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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Infections: Monitor patients for signs and symptoms of infection. Withhold treatment for Grade 3 and higher infections until resolution ( 5.1 ). • Hyperglycemia: Start each infusion once optimal blood glucose control is achieved. Withhold treatment, reduce dose, or discontinue treatment depending on the severity and persistence of hyperglycemia ( 5.2 ). • Hypertension: Withhold treatment in patients until both the systolic blood pressure (BP) is less than 150 mmHg and the diastolic BP is less than 90 mmHg. Consider reducing dose if anti-hypertensive treatment is required. Discontinue in patients with BP that is uncontrolled or with life-threatening consequences ( 5.3 ). • Non-infectious pneumonitis (NIP): Treat NIP and reduce dose. Discontinue treatment if Grade 2 NIP recurs or in patients experiencing Grade 3 or higher NIP ( 5.4 ). • Neutropenia: Monitor blood counts at least weekly while under treatment. Withhold treatment until ANC ≥0.5 x 10 3 cells/mm 3 ( 5.5 ). • Severe Cutaneous Reactions: Withhold treatment, reduce dose, or discontinue treatment depending on the severity and persistence of severe cutaneous reactions ( 5.6 ). • Embryo-Fetal Toxicity: ALIQOPA can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception ( 5.7 , 8.1 , 8.3 ). 5.1 Infections Serious, including fatal, infections occurred in 19% of 317 patients treated with ALIQOPA monotherapy. The most common serious infection was pneumonia [see Adverse Reactions ( 6.1 )] . Monitor patients for signs and symptoms of infection and withhold ALIQOPA for Grade 3 and higher infection [see Dosage and Administration ( 2.4 )] . Serious pneumocystis jiroveci pneumonia (PJP) occurred in 0.6% of 317 patients treated with ALIQOPA monotherapy [see Adverse Reactions ( 6.1 )]. Before initiating treatment with ALIQOPA, consider PJP prophylaxis for populations at risk. Withhold ALIQOPA in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis [see Dosage and Administration ( 2.4 )] . Grade 1 or 2 cytomegalovirus (CMV) reactivation or infection has occurred in 0.97% of patients treated with ALIQOPA monotherapy. Monitor for CMV infection during treatment with ALIQOPA in patients with a history of CMV infection. For clinical CMV infection or viremia, withhold ALIQOPA until infection or viremia resolves. If ALIQOPA is resumed, administer at the previous dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly [see Dosage and Administration ( 2.4 )]. 5.2 Hyperglycemia Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with ALIQOPA monotherapy [see Adverse Reactions ( 6.1 )] . Serious hyperglycemic events occurred in 2.8% of patients. Treatment with ALIQOPA may result in infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours post-infusion and subsequently declined to baseline levels for a majority of patients; blood glucose levels remained elevated in 17.7% of patients one day after ALIQOPA infusion. Of 155 patients with baseline HbA1c <5.7%, 16 (10%) patients had HbA1c >6.5% at the end of treatment. Of the twenty patients with diabetes mellitus treated in CHRONOS-1, seven developed Grade 4 hyperglycemia and two discontinued treatment. Patients with diabetes mellitus should only be treated with ALIQOPA following adequate glucose control and should be monitored closely. Achieve optimal blood glucose control before starting each ALIQOPA infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hyperglycemia [see Dosage and Administration ( 2.4 )] . 5.3 Hypertension Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with ALIQOPA monotherapy [see Adverse Reactions ( 6.1 )] . Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with ALIQOPA may result in infusion-related hypertension. The mean change of systolic and diastolic BP from baseline to 2 hours post-infusion on Cycle 1 Day 1 was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately 2 hours post-infusion; BP remained elevated for 6 to 8 hours after the start of the ALIQOPA infusion. Optimal BP control should be achieved before starting each ALIQOPA infusion. Monitor BP pre- and post-infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hypertension [see Dosage and Administration ( 2.4 )] . 5.4 Non-Infectious Pneumonitis Non-infectious pneumonitis occurred in 5% of 317 patients treated with ALIQOPA monotherapy [see Adverse Reactions ( 6.1 )]. Withhold ALIQOPA and conduct a diagnostic examination of a patient who is experiencing pulmonary symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. Patients with pneumonitis thought to be caused by ALIQOPA have been managed by withholding ALIQOPA and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of non-infectious pneumonitis [see Dosage and Administration ( 2.4 )] . 5.5 Neutropenia Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with ALIQOPA monotherapy. Serious neutropenic events occurred in 1.3% [see Adverse Reactions ( 6.1 )] . Monitor blood counts at least weekly during treatment with ALIQOPA. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of neutropenia [see Dosage and Administration ( 2.4 )] . 5.6 Severe Cutaneous Reactions Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with ALIQOPA monotherapy, respectively [see Adverse Reactions ( 6.1 )]. Serious cutaneous reaction events were reported in 0.9%. The reported events included dermatitis exfoliative, exfoliative rash, pruritus, and rash (including maculo-papular rash). Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of severe cutaneous reactions [see Dosage and Administration ( 2.4 )] . 5.7 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, ALIQOPA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis caused embryo-fetal death and fetal abnormalities in rats at maternal doses as low as 0.75 mg/kg/day (4.5 mg/m 2 /day body surface area) corresponding to approximately 12% the recommended dose for patients. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for one month after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )] .
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. • Infections [see Warnings and Precautions ( 5.1 )] • Hyperglycemia [see Warnings and Precautions ( 5.2 )] • Hypertension [see Warnings and Precautions ( 5.3 )] • Non-infectious pneumonitis [see Warnings and Precautions ( 5.4 )] • Neutropenia [see Warnings and Precautions ( 5.5 )] • Severe cutaneous reactions [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (≥20%) are hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, thrombocytopenia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Bayer Healthcare Pharmaceuticals Inc. at 1-888-842-2937 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 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 the general patient population. The safety data reflect exposure to ALIQOPA in 168 adults with follicular lymphoma and other hematologic malignancies treated with ALIQOPA 60 mg or 0.8 mg/kg equivalent in clinical trials. The median duration of treatment was 22 weeks (range 1 to 206 weeks). Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). The most common adverse reactions (≥20%) were hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and thrombocytopenia. Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most common reasons for dose reduction were hyperglycemia (7%), neutropenia (5%), and hypertension (5%). The most common reasons for drug discontinuation were pneumonitis (2%) and hyperglycemia (2%). Table 2 provides the adverse reactions occurring in at least 10% of patients receiving ALIQOPA monotherapy, and Table 3 provides the treatment-emergent laboratory abnormalities in ≥20% of patients and ≥4% of Grade ≥3 treated with ALIQOPA. Table 2: Adverse Reactions Reported in ≥10% of Patients with Follicular Lymphoma and Other Hematological Malignancies Treated with ALIQOPA ADVERSE REACTIONS ALIQOPA N = 168 Any Grade n (%) Grade 3 n (%) Grade 4 n (%) Metabolism and nutrition disorders Hyperglycemia 90 (54%) 56 (33%) 10 (6%) Blood and lymphatic system disorders Leukopenia 61 (36%) 20 (12%) 26 (15%) Neutropenia (including febrile neutropenia) 53 (32%) 16 (10%) 26 (15%) Thrombocytopenia 37 (22%) 12 (7%) 2 (1%) General disorders and administration site conditions Decreased general strength and energy (includes fatigue and asthenia) 61 (36%) 6 (4%) 0 Gastrointestinal disorders Diarrhea 60 (36%) 8 (5%) 0 Nausea 43 (26%) 1 (<1%) 0 Stomatitis (includes oropharyngeal erosion and ulcer, oral pain) 24 (14%) 3 (2%) 0 Vomiting 21 (13%) 0 0 Vascular disorders Hypertension (includes secondary hypertension) 59 (35%) 46 (27%) 0 Infections Lower respiratory tract infections (includes pneumonia, pneumonia bacterial, pneumonia pneumococcal, pneumonia fungal, pneumonia viral, pneumocystis jiroveci pneumonia, bronchopulmonary aspergillosis and lung infection) 35 (21%) 20 (12%) 3 (2%) Skin and subcutaneous tissue disorders Rash (includes exfoliative skin reactions) 26 (15%) 2 (1%) 1 (<1%) Additional adverse drug reactions reported at a frequency of <10% in patients with follicular lymphoma and other hematologic malignancies include pneumonitis (9%), mucosal inflammation (8%), and paresthesia and dysesthesia (7%). Table 3: Treatment-emergent Laboratory Abnormalities in ≥20% of Patients and ≥4% of Grade ≥3 Treated with ALIQOPA Laboratory Parameter ALIQOPA N = 168* Any Grade** n (%) Grade 3** n (%) Grade 4** n (%) Hematology abnormalities Decreased hemoglobin 130 (78%) 7 (4%) 0 Lymphocyte count decreased 126 (78%) 43 (27%) 4 (2%) White blood cell decreased 118 (71%) 30 (18%) 3 (2%) Platelet count decreased 109 (65%) 11 (7%) 3 (2%) Neutrophil count decreased 104 (63%) 20 (12%) 25 (15%) Serum chemistry abnormalities Hyperglycemia 160 (95%) 72 (43%) 9 (5%) Hypertriglyceridemia 74 (58%) 6 (5%) 0 Hypophosphatemia 72 (44%) 24 (15%) 0 Hyperuricemia 42 (25%) 40 (24%) 2 (1%) Serum lipase increased 34 (21%) 11 (7%) 2 (1%) *Denominator for each laboratory parameter may vary based on number of patients with specific numeric laboratory values available. **NCI-CTCAE v4.03