DRUG INTERACTIONS

 CYP3A Inducers:                                                                                                            Avoid concomitant use with strong CYP3A inducers  

CYP3A Inhibitors:                                                                                                         Reduce the ALIQOPA dose to 45 mg when concomitantly administered with strong CYP3A inhibitors 

U.S. FDA APPROVED  DRUGS DURING 2017

 ADVERSE REACTIONS

The most common adverse reactions (=20%) are

hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, thrombocytopenia .

Hypertension:                                                                                                          Withhold treatment in patients until both the systolic blood pressure (BP) is less than 150 mmHg and the diastolic BP is less than 90 mmHg. Consider reducing dose if anti-hypertensive treatment is required. Discontinue in patients with BP that is uncontrolled or with life-threatening consequences 

 Non-infectious pneumonitis (NIP):                                                                              Treat NIP and reduce dose. Discontinue treatment if Grade 2 NIP recurs or in patients experiencing Grade 3 or higher NIP 

 Neutropenia:                                                                                                             Monitor blood counts at least weekly while under treatment. Withhold treatment until ANC =0.5 x 103 cells/mm3 

 Severe Cutaneous Reactions:                                                                              Withhold treatment, reduce dose, or discontinue treatment depending on the severity and persistence of severe cutaneous reactions 

 Embryo-Fetal Toxicity:                                                                                               ALIQOPA can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception

 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 

• 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 

• 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 

• Non-infectious pneumonitis –                                                                                 Advise patients of the possibility of pneumonitis, and to report any new or worsening respiratory symptoms including cough or difficulty breathing 

 • 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 

• 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)

• Pregnancy –                                                                                                                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 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 at least one month after the last dose 

• Lactation –                                                                                                                Advise women not to breastfeed during treatment with ALIQOPA and for at least 1 month after the last dose 

Manufactured for: Reference ID: 

Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 USA © 2017 Bayer H

CLINICAL PHARMACOLOGY

1. Mechanism of Action

Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-a and PI3K-d 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 NF?B signaling in lymphoma cell lines.

2. Pharmacodynamics

At 60 mg (or 0.8 mg/kg) of ALIQOPA dose, the elevation of plasma glucose was associated with higher copanlisib exposure. 

3. Pharmacokinetics 

The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) 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.

There is no time-dependency and no accumulation in the pharmacokinetics 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 PI3K-a and PI3K-d

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

Copanlisib pharmacokinetic differences in the subpopulations listed below are assessed using population pharmacokinetic analyses

 Age (20 to 90 years), gender, race (White, Asian, Hispanic, and Black), smoking status, body weight (41 to 130 kg), mild hepatic impairment [total bilirubin (TB) = upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or TB < 1-1.5 x ULN and any AST], and mild to moderate renal impairment [CLcr = 30 mL/min as estimated by Cockcroft-Gault (C-G) equation] had no clinically significant effect on the pharmacokinetics of copanlisib.

The pharmacokinetics of copanlisib in patients with moderate to severe hepatic impairment (TB = 1.5 x ULN, any AST), severe renal impairment (CLcr = 15-29 mL/min by C-G equation), or end stage renal disease (CLcr < 15 mL/min by C-G equation) with or without dialysis is unknown.

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 63% decrease in the mean AUC and a 15% decrease in Cmax of copanlisib 

USE IN SPECIFIC POPULATIONS

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 

There are no available data in pregnant women to inform the drug-associated risk. 

 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.

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

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 at least 1 month after the last dose.

3.Females and Males of Reproductive Potential Pregnancy Testing

ALIQOPA can cause fetal harm when administered to a pregnant woman . 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 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 

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

5.Geriatric 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.