ALIQOPA

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

4 CONTRAINDICATIONS None. None ( 4 ).

11 DESCRIPTION ALIQOPA (copanlisib) is a kinase inhibitor for intravenous infusion. The active pharmaceutical ingredient is copanlisib dihydrochloride which exists as a non-stoichiometric hydrate and has the molecular formula of C 23 H 28 N 8 O 4 2HCl and a molecular weight of 553.45 g/mol. The molecular formula and molecular weight are based on the anhydrous form. The chemical name is 2-amino-N-{7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide dihydrochloride. Copanlisib dihydrochloride has the following structural formula: ALIQOPA is supplied in single-dose vials as a sterile lyophilized solid for reconstitution and further dilution for intravenous infusion. The product is white to slightly yellowish. After reconstitution, the solution is colorless to slightly yellowish. Each vial contains 60 mg copanlisib free base (equivalent to 69.1 mg copanlisib dihydrochloride). After reconstitution, each mL contains 15 mg copanlisib free base (equivalent to 17.3 mg copanlisib dihydrochloride). Inactive ingredients: Each vial contains 5.8 mg citric acid anhydrous (might increase to 6.1 mg in case pH correction is necessary), 120 mg mannitol (bulking agent). Citric acid anhydrous acts as a buffering agent and may be used together with sodium hydroxide for pH adjustment. Chem structure

2 DOSAGE AND ADMINISTRATION • Recommended dosage: 60 mg administered as a 1-hour intravenous infusion on Days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Modify dosage for toxicity ( 2.1 , 2.4 ). • Reduce ALIQOPA dose to 45 mg in patients with moderate hepatic impairment (Child-Pugh B) or to 30 mg in patients with severe hepatic impairment (Child-Pugh C) ( 2.2 , 8.6 ). • See full prescribing information for important preparation and administration information ( 2.5 , 2.6 , 2.7 ). 2.1 Recommended Dosage The recommended dose of ALIQOPA is 60 mg administered as a 1-hour intravenous infusion on Days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Continue treatment until disease progression or unacceptable toxicity [see Warnings and Precautions ( 5 )] . 2.2 Dose Modification for Moderate or Severe Hepatic Impairment Reduce ALIQOPA dose to 45 mg in patients with moderate hepatic impairment (Child-Pugh B). Reduce ALIQOPA dose to 30 mg in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations ( 8.6 )]. 2.3 Dose Modification for Use with Strong CYP3A Inhibitors Reduce ALIQOPA dose to 45 mg if a strong CYP3A inhibitor must be used. Concomitant use of ALIQOPA with strong CYP3A inhibitors increases copanlisib exposure (AUC) and may increase the risk for toxicity [see Drug Interactions ( 7.1 )] . 2.4 Dosage Modifications for Toxicities Manage toxicities per Table 1 with dose reduction, treatment delay, or discontinuation of ALIQOPA. Discontinue ALIQOPA if life-threatening ALIQOPA-related toxicity occurs. Table 1: Dosage Modification and Toxicity Management a Toxicities Adverse Reaction Grade b Recommended Management Infections [see Warnings and Precautions ( 5.1 )] Grade 3 or higher Withhold ALIQOPA until resolution. Suspected pneumocystis jiroveci pneumonia (PJP) infection of any grade Withhold ALIQOPA. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis. Hyperglycemia [see Warnings and Precautions ( 5.2 )] Pre-dose fasting blood glucose 160 mg/dL or more or random/non-fasting blood glucose of 200 mg/dL or more Withhold ALIQOPA until fasting glucose is 160 mg/dL or less, or a random/non-fasting blood glucose of 200 mg/dL or less. Pre-dose or post-dose blood glucose 500 mg/dL or more On first occurrence, withhold ALIQOPA until fasting blood glucose is 160 mg/dL or less, or a random/non-fasting blood glucose of 200 mg/dL or less. Then reduce ALIQOPA from 60 mg to 45 mg and maintain. On subsequent occurrences, withhold ALIQOPA until fasting blood glucose is 160 mg/dL or less, or a random/non-fasting blood glucose of 200 mg/dL or less. Then reduce ALIQOPA from 45 mg to 30 mg and maintain. If persistent at 30 mg, discontinue ALIQOPA. Hypertension [see Warnings and Precautions ( 5.3 )] Pre-dose blood pressure (BP) 150/90 or greater c Withhold ALIQOPA until BP is less than 150/90 based on two consecutive BP measurements at least 15 minutes apart. Post-dose BP 150/90 or greater c (non-life-threatening) If anti-hypertensive treatment is not required, continue ALIQOPA at previous dose. If anti-hypertensive treatment is required, consider reduction of ALIQOPA from 60 mg to 45 mg or from 45 mg to 30 mg. Discontinue ALIQOPA if BP remains uncontrolled (BP greater than 150/90) despite anti-hypertensive treatment Post-dose elevated BP with life-threatening consequences Discontinue ALIQOPA. Non-infectious pneumonitis (NIP) [see Warnings and Precautions ( 5.4 )] Grade 2 Withhold ALIQOPA and treat NIP. If NIP recovers to Grade 0 or 1, resume ALIQOPA at 45 mg. If Grade 2 NIP recurs, discontinue ALIQOPA. Grade 3 or higher Discontinue ALIQOPA. Neutropenia [see Warnings and Precautions ( 5.5 )] Absolute neutrophil count (ANC) 0.5 to 1.0 x 10 3 cells/mm 3 Maintain ALIQOPA dose. Monitor ANC at least weekly. ANC less than 0.5 x 10 3 cells/mm 3 Withhold ALIQOPA. Monitor ANC at least weekly until ANC 0.5 x 10 3 cells/mm 3 or greater, then resume ALIQOPA at previous dose. If ANC 0.5 x 10 3 cells/mm 3 or less recurs, then reduce ALIQOPA to 45 mg. Severe cutaneous reactions [see Warnings and Precautions ( 5.6 )] Grade 3 Withhold ALIQOPA until toxicity is resolved and reduce ALIQOPA from 60 mg to 45 mg or from 45 mg to 30 mg. Life-threatening Discontinue ALIQOPA. Thrombocytopenia [see Adverse Reactions ( 6.1 )] Less than 25 x 10 9 /L Withhold ALIQOPA; resume when platelet levels return to 75.0 x 10 9 /L or greater. If recovery occurs within 21 days, reduce ALIQOPA from 60 mg to 45 mg or from 45 mg to 30 mg. If recovery does not occur within 21 days, discontinue ALIQOPA. Other severe and non-life-threatening toxicities [see Adverse Reactions ( 6.1 )] Grade 3 Withhold ALIQOPA until toxicity is resolved and reduce ALIQOPA from 60 mg to 45 mg or from 45 mg to 30 mg. a Ensure a minimum of 7 days between any two consecutive infusions. b National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03. c Both systolic of less than 150 mmHg and diastolic of less than 90 mmHg are required. 2.5 Preparation and Administration For intravenous infusion only. Administer ALIQOPA as a single agent, following reconstitution and dilution. Mix only with sterile 0.9% Sodium Chloride Injection, USP solution. Do not mix or inject ALIQOPA with other drugs or other diluents. 2.6 Reconstitution Instructions Reconstitute ALIQOPA with 4.4 mL of sterile 0.9% Sodium Chloride Injection, USP solution leading to a concentration of 15 mg/mL. • Withdraw 4.4 mL of sterile 0.9% Sodium Chloride Injection, USP solution by using a 5 mL sterile syringe with needle. • Inject the measured volume through the disinfected stopper surface into the vial of ALIQOPA. • Dissolve the lyophilized solid by gently shaking the injection vial for 30 seconds. • Allow to stand for one minute to let bubbles rise to the surface. • Check if any undissolved substance is still seen. If yes, repeat the gentle shaking and settling procedure. • Inspect visually for discoloration and particulate matter. After reconstitution, the solution should be colorless to slightly yellowish. • Once the solution is free of visible particles, withdraw the reconstituted solution for further dilution. 2.7 Dilution Instructions for Intravenous Use Further dilute the reconstituted solution in 100 mL sterile 0.9% Sodium Chloride Injection, USP solution for injection. With a sterile syringe, withdraw the required amount of the reconstituted solution for the desired dosage: 60 mg: Withdraw 4 mL of the reconstituted solution with a sterile syringe. 45 mg: Withdraw 3 mL of the reconstituted solution with a sterile syringe. 30 mg: Withdraw 2 mL of the reconstituted solution with a sterile syringe. Inject the contents of the syringe into the patient infusion bag of 100 mL sterile 0.9% Sodium Chloride Injection, USP solution. Mix the dose well by inverting. Discard any unused reconstituted or diluted solution appropriately. Use reconstituted and diluted ALIQOPA immediately or store the reconstituted solution in the vial or diluted solution in the infusion bag at 2°C to 8°C (36°F to 46°F) for up to 24 hours before use. Allow the product to adapt to room temperature before use following refrigeration. Avoid exposure of the diluted solution to direct sunlight.

1 INDICATIONS AND USAGE ALIQOPA is indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. Accelerated approval was granted for this indication based on overall response rate [see Clinical Studies ( 14.1 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ALIQOPA is a kinase inhibitor indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies ( 1 ). Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

7 DRUG INTERACTIONS • CYP3A Inducers: Avoid concomitant use with strong CYP3A inducers ( 7.1 ). • CYP3A Inhibitors: Reduce the ALIQOPA dose to 45 mg when concomitantly administered with strong CYP3A inhibitors ( 7.1 ). 7.1 Effect of Other Drugs on Copanlisib Table 4 lists the potential effects of coadministration of ALIQOPA with strong CYP3A inhibitors and inducers. Table 4: Drug Interactions with ALIQOPA that affect Copanlisib Concentrations Strong CYP3A inducers Clinical impact • Concomitant use of ALIQOPA with strong CYP3A inducers may decrease copanlisib AUC and C max [see Clinical Pharmacology ( 12.3 )] . Prevention management • Avoid concomitant use of ALIQOPA with strong CYP3A inducers Strong CYP3A inhibitors Clinical impact • Concomitant use of ALIQOPA with strong CYP3A inhibitors increases the copanlisib AUC [see Clinical Pharmacology ( 12.3 )] . • An increase in the copanlisib AUC may increase the risk of adverse reactions Prevention management • If concomitant use with strong CYP3A inhibitors cannot be avoided, reduce the ALIQOPA dose to 45 mg [see Dosage and Administration ( 2.3 )]

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines. 12.2 Pharmacodynamics At 60 mg (or 0.8 mg/kg) of ALIQOPA dose, the elevation of plasma glucose was associated with higher copanlisib exposure. Cardiac Electrophysiology ALIQOPA does not cause a large mean increase in QTc interval > 20 milliseconds at the recommended dose. The effect of the recommended ALIQOPA dose of 60 mg on the QTc interval was evaluated in an open label, dedicated QT study of 25 patients with advanced cancer. A decrease in the change-from-baseline QTc (DQTc) was observed after the start of ALIQOPA administration, followed by an increase in DQTc between 12 and 24 hours post-treatment. The observed changes in DQTc are not likely due to direct inhibition of cardiac ion channels. 12.3 Pharmacokinetics The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) of ALIQOPA increase dose-proportionally over 5 to 93 mg (0.08 to 1.55 times the approved recommended dose) absolute dose range and exhibit linear pharmacokinetics (PK). There is no time-dependency and no accumulation in the PK of copanlisib. The geometric mean (range) steady state copanlisib exposure at 0.8 mg/kg (approximately the approved recommended dose of 60 mg) are 463 (range: 105 to 1670; SD: 584) ng/mL for C max and 1570 (range: 536 to 3410; SD: 338) ng.hr/mL for AUC 0-25h . Distribution The in vitro human plasma protein binding of copanlisib is 84.2%. Albumin is the main binding protein. The in vitro mean blood-to-plasma ratio is 1.7 (range: 1.5 to 2.1). The geometric mean volume of distribution is 871 (range: 423 to 2150; SD: 479) L. Elimination The geometric mean terminal elimination half-life of copanlisib is 39.1 (range: 14.6 to 82.4; SD: 15.0) hours. The geometric mean clearance is 17.9 (range: 7.3 to 51.4; SD: 8.5) L/hr. Metabolism Approximately >90% of copanlisib metabolism is mediated by CYP3A and <10% by CYP1A1. The M-1 metabolite accounts for 5% of total radioactivity AUC and its pharmacological activity is comparable to the parent compound copanlisib for the tested kinases PI3KαandPI3Kβ. Excretion Copanlisib is excreted approximately 50% as unchanged compound and 50% as metabolites in humans. Following a single intravenous dose of 12 mg (0.2 times the recommended approved dose) radiolabeled copanlisib, approximately 64% of the administered dose was recovered in feces and 22% in urine within 20 to 34 days. Unchanged copanlisib represented approximately 30% of the administered dose in feces and 15% in urine. Metabolites resulting from CYP450-mediated oxidation metabolism accounted for 41% of the administered dose. Specific Populations Age (20 to 90 years), gender, race (White, Asian, Hispanic, and Black), smoking status, body weight (41 to 130 kg), and mild, moderate, and severe renal impairment [CLcr ≥ 15 mL/min as estimated by Cockcroft-Gault (C-G) equation] had no clinically significant effect on the PK of copanlisib. The PK of copanlisib in patients with end stage renal disease (CLcr < 15 mL/min by C-G equation) with or without dialysis is unknown. Patients with Hepatic Impairment Based on a population PK analysis in patients with cancer, mild hepatic impairment [total bilirubin ≤ 1 x ULN and AST > ULN, or total bilirubin > 1-1.5 x ULN and any AST] had no clinically relevant effect on the PK of copanlisib. In a dedicated PK study evaluating a single intravenous dose of 12 mg (0.2 times the recommended approved dose of 60 mg) of ALIQOPA in subjects with hepatic impairment, the geometric mean of total copanlisib C max and AUC increased 1.38-fold and 1.71-fold, respectively, in subjects with moderate hepatic impairment (Child-Pugh B) and 1.44-fold and 2.71-fold, respectively, in patients with severe hepatic impairment (Child‑Pugh C) as compared to normal hepatic function. The geometric mean unbound AUC of copanlisib increased 1.23-fold and 3.77-fold in patients with moderate and severe hepatic impairment, respectively. The geometric mean unbound Cmax of copanlisib did not increase in patients with moderate hepatic impairment, but increased 1.92-fold in patients with severe hepatic impairment. Drug Interaction Studies Clinical Studies Effect of CYP3A and P-gp Inducers on Copanlisib Rifampin, a strong CYP3A and a P-glycoprotein (P-gp) transporter inducer, administered at a dose of 600 mg once daily for 12 days with a single intravenous dose of 60 mg ALIQOPA in patients with cancer resulted in a 60% decrease in the mean AUC and a 12% decrease in C max of copanlisib [see Drug Interactions ( 7.1 )] . Effect of CYP3A, P-gp and BCRP Inhibitors on Copanlisib Itraconazole, a strong CYP3A inhibitor and a P-gp and Breast Cancer Resistance Protein (BCRP) transporter inhibitor, administered at a dose of 200 mg once daily for 10 days increased the mean AUC of a single intravenous dose of 60 mg ALIQOPA by 53% (or 1.53-fold) with no effect on C max (1.03-fold) in patients with cancer [see Drug Interactions ( 7.1 )]. In Vitro Studies Effect of Transporters on Copanlisib: Copanlisib is a substrate of P-gp and BCRP, but not a substrate for organic cation transporter (OCT) 1, OCT2, and OCT3, organic anion transporter (OAT) 1 and OAT3, organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3, multidrug and toxin extrusion protein 1(MATE1) or MATE2-K. Effect of Copanlisib on CYP and non-CYP Enzymes Copanlisib is not an inhibitor of the metabolism of drugs that are substrates of the major CYP isoforms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) or uridine diphosphate-glucuronosyltransferase isoforms (UGT) or dihydropyrimidine dehydrogenase (DPD) at therapeutic 60 mg dose plasma concentrations. Copanlisib is not an inducer of CYP1A2, CYP2B6 and CYP3A. Effect of Copanlisib on Drug Transporter Substrates Copanlisib is not an inhibitor of P-gp, BCRP, multi-drug resistance-associated protein (MRP2), bile salt export pump (BSEP), OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, and MATE1 at therapeutic 60 mg dose plasma concentrations. Copanlisib is an inhibitor of MATE2-K (IC 50 : 0.09 μM). Inhibition may occur after copanlisib infusion at approved recommended dosage. The clinical significance of this potential inhibition on plasma concentrations of concomitantly administered drugs that are MATE2-K substrates is unknown.

12.1 Mechanism of Action Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.

12.2 Pharmacodynamics At 60 mg (or 0.8 mg/kg) of ALIQOPA dose, the elevation of plasma glucose was associated with higher copanlisib exposure. Cardiac Electrophysiology ALIQOPA does not cause a large mean increase in QTc interval > 20 milliseconds at the recommended dose. The effect of the recommended ALIQOPA dose of 60 mg on the QTc interval was evaluated in an open label, dedicated QT study of 25 patients with advanced cancer. A decrease in the change-from-baseline QTc (DQTc) was observed after the start of ALIQOPA administration, followed by an increase in DQTc between 12 and 24 hours post-treatment. The observed changes in DQTc are not likely due to direct inhibition of cardiac ion channels.

12.3 Pharmacokinetics The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) of ALIQOPA increase dose-proportionally over 5 to 93 mg (0.08 to 1.55 times the approved recommended dose) absolute dose range and exhibit linear pharmacokinetics (PK). There is no time-dependency and no accumulation in the PK of copanlisib. The geometric mean (range) steady state copanlisib exposure at 0.8 mg/kg (approximately the approved recommended dose of 60 mg) are 463 (range: 105 to 1670; SD: 584) ng/mL for C max and 1570 (range: 536 to 3410; SD: 338) ng.hr/mL for AUC 0-25h . Distribution The in vitro human plasma protein binding of copanlisib is 84.2%. Albumin is the main binding protein. The in vitro mean blood-to-plasma ratio is 1.7 (range: 1.5 to 2.1). The geometric mean volume of distribution is 871 (range: 423 to 2150; SD: 479) L. Elimination The geometric mean terminal elimination half-life of copanlisib is 39.1 (range: 14.6 to 82.4; SD: 15.0) hours. The geometric mean clearance is 17.9 (range: 7.3 to 51.4; SD: 8.5) L/hr. Metabolism Approximately >90% of copanlisib metabolism is mediated by CYP3A and <10% by CYP1A1. The M-1 metabolite accounts for 5% of total radioactivity AUC and its pharmacological activity is comparable to the parent compound copanlisib for the tested kinases PI3KαandPI3Kβ. Excretion Copanlisib is excreted approximately 50% as unchanged compound and 50% as metabolites in humans. Following a single intravenous dose of 12 mg (0.2 times the recommended approved dose) radiolabeled copanlisib, approximately 64% of the administered dose was recovered in feces and 22% in urine within 20 to 34 days. Unchanged copanlisib represented approximately 30% of the administered dose in feces and 15% in urine. Metabolites resulting from CYP450-mediated oxidation metabolism accounted for 41% of the administered dose. Specific Populations Age (20 to 90 years), gender, race (White, Asian, Hispanic, and Black), smoking status, body weight (41 to 130 kg), and mild, moderate, and severe renal impairment [CLcr ≥ 15 mL/min as estimated by Cockcroft-Gault (C-G) equation] had no clinically significant effect on the PK of copanlisib. The PK of copanlisib in patients with end stage renal disease (CLcr < 15 mL/min by C-G equation) with or without dialysis is unknown. Patients with Hepatic Impairment Based on a population PK analysis in patients with cancer, mild hepatic impairment [total bilirubin ≤ 1 x ULN and AST > ULN, or total bilirubin > 1-1.5 x ULN and any AST] had no clinically relevant effect on the PK of copanlisib. In a dedicated PK study evaluating a single intravenous dose of 12 mg (0.2 times the recommended approved dose of 60 mg) of ALIQOPA in subjects with hepatic impairment, the geometric mean of total copanlisib C max and AUC increased 1.38-fold and 1.71-fold, respectively, in subjects with moderate hepatic impairment (Child-Pugh B) and 1.44-fold and 2.71-fold, respectively, in patients with severe hepatic impairment (Child‑Pugh C) as compared to normal hepatic function. The geometric mean unbound AUC of copanlisib increased 1.23-fold and 3.77-fold in patients with moderate and severe hepatic impairment, respectively. The geometric mean unbound Cmax of copanlisib did not increase in patients with moderate hepatic impairment, but increased 1.92-fold in patients with severe hepatic impairment. Drug Interaction Studies Clinical Studies Effect of CYP3A and P-gp Inducers on Copanlisib Rifampin, a strong CYP3A and a P-glycoprotein (P-gp) transporter inducer, administered at a dose of 600 mg once daily for 12 days with a single intravenous dose of 60 mg ALIQOPA in patients with cancer resulted in a 60% decrease in the mean AUC and a 12% decrease in C max of copanlisib [see Drug Interactions ( 7.1 )] . Effect of CYP3A, P-gp and BCRP Inhibitors on Copanlisib Itraconazole, a strong CYP3A inhibitor and a P-gp and Breast Cancer Resistance Protein (BCRP) transporter inhibitor, administered at a dose of 200 mg once daily for 10 days increased the mean AUC of a single intravenous dose of 60 mg ALIQOPA by 53% (or 1.53-fold) with no effect on C max (1.03-fold) in patients with cancer [see Drug Interactions ( 7.1 )]. In Vitro Studies Effect of Transporters on Copanlisib: Copanlisib is a substrate of P-gp and BCRP, but not a substrate for organic cation transporter (OCT) 1, OCT2, and OCT3, organic anion transporter (OAT) 1 and OAT3, organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3, multidrug and toxin extrusion protein 1(MATE1) or MATE2-K. Effect of Copanlisib on CYP and non-CYP Enzymes Copanlisib is not an inhibitor of the metabolism of drugs that are substrates of the major CYP isoforms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) or uridine diphosphate-glucuronosyltransferase isoforms (UGT) or dihydropyrimidine dehydrogenase (DPD) at therapeutic 60 mg dose plasma concentrations. Copanlisib is not an inducer of CYP1A2, CYP2B6 and CYP3A. Effect of Copanlisib on Drug Transporter Substrates Copanlisib is not an inhibitor of P-gp, BCRP, multi-drug resistance-associated protein (MRP2), bile salt export pump (BSEP), OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, and MATE1 at therapeutic 60 mg dose plasma concentrations. Copanlisib is an inhibitor of MATE2-K (IC 50 : 0.09 μM). Inhibition may occur after copanlisib infusion at approved recommended dosage. The clinical significance of this potential inhibition on plasma concentrations of concomitantly administered drugs that are MATE2-K substrates is unknown.

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3 DOSAGE FORMS AND STRENGTHS For injection: 60 mg of copanlisib as a lyophilized solid in single-dose vial for reconstitution. For injection: 60 mg of copanlisib as a lyophilized solid in single-dose vial for reconstitution ( 3 ).

ALIQOPA copanlisib COPANLISIB COPANLISIB ANHYDROUS CITRIC ACID MANNITOL SODIUM HYDROXIDE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with copanlisib. Copanlisib did not cause genetic damage in in vitro or in vivo assays. Fertility studies with copanlisib were not conducted; however, adverse findings in male and female reproductive systems were observed in the repeat dose toxicity studies. Findings in the male rats and/or dogs included effects on the testes (germinal epithelial degeneration, decreased weight, and/or tubular atrophy), epididymides (spermatic debris, decreased weight, and/or oligospermia/aspermia), and prostate (reduced secretion and/or decreased weight). Findings in female rats included effects on ovaries (hemorrhage, hemorrhagic cysts, and decreased weight), uterus (atrophy, decreased weight), vagina (mononuclear infiltration), and a dose-related reduction in the numbers of female rats in estrus.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with copanlisib. Copanlisib did not cause genetic damage in in vitro or in vivo assays. Fertility studies with copanlisib were not conducted; however, adverse findings in male and female reproductive systems were observed in the repeat dose toxicity studies. Findings in the male rats and/or dogs included effects on the testes (germinal epithelial degeneration, decreased weight, and/or tubular atrophy), epididymides (spermatic debris, decreased weight, and/or oligospermia/aspermia), and prostate (reduced secretion and/or decreased weight). Findings in female rats included effects on ovaries (hemorrhage, hemorrhagic cysts, and decreased weight), uterus (atrophy, decreased weight), vagina (mononuclear infiltration), and a dose-related reduction in the numbers of female rats in estrus.

NDA209936

ALIQOPA

copanlisib

50419-385

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL [The following is a representative example of Aliqopa labeling.] NDC 50419-385-01 Rx only Aliqopa (copanlisib) 60 mg* *Equivalent to 69.1 mg copanlisib dihydrochloride For intravenous infusion only. Must be reconstituted and diluted. Single dose vial - discard unused portion Aliqopa Carton

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). • Infections – Advise patients that ALIQOPA can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection [see Warnings and Precautions ( 5.1 )] . • Hyperglycemia – Advise patients that an infusion-related increase in blood glucose may occur, and to notify their healthcare provider of any symptoms such as pronounced hunger, excessive thirst, headaches, or frequently urinating. Blood glucose levels should be well controlled prior to infusion [see Warnings and Precautions ( 5.2 )]. • Hypertension – Advise patients that an infusion-related increase in blood pressure may occur, and to notify their healthcare provider of any symptoms such as dizziness, passing out, headache, and/or a pounding heart. Blood pressure should be normal or well controlled prior to infusion [see Warnings and Precautions ( 5.3 )]. • Non-infectious pneumonitis – Advise patients of the possibility of pneumonitis, and to report any new or worsening respiratory symptoms including cough or difficulty breathing [see Warnings and Precautions ( 5.4 )] . • Neutropenia – Advise patients of the need for periodic monitoring of blood counts and to notify their healthcare provider immediately if they develop a fever or any signs of infection [see Warnings and Precautions ( 5.5 )]. • Severe cutaneous reactions – Advise patients that a severe cutaneous reaction may occur, and to notify their healthcare provider if they develop skin reactions (rash, redness, swelling, itching or peeling of the skin) [see Warnings and Precautions ( 5.6 )] . • Pregnancy – Advise females of reproductive potential to use effective contraceptive methods and to avoid becoming pregnant during treatment with ALIQOPA and for one month after the last dose. Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during ALIQOPA treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIQOPA and for one month after the last dose [see Warnings and Precautions ( 5.7 )]. • Lactation – Advise not to breastfeed during treatment with ALIQOPA and for 1 month after the last dose [see Use in Specific Populations ( 8.2 )] . © 2017 Bayer HealthCare Pharmaceuticals Inc.

Clinical Studies Effect of CYP3A and P-gp Inducers on Copanlisib Rifampin, a strong CYP3A and a P-glycoprotein (P-gp) transporter inducer, administered at a dose of 600 mg once daily for 12 days with a single intravenous dose of 60 mg ALIQOPA in patients with cancer resulted in a 60% decrease in the mean AUC and a 12% decrease in C max of copanlisib [see Drug Interactions ( 7.1 )] . Effect of CYP3A, P-gp and BCRP Inhibitors on Copanlisib Itraconazole, a strong CYP3A inhibitor and a P-gp and Breast Cancer Resistance Protein (BCRP) transporter inhibitor, administered at a dose of 200 mg once daily for 10 days increased the mean AUC of a single intravenous dose of 60 mg ALIQOPA by 53% (or 1.53-fold) with no effect on C max (1.03-fold) in patients with cancer [see Drug Interactions ( 7.1 )].

8.5 Geriatric Use No dosage adjustment of ALIQOPA is necessary in patients ≥65 years of age. Of 168 patients with follicular lymphoma and other hematologic malignancies treated with ALIQOPA, 48% were age 65 or older while 16% were age 75 or older. No clinically relevant differences in efficacy were observed between elderly and younger patients. In patients ≥65 years of age, 30% experienced serious adverse reactions and 21% experienced adverse reactions leading to discontinuation. In the patients <65 years of age, 23% experienced serious adverse reactions and 11% experienced adverse reactions leading to discontinuation.

8.4 Pediatric Use Safety and effectiveness of ALIQOPA have not been established in pediatric patients.

8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, ALIQOPA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis resulted in embryo-fetal death and fetal abnormalities at maternal doses approximately 12% of the recommended dose for patients (see Data) . Advise pregnant women of the potential risk to a fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study in rats, pregnant animals received intravenous doses of copanlisib of 0, 0.75, or 3 mg/kg/day during the period of organogenesis. Administration of copanlisib at the dose of 3 mg/kg/day resulted in maternal toxicity and no live fetuses. Copanlisib administration at the dose of 0.75 mg/kg/day was maternally toxic and resulted in embryo-fetal death (increased resorptions, increased post-implantation loss, and decreased numbers of fetuses/dam). The dose of 0.75 mg/kg/day also resulted in increased incidence of fetal gross external (domed head, malformed eyeballs or eyeholes), soft tissue (hydrocephalus internus, ventricular septal defects, major vessel malformations), and skeletal (dysplastic forelimb bones, malformed ribs and vertebrae, and pelvis shift) abnormalities. The dose of 0.75 mg/kg/day (4.5 mg/m 2 body surface area) in rats is approximately 12% of the recommended dose for patients. Following administration of radiolabeled copanlisib to pregnant rats approximately 1.5% of the radioactivity (copanlisib and metabolites) reached the fetal compartment.

8 USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed ( 8.2 ). 8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, ALIQOPA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis resulted in embryo-fetal death and fetal abnormalities at maternal doses approximately 12% of the recommended dose for patients (see Data) . Advise pregnant women of the potential risk to a fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study in rats, pregnant animals received intravenous doses of copanlisib of 0, 0.75, or 3 mg/kg/day during the period of organogenesis. Administration of copanlisib at the dose of 3 mg/kg/day resulted in maternal toxicity and no live fetuses. Copanlisib administration at the dose of 0.75 mg/kg/day was maternally toxic and resulted in embryo-fetal death (increased resorptions, increased post-implantation loss, and decreased numbers of fetuses/dam). The dose of 0.75 mg/kg/day also resulted in increased incidence of fetal gross external (domed head, malformed eyeballs or eyeholes), soft tissue (hydrocephalus internus, ventricular septal defects, major vessel malformations), and skeletal (dysplastic forelimb bones, malformed ribs and vertebrae, and pelvis shift) abnormalities. The dose of 0.75 mg/kg/day (4.5 mg/m 2 body surface area) in rats is approximately 12% of the recommended dose for patients. Following administration of radiolabeled copanlisib to pregnant rats approximately 1.5% of the radioactivity (copanlisib and metabolites) reached the fetal compartment. 8.2 Lactation Risk Summary There are no data on the presence of copanlisib and/or metabolites in human milk, the effects on the breastfed child, or on milk production. Following administration of radiolabeled copanlisib to lactating rats, approximately 2% of the radioactivity was secreted into milk; the milk to plasma ratio of radioactivity was 25-fold. Because of the potential for serious adverse reactions in a breastfed child from copanlisib, advise a lactating woman not to breastfeed during treatment with ALIQOPA and for 1 month after the last dose. 8.3 Females and Males of Reproductive Potential ALIQOPA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Pregnancy Testing Conduct pregnancy testing prior to initiation of ALIQOPA treatment. Contraception Females Advise female patients of reproductive potential to use highly effective contraception (contraception with a failure rate <1% per year) during treatment with ALIQOPA and for one month after the last dose. Males Advise male patients with female partners of reproductive potential to use highly effective contraception during treatment with ALIQOPA and for one month after the last dose. Infertility There are no data on the effect of ALIQOPA on human fertility. Due to the mechanism of action of copanlisib, and findings in animal studies, adverse effects on reproduction, including fertility, are expected [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use Safety and effectiveness of ALIQOPA have not been established in pediatric patients. 8.5 Geriatric Use No dosage adjustment of ALIQOPA is necessary in patients ≥65 years of age. Of 168 patients with follicular lymphoma and other hematologic malignancies treated with ALIQOPA, 48% were age 65 or older while 16% were age 75 or older. No clinically relevant differences in efficacy were observed between elderly and younger patients. In patients ≥65 years of age, 30% experienced serious adverse reactions and 21% experienced adverse reactions leading to discontinuation. In the patients <65 years of age, 23% experienced serious adverse reactions and 11% experienced adverse reactions leading to discontinuation. 8.6 Hepatic Impairment Reduce ALIQOPA dose to 45 mg for patients with moderate hepatic impairment (Child-Pugh B). Reduce ALIQOPA dose to 30 mg for patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration ( 2.2 )] . No dose adjustment is required for patients with mild hepatic impairment (total bilirubin ≤1 × upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN, or total bilirubin >1 to 1.5 × ULN and any AST) [see Clinical Pharmacology ( 12.3 )].

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ALIQOPA is contained in a colorless glass vial closed with bromobutyl stopper with a flanged closure. Each vial of ALIQOPA contains copanlisib as a lyophilized solid. NDC Strength Reconstituted Concentration 50419-385-01 60 mg (one single-dose vial per carton) 15 mg/mL Storage and Handling ALIQOPA vials must be refrigerated at 2°C to 8°C (36°F to 46°F).