Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Aliqopa: 60 mg (1 ea)
Pharmacology
Mechanism of Action
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.
Pharmacokinetics/Pharmacodynamics
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 in Specific Populations
Special Populations: Hepatic Function Impairment
In a pharmacokinetic study evaluating a single 12 mg IV copanlisib dose in subjects with hepatic impairment, the geometric mean of total copanlisib Cmax and AUC increased 1.38- and 1.71-fold, respectively, in subjects with moderate impairment (Child-Pugh class B) when compared to subjects with normal hepatic function. The geometric mean unbound AUC of copanlisib was increased by 1.23-fold (with no effect on Cmax).
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
Dosage and Administration
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 (Dreyling 2017).
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: Adjustment for Toxicity
Note: A minimum of 7 days should elapse 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
Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification
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
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy
Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
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. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
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
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
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
Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification
Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
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
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
Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification
Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). 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
Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination
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. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination
Adverse Reactions
>10%:
Cardiovascular: Hypertension (35%)
Central nervous system: Fatigue (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, pruritus, 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 copanlisib 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
Pregnancy Considerations
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to copanlisib may cause fetal harm.
Pregnancy testing should be conducted prior to therapy in women of reproductive potential. Highly effective contraception (contraception with a failure rate of <1% per year) is recommended in women of reproductive potential during treatment and for at least 1 month after the last dose. Males with female partners of reproductive potential should also use highly effective contraception during treatment and for at least 1 month after the last copanlisib dose.
Patient Education
What is this drug used for?
- It is used to treat a type of lymphoma.
Frequently reported side effects of this drug
- Diarrhea
- Nausea
- Vomiting
- Fatigue
- Mouth irritation
- Mouth sores
- Common cold symptoms
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Infection
- High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
- Severe headache
- Severe dizziness
- Passing out
- Vision changes
- Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse
- Low phosphate like vision changes, confusion, mood changes, muscle pain, muscle weakness, shortness of breath, trouble breathing, or trouble swallowing
- Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; menstruation; bruises without a reason or that get bigger; or any severe or persistent bleeding
- Burning or numbness feeling
- Severe loss of strength and energy
- Signs of a significant reaction like 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. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
