ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. oInfections [see Warnings and Precautions (5.1)]oHyperglycemia [see Warnings and Precautions (5.2)]oHypertension [see Warnings and Precautions (5.3)]oNon-infectious pneumonitis [see Warnings and Precautions (5.4)]oNeutropenia [see Warnings and Precautions (5.5)]oSevere cutaneous reactions [see Warnings and Precautions (5.6)]. oInfections [see Warnings and Precautions (5.1)]. oHyperglycemia [see Warnings and Precautions (5.2)]. oHypertension [see Warnings and Precautions (5.3)]. oNon-infectious pneumonitis [see Warnings and Precautions (5.4)]. oNeutropenia [see Warnings and Precautions (5.5)]. oSevere 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 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 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 provides the adverse reactions occurring in at least 10% of patients receiving ALIQOPA monotherapy, and Table 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 REACTIONSALIQOPA = 168Any Graden (%)Grade 3n (%)Grade 4n (%)Metabolism and nutrition disorders Hyperglycemia90 (54%)56 (33%)10 (6%)Blood and lymphatic system disorders Leukopenia61 (36%)20 (12%) 26 (15%) Neutropenia (including febrile neutropenia)53 (32%) 16 (10%) 26 (15%) Thrombocytopenia37 (22%)12 (7%)2 (1%)General disorders and administration site conditions Decreased general strength and energy (includes fatigue and asthenia)61 (36%)6 (4%)0Gastrointestinal disorders Diarrhea60 (36%)8 (5%)0 Nausea43 (26%)1 (<1%)0 Stomatitis (includes oropharyngeal erosion and ulcer, oral pain)24 (14%)3 (2%)0 Vomiting21 (13%)00Vascular disorders Hypertension (includes secondary hypertension)59 (35%) 46 (27%) 0Infections 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%) (2%)Skin and subcutaneous tissue disorders Rash (includes exfoliative skin reactions)26 (15%) (1%)1 (<1%)Additional adverse drug reactions reported at 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 ALIQOPALaboratory ParameterALIQOPA = 168Any Graden (%)Grade 3n (%)Grade 4n (%)Hematology abnormalities Decreased hemoglobin130 (78%)7 (4%)0 Lymphocyte count decreased126 (78%)43 (27%)4 (2%) White blood cell decreased118 (71%)30 (18%)3 (2%) Platelet count decreased109 (65%)11 (7%)3 (2%) Neutrophil count decreased104 (63%)20 (12%)25 (15%)Serum chemistry abnormalities Hyperglycemia160 (95%)72 (43%)9 (5%) Hypertriglyceridemia74 (58%)6 (5%)0 Hypophosphatemia72 (44%)24 (15%)0 Hyperuricemia42 (25%)40 (24%)2 (1%) Serum lipase increased34 (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. Hyperglycemia. Leukopenia. Neutropenia (including febrile neutropenia). Thrombocytopenia. Decreased general strength and energy (includes fatigue and asthenia). Diarrhea. Nausea. Stomatitis (includes oropharyngeal erosion and ulcer, oral pain). Vomiting. Hypertension (includes secondary hypertension). Lower respiratory tract infections (includes pneumonia, pneumonia bacterial, pneumonia pneumococcal, pneumonia fungal, pneumonia viral, pneumocystis jiroveci pneumonia, bronchopulmonary aspergillosis and lung infection). Rash (includes exfoliative skin reactions).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, 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 dose-related reduction in the numbers of female rats in estrus.

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY 12.1Mechanism of Action Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K- and PI3K- isoforms expressed in malignant cells. Copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant cell lines. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant cells, and NFB signaling in lymphoma cell lines.. 12.2Pharmacodynamics At 60 mg (or 0.8 mg/kg) of ALIQOPA dose, the elevation of plasma glucose was associated with higher copanlisib exposure. Cardiac Electrophysiology 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. No large mean QTc prolongation >20 ms above baseline was observed.. 12.3Pharmacokinetics The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of ALIQOPA increase dose-proportionally over 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 Cmax and 1570 (range: 536 to 3410; SD: 338) ng.hr/mL for AUC0-25h. 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 PI3KandPI3K.. Excretion Copanlisib is excreted approximately 50% as unchanged compound and 50% as metabolites in humans. Following 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 population PK analysis in patients with cancer, mild hepatic impairment [total bilirubin <= x ULN and AST ULN, or total bilirubin 1-1.5 ULN and any AST] had no clinically relevant effect on the PK of copanlisib.In dedicated PK study evaluating 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 Cmax and AUC increased 1.38-fold and 1.71-fold, respectively, in subjects with moderate hepatic impairment (Child-Pugh B) as compared to normal hepatic function. The geometric mean unbound AUC of copanlisib was increased by 1.23-fold with no effect on Cmax. The PK of copanlisib in patients with severe hepatic impairment (Child-Pugh or total bilirubin 3-10 ULN and any AST) is unknown.. Drug Interaction Studies Clinical Studies Effect of CYP3A and P-gp Inducers on CopanlisibRifampin, strong CYP3A and P-glycoprotein (P-gp) transporter inducer, administered at dose of 600 mg once daily for 12 days with single intravenous dose of 60 mg ALIQOPA in patients with cancer resulted in 60% decrease in the mean AUC and 12% decrease in Cmax of copanlisib [see Drug Interactions (7.1)].Effect of CYP3A, P-gp and BCRP Inhibitors on CopanlisibItraconazole, strong CYP3A inhibitor and P-gp and Breast Cancer Resistance Protein (BCRP) transporter inhibitor, administered at dose of 200 mg once daily for 10 days increased the mean AUC of single intravenous dose of 60 mg ALIQOPA by 53% (or 1.53-fold) with no effect on Cmax (1.03-fold) in patients with cancer [see Drug Interactions (7.1)]. In Vitro Studies Effect of Transporters on Copanlisib: Copanlisib is substrate of P-gp and BCRP, but not substrate for organic cation transporter (OCT) 1, OCT2, and OCT3, organic anion transporter (OAT) 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 SubstratesCopanlisib 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 (IC50: 0.09 uM). 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.

CLINICAL STUDIES SECTION.

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

CONTRAINDICATIONS SECTION.

4CONTRAINDICATIONS None. None (4).

DESCRIPTION SECTION.

11DESCRIPTION ALIQOPA (copanlisib) is kinase inhibitor for intravenous infusion. The active pharmaceutical ingredient is copanlisib dihydrochloride which exists as non-stoichiometric hydrate and has the molecular formula of C23H28N8O4 2HCl and 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-ylpyrimidine-5-carboxamide dihydrochloride. Copanlisib dihydrochloride has the following structural formula:ALIQOPA is supplied in single-dose vials as 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 buffering agent and may be used together with sodium hydroxide for pH adjustment.. Chem structure.

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION oRecommended dosage: 60 mg administered as 1-hour intravenous infusion on Days 1, 8, and 15 of 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Modify dosage for toxicity (2.1, 2.4).oReduce the ALIQOPA dose to 45 mg in patients with moderate hepatic impairment (Child-Pugh B) (2.2, 8.6).oSee full prescribing information for important preparation and administration information (2.5, 2.6, 2.7).. oRecommended dosage: 60 mg administered as 1-hour intravenous infusion on Days 1, 8, and 15 of 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Modify dosage for toxicity (2.1, 2.4).. oReduce the ALIQOPA dose to 45 mg in patients with moderate hepatic impairment (Child-Pugh B) (2.2, 8.6).. oSee full prescribing information for important preparation and administration information (2.5, 2.6, 2.7).. 2.1Recommended Dosage The recommended dose of ALIQOPA is 60 mg administered as 1-hour intravenous infusion on Days 1, 8, and 15 of 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 Hepatic Impairment Reduce ALIQOPA dose to 45 mg in patients with moderate hepatic impairment (Child-Pugh B) [see Hepatic Impairment (8.6)]. 2.3 Dose Modification for Use with Strong CYP3A Inhibitors Reduce ALIQOPA dose to 45 mg if 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)].. 2.4Dose Modification for Toxicities Manage toxicities per Table with dose reduction, treatment delay, or discontinuation of ALIQOPA. Discontinue ALIQOPA if life-threatening ALIQOPA-related toxicity occurs.Table 1: Dose Modification and Toxicity Managementa ToxicitiesAdverse Reaction Gradeb Recommended ManagementInfections Grade or higherWithhold ALIQOPA until resolution. Suspected pneumocystis jiroveci pneumonia (PJP) infection of any gradeWithhold ALIQOPA. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis.Hyperglycemia Pre-dose fasting blood glucose 160 mg/dL or more or random/non-fasting blood glucose of 200 mg/dL or moreWithhold ALIQOPA until fasting glucose is 160 mg/dL or less, or random/non-fasting blood glucose of 200 mg/dL or less.Pre-dose or post-dose blood glucose 500 mg/dL or moreOn first occurrence, withhold ALIQOPA until fasting blood glucose is 160 mg/dL or less, or 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 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 Pre-dose blood pressure (BP) 150/90 or greaterc 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 greaterc (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 [see Warnings and Precautions (5.3)]. Post-dose elevated BP with life-threatening consequencesDiscontinue ALIQOPA.Non-infectious pneumonitis (NIP) Grade 2Withhold ALIQOPA and treat NIP. If NIP recovers to Grade or 1, resume ALIQOPA at 45 mg. If Grade NIP recurs, discontinue ALIQOPA.Grade or higherDiscontinue ALIQOPA.NeutropeniaAbsolute neutrophil count (ANC) 0.5 to 1.0 103 cells/mm3 Maintain ALIQOPA dose. Monitor ANC at least weekly.ANC less than 0.5 103 cells/mm3 Withhold ALIQOPA. Monitor ANC at least weekly until ANC 0.5 103 cells/mm3 or greater, then resume ALIQOPA at previous dose. If ANC 0.5 103 cells/mm3 or less recurs, then reduce ALIQOPA to 45 mg.Severe cutaneous reactionsGrade 3Withhold ALIQOPA until toxicity is resolved and reduce ALIQOPA from 60 mg to 45 mg or from 45 mg to 30 mg.Life-threateningDiscontinue ALIQOPA.ThrombocytopeniaLess than 25 109/L Withhold ALIQOPA; resume when platelet levels return to 75.0 109/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 Grade 3Withhold ALIQOPA until toxicity is resolved and reduce ALIQOPA from 60 mg to 45 mg or from 45 mg to 30 mg.aEnsure minimum of days between any two consecutive infusions.bNational Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03.cBoth systolic of less than 150 mmHg and diastolic of less than 90 mmHg are required.. 2.5Preparation and Administration For intravenous infusion only.Administer ALIQOPA as 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.. 2.6Reconstitution Instructions Reconstitute ALIQOPA with 4.4 mL of sterile 0.9% Sodium Chloride Injection, USP solution leading to concentration of 15 mg/mL. oWithdraw 4.4 mL of sterile 0.9% Sodium Chloride Injection, USP solution by using 5 mL sterile syringe with needle.oInject the measured volume through the disinfected stopper surface into the vial of ALIQOPA.oDissolve the lyophilized solid by gently shaking the injection vial for 30 seconds.oAllow to stand for one minute to let bubbles rise to the surface.oCheck if any undissolved substance is still seen. If yes, repeat the gentle shaking and settling procedure. oInspect visually for discoloration and particulate matter. After reconstitution, the solution should be colorless to slightly yellowish. oOnce the solution is free of visible particles, withdraw the reconstituted solution for further dilution. oWithdraw 4.4 mL of sterile 0.9% Sodium Chloride Injection, USP solution by using 5 mL sterile syringe with needle.. oInject the measured volume through the disinfected stopper surface into the vial of ALIQOPA.. oDissolve the lyophilized solid by gently shaking the injection vial for 30 seconds.. oAllow to stand for one minute to let bubbles rise to the surface.. oCheck if any undissolved substance is still seen. If yes, repeat the gentle shaking and settling procedure. oInspect visually for discoloration and particulate matter. After reconstitution, the solution should be colorless to slightly yellowish. oOnce the solution is free of visible particles, withdraw the reconstituted solution for further dilution. 2.7Dilution Instructions for Intravenous Use Further dilute the reconstituted solution in 100 mL sterile 0.9% Sodium Chloride Injection, USP solution for injection. With sterile syringe, withdraw the required amount of the reconstituted solution for the desired dosage: 60 mg: Withdraw mL of the reconstituted solution with sterile syringe.45 mg: Withdraw mL of the reconstituted solution with sterile syringe.30 mg: Withdraw mL of the reconstituted solution with 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 2C to 8C (36F to 46F) 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.

DOSAGE FORMS & STRENGTHS SECTION.

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

DRUG INTERACTIONS SECTION.

7DRUG INTERACTIONS oCYP3A Inducers: Avoid concomitant use with strong CYP3A inducers (7.1).oCYP3A Inhibitors: Reduce the ALIQOPA dose to 45 mg when concomitantly administered with strong CYP3A inhibitors (7.1).. oCYP3A Inducers: Avoid concomitant use with strong CYP3A inducers (7.1).. oCYP3A Inhibitors: Reduce the ALIQOPA dose to 45 mg when concomitantly administered with strong CYP3A inhibitors (7.1).. 7.1Effect of Other Drugs on Copanlisib Table lists the potential effects of coadministration of ALIQOPA with strong CYP3A inhibitors and inducers.Table 4: Drug Interactions with ALIQOPA that affect Copanlisib ConcentrationsStrong CYP3A inducersClinical impactoConcomitant use of ALIQOPA with strong CYP3A inducers may decrease copanlisib AUC and Cmax[see Clinical Pharmacology (12.3)].Prevention managementoAvoid concomitant use of ALIQOPA with strong CYP3A inducersStrong CYP3A inhibitorsClinical impactoConcomitant use of ALIQOPA with strong CYP3A inhibitors increases the copanlisib AUC [see Clinical Pharmacology (12.3)].oAn increase in the copanlisib AUC may increase the risk of adverse reactionsPrevention managementoIf concomitant use with strong CYP3A inhibitors cannot be avoided, reduce the ALIQOPA dose to 45 mg [see Dosage and Administration (2.3)]. oConcomitant use of ALIQOPA with strong CYP3A inducers may decrease copanlisib AUC and Cmax[see Clinical Pharmacology (12.3)].. oAvoid concomitant use of ALIQOPA with strong CYP3A inducers. oConcomitant use of ALIQOPA with strong CYP3A inhibitors increases the copanlisib AUC [see Clinical Pharmacology (12.3)].. oAn increase in the copanlisib AUC may increase the risk of adverse reactions. oIf concomitant use with strong CYP3A inhibitors cannot be avoided, reduce the ALIQOPA dose to 45 mg [see Dosage and Administration (2.3)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3Females and Males of Reproductive Potential Pregnancy Testing ALIQOPA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations 8.1)]. Conduct pregnancy testing prior to initiation of ALIQOPA treatment. Contraception Females Advise female patients of reproductive potential to use highly effective contraception (contraception with failure rate <1% per year) during treatment with ALIQOPA and for at least 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 at least 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)].

GERIATRIC USE SECTION.

8.5Geriatric Use No dose adjustment 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.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING 16.1How Supplied ALIQOPA is contained in colorless glass vial closed with bromobutyl stopper with flanged closure. Each vial of ALIQOPA contains copanlisib as lyophilized solid. NDCStrengthReconstituted Concentration50419-385-0160 mg(one single-dose vial per carton)15 mg/mL. 16.2Storage and Handling Product as packaged for sale. ALIQOPA vials must be refrigerated at 2C to 8C (36F to 46F). Product after reconstitution. Administer reconstituted and diluted solution immediately. If not, refrigerate at 2C to 8C (36F to 46F) and use within 24 hours. After refrigeration, allow the product to adapt to room temperature before use. Avoid exposure of the diluted solution to direct sunlight.Mix only with sterile 0.9% Sodium Chloride Injection, USP solution. Do not mix or inject ALIQOPA with other drugs or other diluents [see Dosage and Administration (2.5)].

INDICATIONS & USAGE SECTION.

1INDICATIONS 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 confirmatory trial.. 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 confirmatory trial.. ALIQOPA is 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 confirmatory trial.

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).oInfections 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)].oHyperglycemia 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)]. oHypertension 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 pounding heart. Blood pressure should be normal or well controlled prior to infusion [see Warnings and Precautions (5.3)]. oNon-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)].oNeutropenia Advise patients of the need for periodic monitoring of blood counts and to notify their healthcare provider immediately if they develop fever or any signs of infection [see Warnings and Precautions (5.5)]. oSevere cutaneous reactions Advise patients that 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)].oPregnancy Advise females of reproductive potential to use effective contraceptive methods and to avoid becoming pregnant during treatment with ALIQOPA and for at least one month after the last dose. Advise patients to notify their healthcare provider immediately in the event of 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 at least one month after the last dose [see Warnings and Precautions (5.7)]. oLactation Advise not to breastfeed during treatment with ALIQOPA and for at least month after the last dose [see Use in Specific Populations (8.2)].(C) 2017 Bayer HealthCare Pharmaceuticals Inc.. oInfections 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)].. oHyperglycemia 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)]. oHypertension 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 pounding heart. Blood pressure should be normal or well controlled prior to infusion [see Warnings and Precautions (5.3)]. oNon-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)].. oNeutropenia Advise patients of the need for periodic monitoring of blood counts and to notify their healthcare provider immediately if they develop fever or any signs of infection [see Warnings and Precautions (5.5)]. oSevere cutaneous reactions Advise patients that 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)].. oPregnancy Advise females of reproductive potential to use effective contraceptive methods and to avoid becoming pregnant during treatment with ALIQOPA and for at least one month after the last dose. Advise patients to notify their healthcare provider immediately in the event of 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 at least one month after the last dose [see Warnings and Precautions (5.7)]. oLactation Advise not to breastfeed during treatment with ALIQOPA and for at least month after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2Lactation 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 breastfed child from copanlisib, advise lactating woman not to breastfeed during treatment with ALIQOPA and for at least month after the last dose.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13NONCLINICAL TOXICOLOGY 13.1Carcinogenesis, 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 dose-related reduction in the numbers of female rats in estrus.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

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

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2Pharmacodynamics At 60 mg (or 0.8 mg/kg) of ALIQOPA dose, the elevation of plasma glucose was associated with higher copanlisib exposure. Cardiac Electrophysiology 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. No large mean QTc prolongation >20 ms above baseline was observed.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of ALIQOPA increase dose-proportionally over 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 Cmax and 1570 (range: 536 to 3410; SD: 338) ng.hr/mL for AUC0-25h. 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 PI3KandPI3K.. Excretion Copanlisib is excreted approximately 50% as unchanged compound and 50% as metabolites in humans. Following 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 population PK analysis in patients with cancer, mild hepatic impairment [total bilirubin <= x ULN and AST ULN, or total bilirubin 1-1.5 ULN and any AST] had no clinically relevant effect on the PK of copanlisib.In dedicated PK study evaluating 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 Cmax and AUC increased 1.38-fold and 1.71-fold, respectively, in subjects with moderate hepatic impairment (Child-Pugh B) as compared to normal hepatic function. The geometric mean unbound AUC of copanlisib was increased by 1.23-fold with no effect on Cmax. The PK of copanlisib in patients with severe hepatic impairment (Child-Pugh or total bilirubin 3-10 ULN and any AST) is unknown.. Drug Interaction Studies Clinical Studies Effect of CYP3A and P-gp Inducers on CopanlisibRifampin, strong CYP3A and P-glycoprotein (P-gp) transporter inducer, administered at dose of 600 mg once daily for 12 days with single intravenous dose of 60 mg ALIQOPA in patients with cancer resulted in 60% decrease in the mean AUC and 12% decrease in Cmax of copanlisib [see Drug Interactions (7.1)].Effect of CYP3A, P-gp and BCRP Inhibitors on CopanlisibItraconazole, strong CYP3A inhibitor and P-gp and Breast Cancer Resistance Protein (BCRP) transporter inhibitor, administered at dose of 200 mg once daily for 10 days increased the mean AUC of single intravenous dose of 60 mg ALIQOPA by 53% (or 1.53-fold) with no effect on Cmax (1.03-fold) in patients with cancer [see Drug Interactions (7.1)]. In Vitro Studies Effect of Transporters on Copanlisib: Copanlisib is substrate of P-gp and BCRP, but not substrate for organic cation transporter (OCT) 1, OCT2, and OCT3, organic anion transporter (OAT) 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 SubstratesCopanlisib 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 (IC50: 0.09 uM). 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.

PREGNANCY SECTION.

8.1Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, ALIQOPA can cause fetal harm when administered to 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 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 mg/kg/day during the period of organogenesis. Administration of copanlisib at the dose of 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/m2 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.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.5, 2.6, 2.7) 11/2020.

RISKS.

Risk Summary Based on findings from animal studies and the mechanism of action, ALIQOPA can cause fetal harm when administered to 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 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.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Package Insert PATIENT INFORMATIONALIQOPA(TM) (AL-ih-KO-pah)(copanlisib)for injection What is ALIQOPAALIQOPA is prescription medicine used to treat adults with follicular lymphoma (FL) when the disease has come back after treatment with at least two prior medicines. It is not known if ALIQOPA is safe and effective in children.Before receiving ALIQOPA, tell your healthcare provider about all of your medical conditions, including if you: ohave an infection ohave lung or breathing problemsohave high blood pressure (hypertension) ohave diabetes or high blood sugar (hyperglycemia) oare pregnant or plan to become pregnant. ALIQOPA can harm your unborn baby. oYour healthcare provider will perform pregnancy test before starting treatment with ALIQOPA. oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with ALIQOPA and for at least month after the last dose of ALIQOPA. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with ALIQOPA. oMales with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ALIQOPA and for at least month after the last dose of ALIQOPA.oare breastfeeding or plan to breastfeed. It is not known if ALIQOPA passes into your breast milk. Do not breastfeed during treatment with ALIQOPA and for at least month after the last dose of ALIQOPA. Talk to your healthcare provider about the best way to feed your child during treatment with ALIQOPA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain other medicines may affect how ALIQOPA works. Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.How will receive ALIQOPAoALIQOPA will be given to you by healthcare provider as an intravenous (IV) injection into your vein over hour. oYou will receive your ALIQOPA treatment time every week for weeks and then stop for week. This is cycle of treatment. ALIQOPA is usually given on Day 1, Day 8, and Day 15 of 28-day treatment cycle.oYour healthcare provider will decide how many treatment cycles you need.oYour healthcare provider may withhold treatment, decrease your dose, temporarily stop, or permanently stop treatment with ALIQOPA if you have certain side effects.What should avoid while receiving ALIQOPAoAvoid taking St. Johns Wort during treatment with ALIQOPA.oAvoid drinking grapefruit juice during treatment with ALIQOPA. What are the possible side effects of ALIQOPAALIQOPA can cause serious side effects, including:oInfections. ALIQOPA can cause serious infections that may lead to death. The most common serious infection was pneumonia. Tell your healthcare provider right away if you have fever or any signs of an infection during treatment with ALIQOPA. oHigh blood sugar (hyperglycemia). High blood sugar is common following ALIQOPA infusion and can sometimes be serious. Tell your healthcare provider if you develop any symptoms of hyperglycemia during treatment with ALIQOPA. Symptoms of hyperglycemia may include: obeing very hungryoheadachesobeing very thirstyofrequent urinationoHigh blood pressure (hypertension). High blood pressure is common following ALIQOPA infusion and can sometimes be serious. oLung or breathing problems. Your healthcare provider may do tests to check your lungs if you have breathing problems during treatment with ALIQOPA. Tell your healthcare provider right away if you develop new or worsening cough, shortness of breath, or difficulty breathing.oLow white blood cell count (neutropenia). Neutropenia is common with ALIQOPA treatment and can sometimes be serious. Your healthcare provider will check your blood counts regularly during treatment with ALIQOPA. Tell your healthcare provider right away if you have fever or any signs of infection during treatment with ALIQOPA.oSevere skin reactions. Skin peeling, rash, and itching are common with ALIQOPA and can sometimes be serious. Tell your healthcare provider if you develop skin peeling, itching, or rash during treatment with ALIQOPA. Your healthcare provider may withhold treatment, decrease your dose, or permanently stop treatment if you develop severe skin reactions during treatment with ALIQOPA.The most common side effects of ALIQOPA include:olow white blood cell count (leukopenia)olow platelets in your blood (thrombocytopenia) odiarrheaodecreased strength and tirednessolower respiratory tract infectiononauseaThese are not all of the possible side effects of ALIQOPA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of ALIQOPAMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about ALIQOPA that is written for health professionals.What are the ingredients in ALIQOPAActive ingredient: copanlisibInactive ingredients: citric acid anhydrous, mannitolManufactured in GermanyManufactured for: Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981 USA(C) 2017 Bayer HealthCare Pharmaceuticals Inc.For more information, go to www.aliqopa.com or call 1-888-842-2937. This Patient Information has been approved by the U.S. Food and Drug AdministrationIssued: May 2021. ohave an infection ohave lung or breathing problems. ohave high blood pressure (hypertension) ohave diabetes or high blood sugar (hyperglycemia) oare pregnant or plan to become pregnant. ALIQOPA can harm your unborn baby. oYour healthcare provider will perform pregnancy test before starting treatment with ALIQOPA. oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with ALIQOPA and for at least month after the last dose of ALIQOPA. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with ALIQOPA. oMales with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ALIQOPA and for at least month after the last dose of ALIQOPA.. oYour healthcare provider will perform pregnancy test before starting treatment with ALIQOPA. oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with ALIQOPA and for at least month after the last dose of ALIQOPA. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with ALIQOPA. oMales with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ALIQOPA and for at least month after the last dose of ALIQOPA.. oare breastfeeding or plan to breastfeed. It is not known if ALIQOPA passes into your breast milk. Do not breastfeed during treatment with ALIQOPA and for at least month after the last dose of ALIQOPA. Talk to your healthcare provider about the best way to feed your child during treatment with ALIQOPA.. oALIQOPA will be given to you by healthcare provider as an intravenous (IV) injection into your vein over hour. oYou will receive your ALIQOPA treatment time every week for weeks and then stop for week. This is cycle of treatment. ALIQOPA is usually given on Day 1, Day 8, and Day 15 of 28-day treatment cycle.. oYour healthcare provider will decide how many treatment cycles you need.. oYour healthcare provider may withhold treatment, decrease your dose, temporarily stop, or permanently stop treatment with ALIQOPA if you have certain side effects.. oAvoid taking St. Johns Wort during treatment with ALIQOPA.. oAvoid drinking grapefruit juice during treatment with ALIQOPA. oInfections. ALIQOPA can cause serious infections that may lead to death. The most common serious infection was pneumonia. Tell your healthcare provider right away if you have fever or any signs of an infection during treatment with ALIQOPA. oHigh blood sugar (hyperglycemia). High blood sugar is common following ALIQOPA infusion and can sometimes be serious. Tell your healthcare provider if you develop any symptoms of hyperglycemia during treatment with ALIQOPA. Symptoms of hyperglycemia may include: obeing very hungry. oheadaches. obeing very thirsty. ofrequent urination. oHigh blood pressure (hypertension). High blood pressure is common following ALIQOPA infusion and can sometimes be serious. oLung or breathing problems. Your healthcare provider may do tests to check your lungs if you have breathing problems during treatment with ALIQOPA. Tell your healthcare provider right away if you develop new or worsening cough, shortness of breath, or difficulty breathing.. oLow white blood cell count (neutropenia). Neutropenia is common with ALIQOPA treatment and can sometimes be serious. Your healthcare provider will check your blood counts regularly during treatment with ALIQOPA. Tell your healthcare provider right away if you have fever or any signs of infection during treatment with ALIQOPA.. oSevere skin reactions. Skin peeling, rash, and itching are common with ALIQOPA and can sometimes be serious. Tell your healthcare provider if you develop skin peeling, itching, or rash during treatment with ALIQOPA. Your healthcare provider may withhold treatment, decrease your dose, or permanently stop treatment if you develop severe skin reactions during treatment with ALIQOPA.. olow white blood cell count (leukopenia). olow platelets in your blood (thrombocytopenia) odiarrhea. odecreased strength and tiredness. olower respiratory tract infection. onausea. This Patient Information has been approved by the U.S. Food and Drug AdministrationIssued: May 2021.

SPL UNCLASSIFIED SECTION.

2.1Recommended Dosage The recommended dose of ALIQOPA is 60 mg administered as 1-hour intravenous infusion on Days 1, 8, and 15 of 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)].

STORAGE AND HANDLING SECTION.

16.2Storage and Handling Product as packaged for sale. ALIQOPA vials must be refrigerated at 2C to 8C (36F to 46F). Product after reconstitution. Administer reconstituted and diluted solution immediately. If not, refrigerate at 2C to 8C (36F to 46F) and use within 24 hours. After refrigeration, allow the product to adapt to room temperature before use. Avoid exposure of the diluted solution to direct sunlight.Mix only with sterile 0.9% Sodium Chloride Injection, USP solution. Do not mix or inject ALIQOPA with other drugs or other diluents [see Dosage and Administration (2.5)].

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS oLactation: Advise not to breastfeed (8.2).. oLactation: Advise not to breastfeed (8.2).. 8.1Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, ALIQOPA can cause fetal harm when administered to 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 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 mg/kg/day during the period of organogenesis. Administration of copanlisib at the dose of 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/m2 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. 8.2Lactation 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 breastfed child from copanlisib, advise lactating woman not to breastfeed during treatment with ALIQOPA and for at least month after the last dose.. 8.3Females and Males of Reproductive Potential Pregnancy Testing ALIQOPA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations 8.1)]. Conduct pregnancy testing prior to initiation of ALIQOPA treatment. Contraception Females Advise female patients of reproductive potential to use highly effective contraception (contraception with failure rate <1% per year) during treatment with ALIQOPA and for at least 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 at least 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)]. 8.4Pediatric Use Safety and effectiveness have not been established in pediatric patients.. 8.5Geriatric Use No dose adjustment 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) [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). ALIQOPA has not been studied in subjects with severe hepatic impairment (Child-Pugh C) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS oInfections: Monitor patients for signs and symptoms of infection. Withhold treatment for Grade and higher infections until resolution (5.1).oHyperglycemia: 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).oHypertension: 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).oNon-infectious pneumonitis (NIP): Treat NIP and reduce dose. Discontinue treatment if Grade NIP recurs or in patients experiencing Grade or higher NIP (5.4).oNeutropenia: Monitor blood counts at least weekly while under treatment. Withhold treatment until ANC >=0.5 103 cells/mm3 (5.5).oSevere Cutaneous Reactions: Withhold treatment, reduce dose, or discontinue treatment depending on the severity and persistence of severe cutaneous reactions (5.6).oEmbryo-Fetal Toxicity: ALIQOPA can cause fetal harm. Advise patients of potential risk to fetus and to use effective contraception (5.7, 8.1, 8.3).. oInfections: Monitor patients for signs and symptoms of infection. Withhold treatment for Grade and higher infections until resolution (5.1).. oHyperglycemia: 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).. oHypertension: 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).. oNon-infectious pneumonitis (NIP): Treat NIP and reduce dose. Discontinue treatment if Grade NIP recurs or in patients experiencing Grade or higher NIP (5.4).. oNeutropenia: Monitor blood counts at least weekly while under treatment. Withhold treatment until ANC >=0.5 103 cells/mm3 (5.5).. oSevere Cutaneous Reactions: Withhold treatment, reduce dose, or discontinue treatment depending on the severity and persistence of severe cutaneous reactions (5.6).. oEmbryo-Fetal Toxicity: ALIQOPA can cause fetal harm. Advise patients of potential risk to fetus and to use effective contraception (5.7, 8.1, 8.3).. 5.1Infections 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 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)].. 5.2 Hyperglycemia Grade or 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 to hours post-infusion and subsequently declined to baseline levels for 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 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)].. 5.3Hypertension Grade 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 hours post-infusion on Cycle Day was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately hours post-infusion; BP remained elevated for to 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)].. 5.4Non-Infectious Pneumonitis Non-infectious pneumonitis occurred in 5% of 317 patients treated with ALIQOPA monotherapy [see Adverse Reactions (6.1)]. Withhold ALIQOPA and conduct diagnostic examination of 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)].. 5.5Neutropenia Grade or 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)].. 5.6Severe Cutaneous Reactions Grade and 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 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/m2/day body surface area) corresponding to approximately 12% the recommended dose for patients. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least one month after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].