2 Clinical Trial Adverse Reactions]. Serious Adverse Events Forty-four percent of patients (n = 49) experienced a serious adverse event while on study or within 30 days after their last dose of FOLOTYN® in the PROPEL study. The most common serious adverse events (≥3%), were pyrexia (7%), febrile neutropenia (5%), sepsis (5%), dehydration (4%), dyspnea (4%), mucosal inflammation (4%), herpes zoster (3%), neutropenia (3%), pneumonia (3%), and thrombocytopenia (3%).
NNOOCC//cc FOLOTYN® (pralatrexate injection) Product Monograph Page 13 of 35 One death from cardiopulmonary arrest in a patient with mucositis and febrile neutropenia was reported in this trial. 2% of patients treated on all FOLOTYN® trials at doses ranging from 30 to 325 mg/m2.
Discontinuations Twenty-three percent of patients (n = 25) in the PROPEL study discontinued treatment with FOLOTYN® due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment were mucosal inflammation (6%, n = 7) and thrombocytopenia (5%, n = 5).
Dose Modifications The target dose of FOLOTYN® was 30 mg/m2 once weekly for 6 weeks in 7-week cycles. Sixty- nine percent (69%, n = 77) of patients in the PROPEL study remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered.
A total of 76 (38%) patients required at least one dose omission mainly due to mucosal inflammation (n = 46; 41%), thrombocytopenia (n = 28; 25%) and neutropenia (n = 14; 13%). Thirty five (32%) patients required a dose reduction; the most common cause was mucosal inflammation (n = 25; 23%).
Other reasons for dose reduction occurring in 2 or more patients were liver function abnormality, thrombocytopenia and fatigue (each n = 2; 2%). 2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.
Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The safety of FOLOTYN® was evaluated in an open-label, single-arm, multi-center, international trial in 111 patients with relapsed or refractory peripheral T-cell lymphoma.
Patients received a starting dose of 30 mg/m2 once weekly for 6 weeks in 7-week cycles [see Clinical Trials]. The median duration of treatment was 70 days (range 1-540 days). Table 5 - Adverse Events Occurring in ≥10% of Patients in pivotal study PROPEL Adverse Events PROPEL Study (n = 111) Total n (%) Grade 3 n (%) Grade 4 n (%) Any Adverse Events 111 (100) 48 (43) 34 (31) Blood and Lymphatic System Disorders Thrombocytopenia* 45 (41) 15 (14) 21 (19) Anaemia* 38 (34) 17 (15) 2 (2) Neutropenia* 27 (24) 14 (13) 8 (7) Leucopenia* 12 (11) 3 (3) 4 (4) Cardiac Disorders Tachycardia 11 (10) 0 (0) 0 (0) FOLOTYN® (pralatrexate injection) Product Monograph Page 14 of 35 Table 5 - Adverse Events Occurring in ≥10% of Patients in pivotal study PROPEL Adverse Events PROPEL Study (n = 111) Total n (%) Grade 3 n (%) Grade 4 n (%) Gastrointestinal Disorders Nausea 44 (40) 4 (4) 0 (0) Constipation 37 (33) 0 (0) 0 (0) Vomiting 28 (25) 2 (2) 0 (0) Diarrhea 23 (21) 2 (2) 0 (0) Abdominal Pain 13 (12) 4 (4) 0 (0) General Disorders Mucosal Inflammation* 78 (70) 19 (17) 4 (4) Fatigue 40 (36) 5 (5) 2 (2) Pyrexia 36 (32) 1 (1) 1 (1) Oedema* 33 (30) 1 (1) 0 (0) Asthenia 11 (10) 1 (1) 0 (0) Infections and Infestations Upper Respiratory Tract Infection 11 (10) 1 (1) 0 (0) Investigations Liver Function Test Abnormal* 14 (13) 6 (5) 0 (0) Metabolism and Nutrition Disorders Anorexia* 17 (15) 3 (3) 0 (0) Hypokalaemia* 17 (15) 4 (4) 1 (1) Musculoskeletal and Connective Tissue Disorders Pain in Extremities 13 (12) 0 (0) 0 (0) Back Pain 12 (11) 3 (3) 0 (0) Respiratory, Thoracic and Mediastinal Disorders Cough 31 (28) 1 (1) 0 (0) Epistaxis 29 (26) 0 (0) 0 (0) Dyspnoea 21 (19) 8 (7) 0 (0) Pharyngolaryngeal Pain 15 (14) 1 (1) 0 (0) Skin and Subcutaneous Disorders Rash 17 (15) 0 (0) 0 (0) Pruritus* 16 (14) 2 (2) 0 (0) Night Sweats 12 (11) 0 (0) 0 (0) *Grouped preferred terms for the following: Thrombocytopenia (including Platelet Count Decreased) Anaemia (including Haemoglobin Decreased) Oedema (including Oedema Peripheral and Pitting Oedema) FOLOTYN® (pralatrexate injection) Product Monograph Page 15 of 35 Neutropenia (including Neutrophil Count Deceased) Anorexia (including Decreased Appetite) Hypokalaemia (including Blood Potassium Decreased) Pruritus (including Pruritus Generalised) Liver Function Test Abnormal (including Alanine Aminotransferase Increased, Alanine Aminotransferase, Aspartate Aminotransferase Increased, Aspartate Aminotransferase and Transaminases Increased) Leucopenia (including White Blood Cell Count Decreased) Mucosal Inflammation (including Stomatitis Anal Inflammation, Vaginal Inflammation, Rectal Mucositis, Oesophagitis, Mouth Ulceration, Oral Mucosal Erythema, Pharyngeal Inflammation and Pharyngitis) Description of selected Adverse Events in the pivotal PROPEL study Mucosal Inflammation Under the grouped term of mucosal inflammation, 78 patients (70%) had an event, which was the most frequently occurring AE when analyzed by grouping similar preferred terms.
The median time to onset for ≥ Grade 3 […]