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Copanlisib

Pronunciation

(koe pan LIS ib)

Index Terms

  • Aliqopa
  • BAY-80-6946 Dihydrochloride
  • Copanlisib Dihydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Aliqopa: 60 mg (1 ea)

Brand Names: U.S.

  • Aliqopa

Pharmacologic Category

  • Antineoplastic Agent, Phosphatidylinositol 3-Kinase Inhibitor

Pharmacology

Copanlisib inhibits phosphatidylinositol 3-kinase (PI3K), primarily the P13K-alpha and P13K-delta isoforms which are expressed in malignant B-cells. Copanlisib induces tumor cell death through apoptosis and inhibition of proliferation of primary malignant B cell lines. In addition, copanlisib inhibits several signaling pathways, including B-cell receptor signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.

Distribution

871 L (range: 423 to 2,150 L)

Metabolism

Primarily hepatic (>90%) though CYP3A and <10% through CYP1A1; the M-1 metabolite has pharmacologic activity comparable to the parent compound (against P13K-alpha and P13K-beta)

Excretion

12 mg IV dose: Feces (~64%; ~30% as unchanged drug); urine (~22%; ~15% as unchanged drug); metabolites account for 41% of the administered dose

Half-Life Elimination

39.1 hours (range: 14.6 to 82.4 hours)

Protein Binding

84.2%, primarily to albumin

Use: Labeled Indications

Follicular lymphoma (relapsed): Treatment of relapsed follicular lymphoma (FL) in adults who have received at least two prior systemic therapies

Contraindications

There are no contraindications listed in the manufacturer's labeling

Dosing: Adult

Follicular lymphoma (relapsed): IV: 60 mg on days 1, 8, and 15 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity.

Dosage adjustment for concomitant strong CYP3A inhibitors:Avoid concomitant use of strong CYP3A inhibitors; if concurrent therapy cannot be avoided, reduce the copanlisib dose to 45 mg.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Note: Renal function may be estimated using the Cockcroft-Gault formula.

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, CrCl ≥30 mL/minute did not significantly affect the pharmacokinetics of copanlisib.

CrCl 15 to 29 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

End-stage renal disease (ESRD): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling; however, mild hepatic impairment did not significantly affect the pharmacokinetics of copanlisib.

Moderate to severe impairment (total bilirubin ≥1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Adjustment for Toxicity

Note: Ensure a minimum of 7 days between any 2 consecutive infusions. Manage toxicities with dose reduction, treatment delay, or therapy discontinuation.

Hematologic toxicity:

Neutropenia:

ANC 500 to 1,000/mm3: Continue current copanlisib dose; monitor ANC at least weekly.

ANC <500/mm3: Interrupt copanlisib therapy. Monitor ANC at least weekly until ≥500/mm3, then resume at the previous dose. If ANC <500/mm3 recurs, then reduce copanlisib dose to 45 mg.

Thrombocytopenia: Platelets <25,000/mm3: Interrupt copanlisib therapy. May resume treatment when platelets recover to ≥75,000/mm3; if recovery occurs within 21 days, reduce dose from 60 mg to 45 mg (or from 45 mg to 30 mg). If recovery does not occur within 21 days, discontinue copanlisib.

Nonhematologic toxicity:

Dermatologic toxicity:

Grade 3 cutaneous reaction: Interrupt copanlisib therapy until toxicity is resolved; upon recovery, reduce dose from 60 mg to 45 mg (or from 45 mg to 30 mg).

Life-threatening: Discontinue copanlisib

Hyperglycemia:

Pre-dose fasting blood glucose ≥160 mg/dL or random (non-fasting) blood glucose ≥200 mg/dL: Withhold copanlisib until fasting glucose is ≤160 mg/dL or a random (non-fasting) blood glucose is ≤200 mg/dL.

Pre-dose or post-dose blood glucose ≥500 mg/dL:

First occurrence: Withhold copanlisib until fasting blood glucose is ≤160 mg/dL, or a random (nonfasting) blood glucose is ≤200 mg/dL. Reduce dose from 60 mg to 45 mg.

Subsequent occurrences: Withhold copanlisib until fasting blood glucose is ≤160 mg/dL, or a random (nonfasting) blood glucose is ≤200 mg/dL. Reduce dose from 45 mg to 30 mg. If hyperglycemia is persistent at the 30 mg dose, discontinue copanlisib.

Hypertension:

Pre-dose blood pressure ≥150/90: Withhold copanlisib until blood pressure is <150/90 (both systolic and diastolic) based on 2 consecutive measurements at least 15 minutes apart.

Post-dose blood pressure ≥150/90 (not life-threatening): If antihypertensive therapy is not required, continue copanlisib at the previous dose. If antihypertensive treatment is necessary, consider copanlisib dose reduction from 60 mg to 45 mg (or from 45 mg to 30 mg). Discontinue copanlisib if blood pressure remains uncontrolled (>150/90) despite appropriate antihypertensive treatment.

Post-dose elevated blood pressure with life-threatening consequences: Discontinue copanlisib.

Infection:

≥ Grade 3: Withhold copanlisib until resolution of infection.

Suspected pneumocystis jirovecii pneumonia (PCP) infection of any grade: Withhold copanlisib; if infection is confirmed, treat infection until resolution, then resume copanlisib at previous dose with concomitant PCP prophylaxis.

Pneumonitis (noninfectious):

Grade 2: Withhold copanlisib and treat pneumonitis appropriately. If noninfectious pneumonitis recovers to grade 0 or 1, resume copanlisib at 45 mg. If grade 2 toxicity recurs, discontinue copanlisib.

≥ Grade 3: Discontinue copanlisib.

Other severe and non-life-threatening toxicities: Grade 3: Withhold copanlisib until resolution and reduce copanlisib from 60 mg to 45 mg (or from 45 mg to 30 mg).

Reconstitution

Use only NS for reconstitution and dilution; do not use other diluents. Reconstitute each vial with 4.4 mL of sterile NS to a concentration of 15 mg/mL; gently shake the vial for 30 seconds. Allow vial to rest for 1 minute to let bubbles rise to the surface; if undissolved substance is still observed, repeat the steps (solutions should be colorless to slightly yellowish). Once fully dissolved, further dilute appropriate dose in 100 mL sterile NS; mix by gentle inversion. If refrigerated, allow solution to come to room temperature prior to infusion; avoid exposure of solution to direct sunlight.

Administration

IV: Infuse over 1 hour. Do not mix with or administer with any other medications. Do not infuse with any solutions other than NS.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Reconstituted solutions and solutions diluted for infusion (if not used immediately) are stable for up to 24 hours at 2°C to 8°C (36°F to 46°F); infuse within 24 hours. Protect solutions diluted for infusion from direct sunlight.

Drug Interactions

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ceritinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of Copanlisib. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Copanlisib. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Copanlisib. Management: If concomitant use of copanlisib and strong CYP3A4 inhibitors cannot be avoided, reduce the copanlisib dose to 45 mg. Monitor patients for increased copanlisib effects/toxicities. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

DilTIAZem: May increase the serum concentration of Copanlisib. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of Copanlisib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Hypertension (35%)

Central nervous system: Decreased energy (36%)

Dermatologic: Skin rash (15%)

Endocrine & metabolic: Hyperglycemia (54% to 95%), hypertriglyceridemia (58%), hypophosphatemia (44%), hyperuricemia (25%)

Gastrointestinal: Diarrhea (36%), nausea (26%), increased serum lipase (21%), stomatitis (14%), vomiting (13%)

Hematologic & oncologic: Decreased hemoglobin (78%; grade 3: 4%), leukopenia (36%; grade 3: 12%; grade 4: 15%), decreased absolute lymphocyte count (78%; grade 3: 27%; grade 4: 2%), neutropenia (32%; grade 3: 10% to ≤24%; grade 4: 15% to ≤24%), thrombocytopenia (22%; grade 3: 7%; grade 4: 1%)

Infection: Serious infection (19%)

Respiratory: Lower respiratory tract infection (21%)

1% to 10%:

Central nervous system: Dysesthesia (≤7%), paresthesia (≤7%)

Endocrine & metabolic: Severe hyperglycemia (3% to 5%)

Gastrointestinal: Mucosal inflammation (8%)

Hematologic & oncologic: Severe neutropenia (1%)

Respiratory: Pneumonitis (5% to 9%), pneumonia (8%)

<1%, postmarketing and/or case reports: Exfoliative dermatitis, pneumonia due to pneumocystis, pruritus

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Leukopenia, neutropenia, thrombocytopenia, lymphopenia, and anemia (including grade 3 or 4 events), have been reported with copanlisib therapy. Grade 3 or 4 neutropenia has occurred in close to one quarter of patients receiving copanlisib; serious neutropenic events also were reported. Monitor blood counts at least weekly during treatment; therapy interruption, dose reduction, or treatment discontinuation may be necessary depending on the severity and persistence of neutropenia.

• Dermatologic toxicity: Dermatologic toxicities, including grade 3 and 4 cutaneous events, have been observed with copanlisib monotherapy. Toxicities included exfoliative dermatitis, exfoliative rash, pruritis, and rash (including maculopapular rash). Therapy interruption, dose reduction, or treatment discontinuation may be necessary depending on the severity and persistence of severe cutaneous reactions.

• GI toxicity: Diarrhea, nausea, vomiting, and stomatitis have been reported.

• Hyperglycemia: Grade 3 or 4 hyperglycemia was reported commonly in patients treated with copanlisib monotherapy, including serious hyperglycemic events; infusion-related hyperglycemia may occur. Serum glucose levels typically peaked at 5 to 8 hours post infusion, and then declined to baseline levels in the majority of patients; some patients had elevated serum glucose levels one day after the infusion. In patients with baseline HbA1c <5.7%, 10% had HbA1c >6.5% at the conclusion of copanlisib therapy. Prior to each copanlisib infusion, achieve optimal serum glucose control; therapy interruption, dose reduction, or treatment discontinuation may be necessary depending on the severity and persistence of hyperglycemia. Patients with diabetes mellitus should only be treated with conanlisib if adequate glucose control is achieved; monitor closely.

• Hypertension: Hypertension (including grade 3 and serious events) has occurred during copanlisib therapy; infusion-related hypertension may occur. Grade 3 hypertension (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg) was reported in over one quarter of patients treated with copanlisib monotherapy. Systolic and diastolic blood pressures increased 16.8 mm Hg and 7.8 mm Hg, respectively, from baseline to 2 hours post infusion (in cycle 1 day 1); the mean blood pressure began decreasing ~2 hours post infusion, however, blood pressure remained elevated for 6 to 8 hours after the start of infusion. Monitor blood pressure before and after infusion; optimize blood pressure control prior to initiating each dose. Therapy interruption, dose reduction, or treatment discontinuation may be necessary depending on the severity and persistence of hypertension.

• Infection: Serious and fatal infections have occurred during treatment with copanlisib. The most commonly reported infection was pneumonia. Monitor for signs and symptoms of infection and interrupt therapy for grade 3 and higher infections. Serious Pneumocystis jirovecii pneumonia (PCP) has also been reported (rarely). Consider PCP prophylaxis in patients at risk; interrupt copanlisib for suspected PCP infection (any grade). If confirmed, treat infection until resolution and then resume copanlisib therapy at the previous dose (with concomitant PCP prophylaxis).

• Pulmonary toxicity: Noninfectious pneumonitis has been reported with copanlisib monotherapy. Interrupt treatment and determine cause in patients with pulmonary symptoms (eg, cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam). Management for copanlisib-induced pneumonitis may include therapy interruption and systemic corticosteroids. Therapy interruption, dose reduction, or treatment discontinuation may be necessary depending on the severity and persistence of non-infectious pneumonitis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Monitor blood counts at least weekly during treatment; blood glucose and blood pressure pre-and post-dose and more frequently if clinically indicated; pregnancy test (prior to treatment in in females of reproductive potential); monitor for signs/symptoms of infection (eg, pneumocystis jirovecii pneumonia), non-infectious pneumonitis, and dermatologic toxicity

Pregnancy Considerations

Based on information from animal reproduction studies and the mechanism of action, fetal harm may occur if exposure to copanlisib occurs during pregnancy.

Pregnancy testing should be conducted prior to therapy in women of reproductive potential. Highly effective contraception is recommended in women of reproductive potential and also in males administered copanlisib with female partners of reproductive potential. Highly effective contraceptives are those with a failure rate of <1% per year and should be used during treatment and for at least 1 month after the last dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, nausea, vomiting, mouth irritation, or mouth sores. Have patient report immediately to prescriber signs of infection, signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), severe headache, severe dizziness, passing out, vision changes, signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), or severe loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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