Copanlisib (Monograph)

Brand name: Aliqopa
Drug class: Antineoplastic Agents

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Introduction

Antineoplastic agent; an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity mainly against PI3K-α and PI3K-δ isoforms.

Uses for Copanlisib

Follicular Lymphoma

Treatment of relapsed follicular lymphoma in patients who previously received ≥2 systemic therapies (designated an orphan drug by FDA for this use).

Current indication based on overall response rate; clinical benefit (e.g., improvement in survival) not established. Continued FDA approval for this indication may be contingent on verification and description of clinical benefit in a confirmatory trial.

Guidelines recommend phosphatidylinositol-3-kinase (PI3K) inhibitors (e.g., copanlisib, idelalisib, or umbralisib) as a treatment option for relapsed or recurrent follicular lymphoma.

Copanlisib Dosage and Administration

General

Pretreatment Screening

• Initiate Pneumocystis jiroveci pneumonia (PJP) prophylaxis in high-risk patients prior to initiating therapy.

• Ensure optimal glycemic control prior to each copanlisib infusion.

• Optimize blood pressure prior to each copanlisib infusion.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor blood pressure after each infusion.

• Monitor CBC weekly during treatment.

• Monitor for cytomegalovirus (CMV) infection in patients with a history of such infection.

Administration

IV Administration

Administer by IV infusion.

Copanlisib hydrochloride lyophilized solid for injection must be reconstituted and diluted prior to administration.

Do not infuse simultaneously through the same IV line with other drugs.

Reconstitution

Reconstitute vial containing 60 mg of copanlisib as a lyophilized solid with 4.4 mL of 0.9% sodium chloride injection to provide a solution containing 15 mg/mL. No other diluent should be used. Gently shake vial for 30 seconds, then allow solution to stand for 1 minute to allow bubbles to rise to surface. If undissolved substance remains in the vial, gently shake vial for another 30 seconds, then allow solution to stand for another minute to settle.

Inspect reconstituted solution visually for particulate matter and discoloration prior to dilution and administration. Reconstituted solution should be colorless to slightly yellow. Once free of visible particles, may withdraw reconstituted solution for further dilution. Discard any unused reconstituted solution appropriately.

Dilution

Dilute appropriate dose in 100 mL of 0.9% sodium chloride injection. For 60-, 45-, or 30-mg doses, withdraw 4, 3, or 2 mL of reconstituted solution with a sterile syringe, respectively, and add to the container. Mix the diluted solution by gentle inversion. Discard any unused diluted solution appropriately.

Rate of Administration

Administer over 60 minutes.

Dosage

Dosage of copanlisib hydrochloride expressed in terms of copanlisib.

Adults

Follicular Lymphoma

Relapsed Follicular Lymphoma Following Failure of ≥2 Prior Systemic Therapies

IV

60 mg on days 1, 8, and 15 of each 28-day cycle on an intermittent schedule (3 weeks on and 1 week off). Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

May need to interrupt therapy, reduce dosage, and/or permanently discontinue copanlisib if toxicity occurs. If therapy is interrupted for toxicity, ≥7 days must elapse between 2 consecutive infusions. Discontinue therapy if life-threatening, copanlisib-related toxicity occurs. See Table 1for dosage modifications based on adverse reaction severity.

Both systolic of <150 mm Hg and diastolic <90 mm Hg are required. Abbreviations: ANC, absolute neutrophil count; BP, blood pressure; CMV, cytomegalovirus; FBG, fasting blood glucose; NIP, non-infectious pneumonitis; PJP, Pneumocystis jiroveci pneumonia.

Dosage Modification for Use with Strong Enzyme Inhibitors

Reduce the dosage of copanlisib to 45 mg when concomitant use of a strong CYP3A enzyme inhibitor is required.

Special Populations

Hepatic Impairment

No dosage adjustment is required for patients with mild hepatic impairment. Reduce dosage to 45 mg for patients with moderate hepatic impairment (Child-Pugh class B). Reduce dosage to 30 mg for patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

Dosage adjustment not necessary in patients ≥65 years of age; nearly half of patients in pivotal efficacy study were geriatric.

Cautions for Copanlisib

Contraindications

• None.

Warnings/Precautions

Warnings

Infections

Serious, including fatal, infections reported in 19% of patients receiving copanlisib therapy in clinical trials. Pneumonia was the most frequently reported serious infection.

Serious Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PJP) reported in 0.6% of patients receiving copanlisib monotherapy in clinical trials. Prior to initiating copanlisib therapy, consider PJP prophylaxis for populations at risk for PJP. If PJP of any grade is suspected, withhold copanlisib. If PJP is confirmed, treat the infection; when the infection resolves, resume copanlisib at previous dosage with concomitant PJP prophylaxis.

Grade 1 or 2 cytomegalovirus (CMV) reactivation or infection reported. In patients with a history of CMV infection, monitor for CMV infection during treatment. Withhold copanlisib if clinical CMV infection or viremia occurs until resolution. If copanlisib therapy is resumed, administer at the prior dose and monitor for CMV reactivation by PCR or antigen test at least monthly.

Monitor for signs and symptoms of infection during copanlisib therapy. If grade 3 or greater infection occurs, withhold copanlisib.

Hyperglycemia

Risk of infusion-related hyperglycemia. Grade 3 or 4 hyperglycemia (blood glucose concentrations ≥250 mg/dL) reported in 41% of patients in clinical studies. Elevated blood glucose concentrations usually peaked 5–8 hours post-infusion, and then gradually declined to baseline within 24 hours in most patients. Blood glucose concentrations remained elevated in 17.7% of patients 1 day after copanlisib infusion. In clinical studies, an increase in glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) concentration exceeding 6.5% occurred at the end of treatment in 10% of patients with a baseline HbA_1c of 5.7% or less.

In patients with diabetes mellitus, achieve adequate glycemic control prior to initiating copanlisib therapy; closely monitor such patients during therapy.

Prior to each copanlisib infusion, achieve optimal glycemic control. If hyperglycemia occurs, temporarily interrupt copanlisib therapy and/or reduce the dosage or discontinue therapy depending on the severity and persistence of hyperglycemia.

Hypertension

Risk of infusion-related hypertension. Grade 3 hypertension (SBP ≥160 mm Hg or DBP ≥100 mm Hg) reported in 26% of patients receiving copanlisib monotherapy in clinical trials; serious hypertensive events reported in 0.9% of these patients. BP peaked approximately 2 hours after infusion, and then gradually decreased; BP remained elevated for 6–8 hours after initiating the infusion.

Achieve optimal BP control prior to each copanlisib infusion. Monitor BP before and following each infusion. May need to interrupt therapy, reduce dosage, and/or permanently discontinue copanlisib depending on severity and persistence of hypertension.

Noninfectious Pneumonitis

Noninfectious pneumonitis reported.

Evaluate patients for possible pneumonitis if pulmonary manifestations (e.g., cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam) occur. If pneumonitis is suspected, withhold therapy.

Treatment for copanlisib-induced pneumonitis has included discontinuance of copanlisib and administration of systemic corticosteroids. May also need to reduce dosage and/or permanently discontinue the drug depending on severity and persistence of pneumonitis.

Neutropenia

Severe (grade 3 or 4) neutropenia reported.

Monitor CBC counts at least weekly during therapy. May need to interrupt therapy, reduce dosage, and/or permanently discontinue copanlisib depending on severity and persistence of neutropenia.

Severe Cutaneous Reactions

Severe dermatologic reactions, including exfoliative dermatitis, pruritus, and rash (e.g., maculopapular rash) reported.

May need to interrupt therapy, reduce dosage, and/or permanently discontinue copanlisib depending on severity and persistence of severe dermatologic reaction.

Fetal/Neonatal Morbidity and Mortality

Based on its mechanism of action and animal findings, copanlisib may cause fetal harm. Embryofetal toxicity and teratogenicity demonstrated in animals.

Perform a pregnancy test prior to initiation of copanlisib therapy in women of childbearing potential. Avoid pregnancy during therapy and for ≥1 month after drug discontinuance. Advise women of childbearing potential and men who are partners of such women to use highly effective contraception (i.e., contraception with a failure rate of <1% per year) while receiving the drug and for ≥1 month after discontinuance of therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Specific Populations

Pregnancy

Based on its mechanism of action and animal findings, may cause fetal harm. Avoid pregnancy during copanlisib therapy.

Lactation

Distributed into milk in rats; not known whether drug and/or metabolites distribute into human milk or if drug has any effect on milk production or the nursing infant.

Because of the potential for serious adverse reactions to copanlisib in nursing infants, women should not breast-feed during therapy and for ≥1 month following drug discontinuance.

Females and Males of Reproductive Potential

Advise females of reproductive potential and men who are partners of such women to use highly effective contraception (i.e., contraception with a failure rate of <1% per year) while receiving copanlisib and for at least 1 month after discontinuance of therapy.

Data on the effects of copanlisib on human fertility are not available. However, due to its mechanism of action and findings in animal studies, adverse effects on reproduction, including fertility, are expected.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

In clinical studies evaluating copanlisib in patients with follicular lymphoma and other hematologic malignancies, 48% of patients were ≥65 years of age and 16% were ≥75 years of age. No clinically important differences in efficacy in geriatric patients (≥65 years of age) compared with younger adults.

Higher incidences of serious adverse reactions and discontinuance of copanlisib due to adverse reactions observed in patients ≥65 years of age compared with younger adults.

Hepatic Impairment

Pharmacokinetics not affected by mild hepatic impairment (bilirubin concentration not greater than ULN with AST concentration greater than ULN, or bilirubin concentration <1–1.5 times ULN with any AST concentration). Data are not available for patients with moderate or severe hepatic impairment. Reduce dosage in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Renal Impairment

Pharmacokinetics not affected by mild, moderate, or severe renal impairment (Cl_cr ≥15 mL/minute). Not studied in patients with end-stage renal disease, including those undergoing dialysis.

Common Adverse Effects

Adverse effects (≥20%) include hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, thrombocytopenia.

Drug Interactions

Metabolized principally by CYP3A and, to a lesser extent (<10%), by CYP1A1.

Not expected to inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, or UGT or dihydropyrimidine dehydrogenase (DPD). Not expected to inhibit efflux transporter P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multi-drug resistance-associated protein (MRP2), bile salt export pump (BSEP), organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion protein 1 (MATE1). Inhibits MATE2-K.

Substrate of P-gp and BCRP; not a substrate of OATP1B1, OATP1B3, OAT1, OAT3, OCT 1, OCT2, OCT3, MATE1 or MATE2-K.

Does not induce CYP isoenzymes 1A2, 2B6, or 3A.

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A: Potential pharmacokinetic interaction (increased systemic exposure to copanlisib and increased risk of toxicity). If concomitant use cannot be avoided, reduce copanlisib dosage.

Potent inducers of CYP3A: Potential pharmacokinetic interaction (decreased systemic exposure to copanlisib). Avoid concomitant use.

Drugs Affecting the P-glycoprotein Transport System

P-gp inhibitors: Potential pharmacokinetic interaction (increased systemic exposure to copanlisib).

P-gp inducers Potential pharmacokinetic interaction (decreased systemic exposure to copanlisib).

Drugs Affected by Other Membrane Transporters

MATE2-K substrates; Based on pharmacokinetics of copanlisib, MATE2-K inhibition may occur following infusion of the drug at the recommended dosage. The clinical importance of this potential inhibition not known.

Specific Drugs and Foods

Copanlisib Pharmacokinetics

Absorption

Plasma Concentrations

AUC and peak plasma concentration increase in a dose-proportional manner over a dosage range of 5–93 mg.

Distribution

Extent

Not known whether copanlisib and/or metabolites distribute into human milk. In lactating rats, approximately 2% of the radioactivity from a radiolabeled dose of copanlisib was secreted into milk; the milk to plasma ratio of radioactivity was 25-fold.

Copanlisib and metabolites cross the placenta. Following administration of radiolabeled drug to pregnant animals, approximately 1.5% of the radioactivity reached the fetal compartment.

Plasma Protein Binding

84.2% (mainly to albumin).

Elimination

Metabolism

Principally metabolized (approximately 90%) by CYP3A and to a lesser extent (<10%) by CYP1A1.

Principal active metabolite is M-1, which accounts for 5% of total radioactivity AUC and has comparable pharmacologic activity (i.e., PI3K-α and PI3K-δ inhibition) as the parent drug.

Elimination Route

Eliminated in feces (approximately 64% [about 30% as unchanged drug]) and urine (approximately 22% [about 15% as unchanged drug]). Metabolites from CYP-mediated metabolism accounted for 41% of administered dose.

Half-life

Mean terminal half-life: 39.1 hours (range: 14.6–82.4 hours).

Special Populations

In a pharmacokinetic population analysis, age (20–90 years), gender, race, smoking status, body weight, mild hepatic impairment, and mild or moderate renal impairment did not have clinically important effects on copanlisib pharmacokinetics.

Not studied in patients with moderate or severe hepatic impairment, severe renal impairment, or end-stage renal disease (with or without dialysis).

Stability

Storage

Parenteral

For IV infusion only

Store unopened vials at 2–8°C.

Following reconstitution or dilution, use solution immediately or store at 2–8°C in the original vial or infusion bag for ≤24 hours.

Following refrigeration of the diluted infusion solution, allow solution to adapt to room temperature prior to administration. Protect diluted solution from direct sunlight.

Actions

• Inhibits phosphatidylinositol-3-kinase (PI3K). Phosphatidylinositol-3-kinases are lipid kinases consisting of a catalytic subunit that exists in 4 different isoforms (α, β, γ, δ). Copanlisib is a pan-class inhibitor of PI3K that is predominantly active against the PI3K-α and PI3K-δ isoforms.

• The PI3K-α and PI3K-δ isoforms are expressed in malignant B cells.

• Induces apoptosis and inhibits proliferation of primary malignant B-cell lines.

• Inhibits several important cell signaling pathways, including B-cell receptor (BCR) signaling, CXCR12-mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.

Advice to Patients

• Risk of serious infections such as pneumonia. Instruct patients to immediately report fever or any other signs of infection.

• Risk of infusion-related hyperglycemia. Advise patients to report signs or symptoms of hyperglycemia (e.g., pronounced hunger, excessive thirst, frequent urination, headaches). Blood glucose concentrations should be well controlled prior to infusions of copanlisib.

• Risk of infusion-related hypertension. Advise patients to inform clinician if any symptoms of hypertension (e.g., dizziness, fainting, headache, pounding heart) occur during therapy. Advise patients that BP should be normal or well controlled prior to copanlisib infusion.

• Risk of noninfectious pneumonitis. Advise patients to inform clinician if new or worsening respiratory symptoms (e.g., cough, dyspnea) occur.

• Risk of neutropenia. Inform patients of need for periodic monitoring of CBC during copanlisib therapy. Instruct patients to immediately inform clinician if fever or other signs of infection occur.

• Risk of severe dermatologic reactions. Advise patients to immediately inform clinician if dermatologic reactions (e.g., rash, redness, swelling, itching or peeling skin) occur during copanlisib therapy.

• Risk of fetal harm. Advise females of childbearing potential to avoid pregnancy and to use effective contraceptive methods while receiving copanlisib and for ≥1 month following discontinuance of therapy. Advise women to inform clinicians immediately if they become pregnant during therapy or think they may be pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.

• Advise women to avoid breast-feeding while receiving copanlisib and for ≥1 month after discontinuance of therapy.

• Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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