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adverse reactions
6 ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: Severe Neutropenia [ see Warnings and Precautions (5.1) and Boxed Warning ] Severe Diarrhea [see Warnings and Precautions (5.2) and Boxed Warning ] Interstitial Lung Disease [see Warnings and Precautions (5.3) ] Severe Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] The most common adverse reactions (≥ 20%) of ONIVYDE: diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common laboratory abnormalities (≥ 10% Grade 3 or 4) were lymphopenia and neutropenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Merrimack Pharmaceuticals, Inc. at 1-844-441-6225 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of ONIVYDE cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. The safety data described below are derived from patients with metastatic adenocarcinoma of the pancreas previously treated with gemcitabine-based therapy who received any part of protocol-specified therapy in Study 1, an international, randomized, active-controlled, open-label trial. Protocol-specified therapy consisted of ONIVYDE 70 mg/m 2 with leucovorin 400 mg/m 2 and fluorouracil 2400 mg/m 2 over 46 hours every 2 weeks (ONIVYDE/5-FU/LV; N=117), ONIVYDE 100 mg/m 2 every 3 weeks (N=147), or leucovorin 200 mg/m 2 and fluorouracil 2000 mg/m 2 over 24 hours weekly for 4 weeks followed by 2 week rest (5-FU/LV; N=134) [see Clinical Studies (14) ]. Serum bilirubin within the institutional normal range, albumin ≥ 3 g/dL, and Karnofsky Performance Status (KPS) ≥ 70 were required for study entry. The median duration of exposure was 9 weeks in the ONIVYDE/5-FU/LV arm, 9 weeks in the ONIVYDE monotherapy arm, and 6 weeks in the 5-FU/LV arm. The most common adverse reactions (≥ 20%) of ONIVYDE were diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common, severe laboratory abnormalities (≥ 10% Grade 3 or 4) were lymphopenia and neutropenia. The most common serious adverse reactions (≥ 2%) of ONIVYDE were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia. Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions resulting in discontinuation of ONIVYDE were diarrhea, vomiting, and sepsis. Dose reductions of ONIVYDE for adverse reactions occurred in 33% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia. ONIVYDE was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia. Table 2 provides the frequency and severity of adverse reactions in Study 1 that occurred with higher incidence (≥5% difference for Grades 1-4 or ≥2% difference for Grades 3-4) in patients who received ONIVYDE/5-FU/LV compared to patients who received 5-FU/LV. Table 2: Adverse Reactions with Higher Incidence (≥5% Difference for Grades 1-4 * or ≥2% Difference for Grades 3 and 4) in the ONIVYDE/5-FU/LV Arm Adverse Reaction ONIVYDE / 5-FU/LV N=117 5-FU/LV N=134 Grades 1-4 (%) Grades 3 - 4 (%) Grades 1-4 (%) Grades 3 - 4 (%) Gastrointestinal disorders Diarrhea 59 13 26 4 Early diarrhea † 30 3 15 0 Late diarrhea ‡ 43 9 17 4 Vomiting 52 11 26 3 Nausea 51 8 34 4 Stomatitis § 32 4 12 1 Infections and infestations 38 17 15 10 Sepsis 4 3 2 1 Neutropenic fever/neutropenic sepsis ♠ 3 3 1 0 Gastroenteritis 3 3 0 0 Intravenous catheter-related infection 3 3 0 0 General disorders and administration site conditions Fatigue/asthenia 56 21 43 10 Pyrexia 23 2 11 1 Metabolism and nutrition disorders Decreased appetite 44 4 32 2 Weight loss 17 2 7 0 Dehydration 8 4 7 2 Skin and subcutaneous tissue disorders Alopecia 14 1 5 0 * NCI CTCAE v4.0 † Early diarrhea: onset within 24 hours of ONIVYDE administration ‡ Late diarrhea: onset >1 day after ONIVYDE administration § Includes stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation. ♠ Includes febrile neutropenia Cholinergic Reaction s : ONIVYDE can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early onset diarrhea . In Study 1, Grade 1 or 2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients. Six of these 12 patients received atropine and in 1 of the 6 patients, atropine was administered for cholinergic symptoms other than diarrhea. Infusion Reaction s : Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of ONIVYDE administration were reported in 3% of patients receiving ONIVYDE or ONIVYDE/5-FU/LV. Laboratory abnormalities that occurred with higher incidence in the ONIVYDE/5-FU/LV arm compared to the 5-FU/LV arm (≥5% difference) are summarized in the following table. Table 3: Laboratory Abnormalities with Higher Incidence (≥5% Difference) in the ONIVYDE/5-FU/LV Arm * # Laboratory abnormality ONIVYDE /5-FU/LV N=117 5-FU/LV N=134 Grades 1-4 (%) Grades 3 - 4 (%) Grades 1-4 (%) Grades 3 - 4 (%) Hematology Anemia 97 6 86 5 Lymphopenia 81 27 75 17 Neutropenia 52 20 6 2 Thrombocytopenia 41 2 33 0 Hepatic Increased alanine aminotransferase (ALT) 51 6 37 1 Hypoalbuminemia 43 2 30 0 Metabolic Hypomagnesemia 35 0 21 0 Hypokalemia 32 2 19 2 Hypocalcemia 32 1 20 0 Hypophosphatemia 29 4 18 1 Hyponatremia 27 5 12 3 Renal Increased creatinine 18 0 13 0 * NCI CTCAE v4.0, worst grade shown. # Percent based on number of patients with a baseline and at least one post-baseline measurement.