Arranon

SIDE EFFECTS

The following clinically-significant adverse reactions are discussed in greater detail in other sections of the label:

• Neurologic [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Hematologic [see WARNINGS AND PRECAUTIONS]
• Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
• Effects on Ability to Drive and Use Machines [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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Relapsed Or Refractory T-ALL And T-LBL

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

Adult Patient

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-ALL/T-cell T-LBL trial and an adult chronic lymphocytic leukemia trial.

The most common adverse reactions in adults were fatigue; gastrointestinal 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 Body System, including severe or life-threatening adverse reactions (NCI CTCAE 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 in Adult Patients Treated With 1500 mg/m² of ARRANON Administered Intravenously Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days

Other Adverse Reactions

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, 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 including all grades (NCI CTCAE) are shown in Table 2.

Table 2: Neurologic Adverse Reactions (≥ 2%) in Adult Patients Treated With 1500 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, were aphasia, convulsion, hemiparesis, and loss of consciousness, each reported in 1 patient (1%). The additional Grade 4 adverse reactions were cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy, each reported in one patient (1%).

The other neurologic adverse reactions 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%).

Pediatric Patient

The safety profile for children is based on data from 84 pediatric patients treated with the recommended dose and schedule in a T-ALL/T-LBL treatment trial.

The most common adverse reactions in pediatric patients 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 including severe or life threatening adverse reactions (NCI CTCAE 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 in Pediatric Patients Treated With 650 mg/m² of ARRANON Administered Intravenously Over 1 Hour Daily for 5 Consecutive DaysRepeated Every 21 Days

Neurologic Adverse Reactions

Nervous system adverse reactions 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 including all grades (NCI CTCAE) are shown in Table 4.

Table 4: Neurologic Adverse Reactions (≥ 2%) 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 was hypertonia reported in 1 patient (1%). The additional Grade 4 neurologic adverse reactions, were third nerve paralysis, and sixth nerve paralysis, each reported in 1 patient (1%).

The other neurologic adverse reactions 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%).

ARRANON In Combination With Multi-Agent Chemotherapy In T-ALL And T-LBL

ARRANON was studied in combination with multi-agent chemotherapy in a randomized clinical trial [NCT00408005]. The safety population in this trial included 804 patients with newly-diagnosed T-ALL (85%) or T-LBL (15%) treated with (n = 411) or without (n =393) ARRANON in combination with the augmented Berlin-Frankfurt-Munster chemotherapy regimen (aBFM) after initial induction therapy. Patients assigned to ARRANON received 650 mg/m² intravenously over 1 hour daily for 5 consecutive days, during consolidation Days 1 to 5 and 43 to 47, delayed intensification Days 29 to 33, and during the initial 3 courses of maintenance Days 29 to 33. The median age on enrollment was 9.5 years (range: 1-29), the majority of patients were male (73%) and white (69%). Sixty-five percent of patients assigned to the ARRANON arms received at least 85% of the planned dose through the third course of maintenance therapy compared to 79% of patients on the control arms who received 3 courses of maintenance therapy.

There was one fatal neurological adverse reaction in the ARRANON arm. The incidence of the following Grades 3 and 4 adverse reactions were higher in the ARRANON treated arms compared to the control arms: abnormal transaminases, motor and sensory neuropathy, nausea and vomiting, and dehydration. The incidence of seizures of any grade was 3% (14 of 411). Rhabdomyolysis was diagnosed in 2% (7 of 411) of ARRANON treated patients and occurred after the first course of ARRANON during the consolidation phase of therapy.

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

Read the entire FDA prescribing information for Arranon (Nelarabine)