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    Small Molecule Antineoplastic Phosphatidylinositol-3-Kinase (PI3K) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    A phosphatidylinositol-3-kinase (PI3K) inhibitor
    Used in adults with relapsed follicular lymphoma
    Severe hyperglycemia and hypertension have been reported

    COMMON BRAND NAMES

    Aliqopa

    HOW SUPPLIED

    Copanlisib Intravenous Inj Pwd: 60mg

    DOSAGE & INDICATIONS

    For the treatment of non-Hodgkin's lymphoma (NHL).
    For the treatment of relapsed follicular lymphoma in patients who have received at least 2 prior systemic therapies.
    NOTE: Copanlisib has been designated an orphan drug by the FDA for the treatment of follicular lymphoma.
    Intravenous dosage
    Adults

    60 mg IV over 1 hour on days 1, 8, and 15 repeated every 28 days until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, or therapy discontinuation may be necessary in patients who develop toxicity. The overall response rate was 59% (complete response rate, 14%) in 104 patients with relapsed follicular B-cell non-Hodgkin lymphoma who received copanlisib in a multicenter, phase II trial (the CHRONOS-1 trial). The median time to response was 1.7 months (range, 1.3 to 9.7 months) and the median duration of response was 12.2 months (range, up to 22.6 months). Patients (median age, 62 years; range, 25 to 81 years) in this study had received a median of 3 prior treatments (range, 2 to 8 treatments) including rituximab and an alkylating agent.

    MAXIMUM DOSAGE

    Adults

    60 mg IV.

    Geriatric

    60 mg IV.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment (total bilirubin level of 1 times the upper limit of normal (ULN) or less and AST level greater than the ULN, or a total bilirubin level greater than 1- to 1.5-times the ULN and any AST level): No dosage adjustment necessary.Moderate hepatic impairment (Child-Pugh class B): Reduce the copanlisib dose to 45 mg IV.Severe hepatic impairment (Child-Pugh class C): Specific guidelines for dosage adjustments are not available; copanlisib has not been evaluated in patients with severe hepatic impairment.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution
    Add 4.4 mL of sterile 0.9% Sodium Chloride injection to the 60-mg lyophilized powder vial by injecting the measured volume through the disinfected stopper surface using a 5-mL sterile syringe; the final concentration of the reconstituted vial is 15 mg/mL.
    Gently shake the vial for 30 seconds to dissolve the powder and then allow the vial to stand for 1 minute letting the bubbles rise to the surface; repeat this procedure if any undissolved powder is observed.
    The solution will be colorless to slightly yellowish after reconstitution.
    Storage of reconstituted vial: if not diluted immediately, store refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours before use; protect from direct sunlight.
    Dilution
    Into an infusion bag containing 100 mL of sterile 0.9% Sodium Chloride injection, add the appropriate volume (based on the desired dose) from the reconstituted vial as follows:
    60-mg dose: 4 mL
    45-mg dose: 3 mL
    30-mg dose: 2 mL
    Invert the infusion bag to mix.
    Discard any unused contents from the reconstituted vial.
    Storage of diluted admixture: if not used immediately, store refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours (from vial reconstitution) before use; protect from direct sunlight.
    Intravenous (IV) Infusion
    Allow the diluted admixture in the infusion bag to warm to room temperature (if stored in refrigerator) prior to administration.
    Administer as an IV infusion over 1 hour.
    Do not mix or inject copanlisib with other drugs or diluents.

    STORAGE

    Aliqopa:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from direct sunlight
    - Reconstituted product should be refrigerated and used within 24 hours if not used immediately
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Infection

    Serious infection has occurred in patients receiving copanlisib therapy; some cases were fatal. Monitor patients for signs and symptoms of infection; hold therapy for grade 3 or higher infection. Serious pneumocystis jiroveci pneumonia (PJP) has occurred with copanlisib use; consider PJP prophylaxis in at-risk patients before initiating therapy. Hold therapy if PJP is suspected. If PJP diagnosis is confirmed, treat the infection until resolution and then resume copanlisib at the previous dose and give PJP prophylaxis for the duration of therapy.

    Diabetes mellitus, hyperglycemia

    Severe hyperglycemia, elevated HbA1c, and infusion-related hyperglycemia have occurred with copanlisib therapy; additionally, serious hyperglycemic events have been reported. Monitor blood glucose levels before and after the copanlisib infusion. Therapy interruption, dose reduction, or therapy discontinuation may be necessary in patients who develop hyperglycemia. Blood glucose levels typically peak at 5 to 8 hours post infusion and then decline to baseline levels in most patients. Use copanlisib with caution in patients with diabetes mellitus. Initiate copanlisib therapy only after these patients have achieved optimal blood glucose control; monitor blood glucose levels in these patients closely.

    Hypertension

    Severe hypertension and infusion-related hypertension have occurred with copanlisib therapy; use copanlisib with caution in patients with pre-existing hypertension. Monitor blood pressure before and after the copanlisib infusion; optimal blood pressure control should be achieved prior to each dose. Therapy interruption, dose reduction, or therapy discontinuation may be necessary in patients who develop hypertension. A mean increase in systolic (+16.8 mmHg) and diastolic (+7.8 mmHg) blood pressure was observed at 2 hours post infusion on day 1 of cycle 1 of copanlisib therapy; blood pressure typically remained elevated for 6 to 8 hours after the start of the infusion.

    Pneumonitis, pulmonary disease

    Non-infectious pneumonitis has occurred with copanlisib therapy; use copanlisib with caution in patients with pre-existing pulmonary disease. Hold therapy and evaluate patients who experience signs or symptoms of pneumonitis (e.g., cough, dyspnea, hypoxia, and interstitial infiltrates on X-ray exam). Therapy interruption, dose reduction, or therapy discontinuation may be necessary in patients who develop pneumonitis. The use of systemic corticosteroid may be beneficial in these patients.

    Neutropenia, thrombocytopenia

    Severe hematologic toxicity including neutropenia and thrombocytopenia has occurred with copanlisib therapy. Monitor complete blood counts at least weekly during treatment. Therapy interruption, dose reduction, or therapy discontinuation may be necessary in patients who develop severe neutropenia or thrombocytopenia.

    Serious rash

    Severe cutaneous reactions (e.g., serious rash) have occurred with copanlisib therapy. Therapy interruption, dose reduction, or therapy discontinuation may be necessary in patients who develop severe skin reactions.

    Hepatic disease

    Reduce the dose of copanlisib in patients with moderate hepatic disease/impairment (Child-Pugh class B). Copanlisib has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Evaluate liver function tests at baseline and as clinically appropriate during therapy.

    Geriatric

    Geriatric patients with follicular lymphoma or other hematologic malignancies had a higher incidence of serious adverse reactions compared with patients aged less than 65 years (30% vs. 23%) after treatment with single-agent copanlisib in a pooled analysis from clinical trials (n = 168). However, an initial dose adjustment is not necessary in patients 65 years or older.

    Pregnancy

    Copanlisib can cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid becoming pregnant while receiving copanlisib. Advise patients to notify their healthcare provider immediately if they become pregnant or if pregnancy is suspected during treatment. Embryo-fetal toxicities including embryo-fetal death and fetal abnormalities (e.g., domed head, malformed eyeballs or eyeholes, hydrocephalus internus, ventricular septal defects, major vessel malformations, dysplastic forelimb bones, malformed ribs and vertebrae, and pelvis shift) were observed when copanlisib was administered to pregnant rats during organogenesis at doses corresponding to approximately 12% the recommended dose in humans.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during copanlisib treatment. Pregnancy testing prior to starting therapy is recommended for females of reproductive potential. These patients should avoid pregnancy and use highly effective contraception during therapy and for at least 1 month after the last copanlisib dose. Due to the risk of male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception during and for at least 1 month after copanlisib therapy. Adverse effects on male and female reproduction (e.g., infertility) are expected based on findings from animal studies.

    Breast-feeding

    It is not known whether copanlisib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because of the potential for serious adverse reactions in nursing infants, women should discontinue breast-feeding during copanlisib therapy and for at least 1 month after the last dose.

    ADVERSE REACTIONS

    Severe

    hyperglycemia / Delayed / 0-41.0
    lymphopenia / Delayed / 0-29.0
    hypertension / Early / 0-27.0
    leukopenia / Delayed / 0-27.0
    neutropenia / Delayed / 0-25.0
    hyperuricemia / Delayed / 25.0-25.0
    infection / Delayed / 0-19.0
    hypophosphatemia / Delayed / 15.0-15.0
    thrombocytopenia / Delayed / 0-8.0
    hypertriglyceridemia / Delayed / 5.0-5.0
    diarrhea / Early / 5.0-5.0
    anemia / Delayed / 0-4.0
    asthenia / Delayed / 0-4.0
    fatigue / Early / 0-4.0
    rash / Early / 0-2.0
    stomatitis / Delayed / 2.0-2.0
    nausea / Early / 0-1.0
    pruritus / Rapid / 0-0.9
    exfoliative dermatitis / Delayed / 0-0.9
    maculopapular rash / Early / 0-0.9

    Moderate

    pneumonitis / Delayed / 5.0-9.0
    dyspnea / Early / Incidence not known
    hypoxia / Early / Incidence not known

    Mild

    vomiting / Early / 13.0-13.0
    paresthesias / Delayed / 7.0-7.0
    dysesthesia / Delayed / 7.0-7.0
    cough / Delayed / Incidence not known

    DRUG INTERACTIONS

    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid the concomitant use of copanlisib and clarithromycin if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; clarithromycin is a strong CYP3A inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the concomitant use of copanlisib and clarithromycin if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; clarithromycin is a strong CYP3A inhibitor.
    Apalutamide: (Major) Avoid the concomitant use of copanlisib and apalutamide; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A4 inducer decreased exposure after a single dose of copanlisib by 60%.
    Atazanavir: (Major) Avoid the concomitant use of copanlisib and atazanavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; atazanavir is a strong CYP3A inhibitor.
    Atazanavir; Cobicistat: (Major) Avoid the concomitant use of copanlisib and atazanavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; atazanavir is a strong CYP3A inhibitor. (Major) Avoid the concomitant use of copanlisib and cobicistat if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. The AUC of copanlisib increased by 53% when a single IV dose of copanlisib 60 mg was administered following 10 days of another strong CYP3A4 inhibitor in a drug interaction study in patients with cancer.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid the concomitant use of copanlisib and phenobarbital; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; phenobarbital is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the concomitant use of copanlisib and phenobarbital; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; phenobarbital is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
    Carbamazepine: (Major) Avoid the concomitant use of copanlisib and carbamazepine; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; carbamazepine is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
    Ceritinib: (Major) Avoid the concomitant use of copanlisib and ceritinib if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; ceritinib is a strong CYP3A inhibitor.
    Chloramphenicol: (Major) Avoid the concomitant use of copanlisib and chloramphenicol if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; chloramphenicol is a strong CYP3A inhibitor.
    Clarithromycin: (Major) Avoid the concomitant use of copanlisib and clarithromycin if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; clarithromycin is a strong CYP3A inhibitor.
    Cobicistat: (Major) Avoid the concomitant use of copanlisib and cobicistat if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. The AUC of copanlisib increased by 53% when a single IV dose of copanlisib 60 mg was administered following 10 days of another strong CYP3A4 inhibitor in a drug interaction study in patients with cancer.
    Conivaptan: (Major) Avoid the concomitant use of copanlisib and conivaptan if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; conivaptan is a strong CYP3A inhibitor.
    Darunavir: (Major) Avoid the concomitant use of copanlisib and darunavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; darunavir is a strong CYP3A inhibitor.
    Darunavir; Cobicistat: (Major) Avoid the concomitant use of copanlisib and cobicistat if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. The AUC of copanlisib increased by 53% when a single IV dose of copanlisib 60 mg was administered following 10 days of another strong CYP3A4 inhibitor in a drug interaction study in patients with cancer. (Major) Avoid the concomitant use of copanlisib and darunavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; darunavir is a strong CYP3A inhibitor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid the concomitant use of copanlisib and cobicistat if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. The AUC of copanlisib increased by 53% when a single IV dose of copanlisib 60 mg was administered following 10 days of another strong CYP3A4 inhibitor in a drug interaction study in patients with cancer. (Major) Avoid the concomitant use of copanlisib and darunavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; darunavir is a strong CYP3A inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of copanlisib and ritonavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor.
    Delavirdine: (Major) Avoid the concomitant use of copanlisib and delavirdine if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; delavirdine is a strong CYP3A inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid the concomitant use of copanlisib and cobicistat if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. The AUC of copanlisib increased by 53% when a single IV dose of copanlisib 60 mg was administered following 10 days of another strong CYP3A4 inhibitor in a drug interaction study in patients with cancer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of copanlisib and cobicistat if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. The AUC of copanlisib increased by 53% when a single IV dose of copanlisib 60 mg was administered following 10 days of another strong CYP3A4 inhibitor in a drug interaction study in patients with cancer.
    Enzalutamide: (Major) Avoid the concomitant use of copanlisib and enzalutamide; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A4 inducer decreased exposure after a single dose of copanlisib by 60%.
    Fluvoxamine: (Major) Avoid the concomitant use of copanlisib and fluvoxamine if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; fluvoxamine is a strong CYP3A inhibitor.
    Fosamprenavir: (Major) Avoid the concomitant use of copanlisib and fosamprenavir if possible due to an unpredictable effect on copanlisib exposure. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash) and/or decreased copanlisib efficacy. Copanlisib is a CYP3A substrate; fosamprenavir is a strong CYP3A4 inhibitor with the potential to also induce CYP3A4.
    Fosphenytoin: (Major) Avoid the concomitant use of copanlisib and fosphenytoin; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; fosphenytoin is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
    Grapefruit juice: (Major) Avoid the concomitant use of copanlisib and grapefruit juice if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; grapefruit juice is a strong CYP3A inhibitor.
    Idelalisib: (Major) Avoid the concomitant use of copanlisib and idelalisib if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; idelalisib is a strong CYP3A inhibitor.
    Indinavir: (Major) Avoid the concomitant use of copanlisib and indinavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; indinavir is a strong CYP3A inhibitor.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of copanlisib and rifampin; decreased copanlisib exposure occurred in a drug interaction study. Copanlisib is a substrate of CYP3A and P-glycoprotein (P-gp); rifampin is a strong CYP3A inducer and also induces P-gp. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of rifampin 600 mg/day in a drug interaction study in patients with cancer.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of copanlisib and rifampin; decreased copanlisib exposure occurred in a drug interaction study. Copanlisib is a substrate of CYP3A and P-glycoprotein (P-gp); rifampin is a strong CYP3A inducer and also induces P-gp. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of rifampin 600 mg/day in a drug interaction study in patients with cancer.
    Itraconazole: (Major) Avoid the concomitant use of copanlisib and itraconazole if possible; increased copanlisib exposure occurred in a drug interaction study. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a substrate of CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP); itraconazole is a strong CYP3A inhibitor and also inhibits P-gp and BCRP. The AUC of copanlisib increased by 53% when a single IV dose of copanlisib 60 mg was administered following 10 days of itraconazole 200 mg/day in a drug interaction study in patients with cancer; the Cmax of copanlisib was not significantly increased.
    Ketoconazole: (Major) Avoid the concomitant use of copanlisib and ketoconazole if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; ketoconazole is a strong CYP3A inhibitor.
    Letermovir: (Moderate) Administering letermovir with copanlisib may increase copanlisib concentration and risk for adverse events. Avoid coadministration in patients who are also receiving treatment with cyclosporine, because the magnitude of this interaction may be amplified. If concurrent use of copanlisib with both letermovir and cyclosporine cannot be avoided, reduce the copanlisib dose to 45 mg and monitor for toxicity. Copanlisib is predominately metabolized by CYP3A4. Letermovir a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of copanlisib by 53% with no effect on Cmax.
    Lopinavir; Ritonavir: (Major) Avoid the concomitant use of copanlisib and lopinavir; ritonavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; lopinavir; ritonavir is a strong CYP3A inhibitor. (Major) Avoid the concomitant use of copanlisib and ritonavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of copanlisib and lumacaftor; ivacaftor; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; lumacaftor is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of copanlisib and lumacaftor; ivacaftor; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; lumacaftor is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
    Mitotane: (Major) Avoid the concomitant use of copanlisib and mitotane; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; mitotane is a strong CYP3A inducer.
    Nefazodone: (Major) Avoid the concomitant use of copanlisib and nefazodone if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; nefazodone is a strong CYP3A inhibitor.
    Nelfinavir: (Major) Avoid the concomitant use of copanlisib and nelfinavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; nelfinavir is a strong CYP3A inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of copanlisib and ritonavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Phenobarbital: (Major) Avoid the concomitant use of copanlisib and phenobarbital; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; phenobarbital is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
    Phenytoin: (Major) Avoid the concomitant use of copanlisib and phenytoin; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; phenytoin is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
    Posaconazole: (Major) Avoid the concomitant use of copanlisib and posaconazole if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; posaconazole is a strong CYP3A inhibitor.
    Primidone: (Major) Avoid the concomitant use of copanlisib and primidone; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; primidone is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
    Rifampin: (Major) Avoid the concomitant use of copanlisib and rifampin; decreased copanlisib exposure occurred in a drug interaction study. Copanlisib is a substrate of CYP3A and P-glycoprotein (P-gp); rifampin is a strong CYP3A inducer and also induces P-gp. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of rifampin 600 mg/day in a drug interaction study in patients with cancer.
    Ritonavir: (Major) Avoid the concomitant use of copanlisib and ritonavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor.
    Saquinavir: (Major) Avoid the concomitant use of copanlisib and saquinavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; saquinavir boosted with ritonavir is a strong CYP3A inhibitor.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of copanlisib and St. John's Wort; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; St. John's Wort is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
    Telithromycin: (Major) Avoid the concomitant use of copanlisib and telithromycin if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; telithromycin is a strong CYP3A inhibitor.
    Tipranavir: (Major) Avoid the concomitant use of copanlisib and tipranavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; tipranavir boosted with ritonavir is a strong CYP3A inhibitor.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Voriconazole: (Major) Avoid the concomitant use of copanlisib and voriconazole if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; voriconazole is a strong CYP3A inhibitor.

    PREGNANCY AND LACTATION

    Pregnancy

    Copanlisib can cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid becoming pregnant while receiving copanlisib. Advise patients to notify their healthcare provider immediately if they become pregnant or if pregnancy is suspected during treatment. Embryo-fetal toxicities including embryo-fetal death and fetal abnormalities (e.g., domed head, malformed eyeballs or eyeholes, hydrocephalus internus, ventricular septal defects, major vessel malformations, dysplastic forelimb bones, malformed ribs and vertebrae, and pelvis shift) were observed when copanlisib was administered to pregnant rats during organogenesis at doses corresponding to approximately 12% the recommended dose in humans.

    It is not known whether copanlisib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because of the potential for serious adverse reactions in nursing infants, women should discontinue breast-feeding during copanlisib therapy and for at least 1 month after the last dose.

    MECHANISM OF ACTION

    Copanlisib is an inhibitor of phosphatidylinositol 3-kinase (PI3K); it works primarily to inhibit PI3K-alpha and PI3K-delta isoforms expressed in malignant B-cells. Copanlisib induces tumor cell death by apoptosis and by inhibiting the proliferation of primary malignant B-cell lines. It also inhibits B-cell receptor (BCR) signaling, CXCR12-mediated chemotaxis of malignant B-cells, and nuclear factor (NF) kappa B signaling in lymphoma cell lines.

    PHARMACOKINETICS

    Copanlisib is administered intravenously (IV). It is 84.2% bound to plasma proteins, primarily albumin. The mean blood-to-plasma ratio is 1.7 (range, 1.5 to 2.1). The geometric mean volume of distribution of copanlisib is 871 L (range, 423 to 2,150 L), the geometric mean terminal elimination half-life is 39.1 hours (range, 14.6 to 82.4 hours), and the geometric mean clearance is 17.9 L/hour (range, 7.3 to 51.4 L/hour). Following a single radiolabeled dose of copanlisib 12 mg IV, approximately 64% of the dose was excreted in the feces and 22% in the urine within 20 to 34 days; about 30% and 15% of the dose was recovered as unchanged copanlisib in the feces and urine, respectively. The M-1 metabolite accounted for 5% of the total radioactivity. Copanlisib is primarily metabolized by CYP3A; a minor pathway for metabolism is CYP1A1. The M-1 metabolite has pharmacological activity comparable to the parent compound copanlisib for the tested kinases PI3K-alpha and PI3K-delta.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP1A1, P-gp, BCRP, MATE2-K
    Copanlisib is a substrate of CYP3A (greater than 90%) and CYP1A1 (less than 10%). Avoid the concomitant use of copanlisib with strong CYP3A inhibitors or inducers. If copanlisib is administered with a strong CYP3A inhibitor, reduce the dose and monitor for signs of copanlisib toxicity. Copanlisib is a substrate of the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters and a multidrug and toxin extrusion member 2 (MATE2)-K inhibitor.

    Intravenous Route

    When administered at approximately the recommended dose of 60 mg, the geometric mean steady-state Cmax and AUC(0-25 hr) values of copanlisib were 463 ng/mL (range, 105 to 1,670 ng/mL) and 1,570 ng X hour/mL (range, 536 to 3,410 ng X hour/mL), respectively. The Cmax and AUC values increased proportionally and exhibited linear pharmacokinetics over a copanlisib dose range of 5 to 93 mg; there was no accumulation.