s):
Arranon
Indication: T-Cell Type Acute Leukaemia
Cyclophosphamide
Indication: T-Cell Type Acute Leukaemia
Bortezomib
Indication: T-Cell Type Acute Leukaemia
Other drugs received by patient: Fentanyl; Fludarabine Phosphate; Cytarabine; Melphalan Hydrochloride
Possible Arranon side effects / adverse reactions in 16 year old male
Reported by a physician from Japan on 2011-12-28
Patient: 16 year old male
Reactions: Dyspnoea, Monoplegia, Muscle Atrophy, Muscular Weakness, Decreased Vibratory Sense, Hypoaesthesia, Fall, Nerve Conduction Studies Abnormal, Areflexia, Respiratory Arrest, Nuclear Magnetic Resonance Imaging Abnormal, Nervous System Disorder
Suspect drug(s):
Arranon
Indication: T-Cell Type Acute Leukaemia
Cyclophosphamide
Indication: T-Cell Type Acute Leukaemia
Bortezomib
Indication: T-Cell Type Acute Leukaemia
Other drugs received by patient: Cytarabine; Fentanyl; Fludarabine Phosphate; Melphalan Hydrochloride
Possible Arranon side effects / adverse reactions in 69 year old male
Reported by a physician from United States on 2012-07-03
Patient: 69 year old male weighing 80.0 kg (176.0 pounds)
Reactions: Neuropathy Peripheral, Disease Progression
Suspect drug(s):
Arranon
Other drugs received by patient: Hydrodiuril; Finasteride; Zyloprim; Xanax; Altace
|