Duvelisib

Dosage Forms

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

Capsule, Oral:

Copiktra: 15 mg, 25 mg

Pharmacology

Mechanism of Action

Duvelisib is an oral PI3K inhibitor with dual inhibitory activity primarily against PI3K-δ and PI3K-γ which are expressed in hematologic malignancies. Inhibition of PI3K-δ reduced tumor cell proliferation while allowing survival of normal cells. Inhibition of PI3K-γ reduces differentiation and migration of tumor microenvironment support cells (Flinn 2018). Duvelisib resulted in reduced viability of cell lines derived from malignant B-cells and CLL cells. Additionally, duvelisib inhibits B-cell receptor signaling pathways and CXCR12-mediated chemotaxis of malignant B-cells as well as CXCL12-induced T cell migration and M-CSF and IL-4 driven M2 macrophage polarization.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 28.5 L

Metabolism

Hepatic; primarily via CYP3A4

Excretion

Feces: 79% (11% as unchanged drug); urine: 14% (<1% as unchanged drug)

Time to Peak

1 to 2 hours

Half-Life Elimination

4.7 hours

Protein Binding

>98%

Use: Labeled Indications

Chronic lymphocytic leukemia/small lymphocytic lymphoma, relapsed or refractory: Treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients after at least 2 prior therapies.

Follicular lymphoma, relapsed or refractory: Treatment of relapsed or refractory follicular lymphoma (FL) in adult patients after at least 2 prior systemic therapies.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Note: Pneumocystis jirovecii pneumonia (PCP) prophylaxis should be provided during treatment; after completion of therapy, continue PCP prophylaxis until the absolute CD4+ count is >200 cells/microliter. Consider providing prophylactic antivirals during duvelisib treatment to prevent cytomegalovirus (CMV) infection or reactivation.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (relapsed or refractory): Oral: 25 mg twice daily

Follicular lymphoma (relapsed or refractory): Oral: 25 mg twice daily

Dosage modification for concomitant CYP3A4 inhibitor use: Reduce duvelisib dose to 15 mg twice daily if administered with strong CYP3A4 inhibitors (eg, ketoconazole).

Missed doses: If a dose is missed by fewer than 6 hours, administer right away and administer the next dose as usual; if a dose is missed by more than 6 hours, wait and administer the next dose at the usual time.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Recommended duvelisib dosage adjustments for toxicity:

Initial dose: 25 mg twice daily

First dose reduction: 15 mg twice daily

Subsequent dosage modification: Discontinue duvelisib if unable to tolerate 15 mg twice daily.

Dermatologic toxicity (cutaneous reactions):

Grade 1 or 2: No dosage change is necessary; initiate supportive therapy with emollients, antihistamines (for pruritus), or topical corticosteroids. Monitor closely.

Grade 3: Withhold duvelisib until resolved; initiate supportive therapy with emollients, antihistamines (for pruritus), or topical corticosteroids. Monitor at least weekly until resolved. Resume at a reduced dose.

Life-threatening: Discontinue duvelisib.

Severe cutaneous reaction that does not improve, worsens, or recurs: Discontinue duvelisib.

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or drug reaction with eosinophilia and systemic symptoms (DRESS), any grade: Discontinue duvelisib.

Gastrointestinal toxicity (non-infectious diarrhea or colitis):

Mild or moderate diarrhea (grades 1 to 2; up to 6 stools/day over baseline) and responsive to antidiarrheal agents or asymptomatic (grade 1) colitis: No dosage change is necessary; initiate supportive therapy with antidiarrheal agents as appropriate. Monitor at least weekly until resolved.

Mild or moderate diarrhea (grades 1 to 2; up to 6 stools/day over baseline) and unresponsive to antidiarrheal agents: Withhold duvelisib until resolved. Initiate supportive therapy with enteric acting corticosteroids (eg, budesonide). Monitor at least weekly until resolved. Resume at a reduced dose.

Abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs or severe diarrhea (grade 3; >6 stools/day over baseline): Withhold duvelisib until resolved. Initiate supportive therapy with enteric acting corticosteroids (eg, budesonide) or systemic corticosteroids. Monitor at least weekly until resolved. Resume at a reduced dose. Perform diagnostic work-up (including colonoscopy) to determine etiology.

Recurrent grade 3 diarrhea or recurrent colitis (any grade): Discontinue duvelisib.

Life-threatening diarrhea or colitis: Discontinue duvelisib.

Hematologic toxicity:

Neutropenia:

ANC 500 to 1,000/mm³: Maintain duvelisib dose and monitor ANC at least weekly.

ANC <500/mm³: Withhold duvelisib and monitor ANC until >500/mm³. Resume duvelisib at the same dose (first occurrence) or at a reduced dose (for subsequent occurrence).

Thrombocytopenia:

Grade 3 (platelets 25,000 to <50,000/mm³) with grade 1 bleeding: No change in dose; monitor platelet count at least weekly.

Grade 3 (platelets 25,000 to <50,000/mm³) with grade 2 bleeding: Withhold duvelisib and monitor platelets until ≥25,000/mm³ and resolution of bleeding (if applicable). Resume duvelisib at the same dose (first occurrence) or at a reduced dose (for subsequent occurrence).

Grade 4 (platelets <25,000/mm³): Withhold duvelisib and monitor platelets until ≥25,000/mm³ and resolution of bleeding (if applicable). Resume duvelisib at the same dose (first occurrence) or at a reduced dose (for subsequent occurrence).

Infection:

Grade 3 or higher infection: Withhold duvelisib until resolved, then resume at the same dose or at a reduced dose.

Clinical CMV infection or viremia (positive PCR or antigen test): Withhold duvelisib until resolved, then resume at the same dose or at a reduced dose. If duvelisib is resumed, monitor for CMV reactivation (by PCR or antigen test) at least monthly.

Pneumocystis jirovecii pneumonia (PCP): Withhold duvelisib for suspected PCP until evaluated; discontinue duvelisib if PCP is confirmed.

Pulmonary toxicity (pneumonitis without suspected infectious etiology):

Moderate (grade 2) symptomatic pneumonitis: Withhold duvelisib; manage with systemic corticosteroid therapy. If pneumonitis recovers to grade 0 or 1, may resume duvelisib at reduced dose. If non-infectious pneumonitis recurs or does not respond to corticosteroid therapy, discontinue duvelisib.

Severe (grade 3) or life-threatening pneumonitis. Discontinue duvelisib; manage with systemic corticosteroid therapy.

Administration

Oral: Administer with or without food. Swallow capsules whole; do not open, break or chew capsules. Provide PCP prophylaxis during treatment and continue until the absolute CD4+ T cell count is >200 cells/microliter; consider prophylactic antivirals during treatment to prevent CMV infection and reactivation.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store in original package until dispensing. Dispense blister packs in original container.

Drug Interactions

Abemaciclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Abemaciclib. Monitor therapy

Acalabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Acalabrutinib. Management: Reduce acalabrutinib dose to 100 mg once daily with concurrent use of a moderate CYP3A4 inhibitor. Monitor patient closely for both acalabrutinib response and evidence of adverse effects with any concurrent use. Consider therapy modification

AmLODIPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine. Monitor therapy

Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification

Avapritinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avapritinib. Management: Avoid use of moderate CYP3A4 inhibitors with avapritinib. If this combination cannot be avoided, reduce the avapritinib dose from 300 mg once daily to 100 mg once daily. Consider therapy modification

Axitinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Axitinib. 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

Benzhydrocodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased. Monitor therapy

Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy

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

Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination

Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

Brigatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inhibitors when possible. If such a combination cannot be avoided, reduce the dose of brigatinib by approximately 40% (ie, from 180 mg to 120 mg, from 120 mg to 90 mg, or from 90 mg to 60 mg). Consider therapy modification

Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Cannabidiol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabidiol. Monitor therapy

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

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

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

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

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

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

Codeine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Codeine. Monitor therapy

Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. See full monograph for details. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification

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 Duvelisib. 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 Duvelisib. Management: Reduce the dose of duvelisib to 15 mg twice a day when used together with a strong CYP3A4 inhibitor. Consider therapy modification

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

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

Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg per day when used together with a moderate inhibitor of CYP3A4. 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

Deflazacort: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. 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

Disopyramide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Disopyramide. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dofetilide. Monitor therapy

Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

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

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Management: When combined with moderate CYP3A4 inhibitors, two elexacaftor/tezacaftor/ivacaftor (100 mg/50 mg/75 mg) tablets should be given in the morning, every other day. Ivacaftor (150 mg) should be given in the morning, every other day on alternate days. Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Encorafenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Encorafenib. Management: Avoid concomitant use of encorafenib and moderate CYP3A4 inhibitors whenever possible. If concomitant administration is unavoidable, decrease the encorafenib dose prior to initiation of the CYP3A4 inhibitor. See full monograph for details. Consider therapy modification

Entrectinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Entrectinib. Management: Avoid moderate CYP3A4 inhibitors during treatment with entrectinib. Reduce dose to 200 mg/day if combination cannot be avoided in adults and those 12 yrs of age or older with a BSA of at least 1.5 square meters. No alternative dosing provided for others. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details. 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

Estrogen Derivatives: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Estrogen Derivatives. Monitor therapy

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for most indications. See full monograph or prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. 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

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination

Fosaprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosaprepitant. Avoid combination

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

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Management: Extreme caution, with possibly increased monitoring of ECGs, should be used if halofantrine is combined with moderate CYP3A4 inhibitors. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. Monitor therapy

HYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: When treating B-cell malignancies, decrease ibrutinib to 280 mg daily when combined with moderate CYP3A4 inhibitors. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions. Consider therapy modification

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

Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy

Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions may be required; consult full monograph content for age- and weight-specific dosage recommendations. Consider therapy modification

Ivosidenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivosidenib. Management: Avoid use of moderate CYP3A4 inhibitors with ivosidenib whenever possible. If combined, monitor for increased ivosidenib toxicities. Drugs listed as exceptions are discussed in further detail in separate drug interaction monographs. Consider therapy modification

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

Lefamulin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lefamulin. Management: Monitor for lefamulin adverse effects during coadministration of lefamulin tablets with moderate CYP3A4 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

Lemborexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lemborexant. Avoid combination

Levamlodipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levamlodipine. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination

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

Lumateperone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lumateperone. Avoid combination

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: Lurasidone US labeling recommends reducing lurasidone dose by half with a moderate CYP3A4 inhibitor. Some non-US labeling recommends initiating lurasidone at 20 mg/day and limiting dose to 40 mg/day; avoid concurrent use of grapefruit products. Consider therapy modification

Manidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Manidipine. Monitor therapy

Meperidine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Meperidine. Monitor therapy

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

Mirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil. Monitor therapy

Naldemedine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naldemedine. Monitor therapy

Nalfurafine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nalfurafine. Monitor therapy

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination

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

Neratinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Neratinib. Avoid combination

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

NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy

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

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

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Consider therapy modification

OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Monitor therapy

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

Pexidartinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pexidartinib. Monitor therapy

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

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

Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Avoid combination

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

Propafenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification

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

Rupatadine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rupatadine. Monitor therapy

Ruxolitinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ruxolitinib. Monitor therapy

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy

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

SAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin. Monitor therapy

Sildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil. Monitor therapy

Silodosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Silodosin. Monitor therapy

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

Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination

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

Sirolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sirolimus. Management: Monitor for increased serum concentrations of sirolimus if combined with a moderate CYP3A4 inhibitor. Lower initial sirolimus doses or sirolimus dose reductions will likely be required. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification

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

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Management: The recommended dose of suvorexant is 5 mg daily in patients receiving a moderate CYP3A4 inhibitor. The dose can be increased to 10 mg daily (maximum dose) if necessary for efficacy. Consider therapy modification

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

Tamsulosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin. Monitor therapy

Tazemetostat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tazemetostat. Management: Avoid coadministration of tazemetostat and moderate CYP3A4 inhibitors. If coadministration cannot be avoided, dose reductions are required. See full monograph for dosing recommendations. Consider therapy modification

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

Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tezacaftor and Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tezacaftor and Ivacaftor. Management: When combined with moderate CYP3A4 inhibitors, tezacaftor/ivacaftor should be given in the morning, every other day. Ivacaftor alone should be given in the morning, every other day on alternate days. Consider therapy modification

Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. 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

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Management: Jynarque dose requires adjustment when used with a moderate CYP3A4 inhibitor. See labeling or full interaction monograph for specific recommendations. Use of Samsca with moderate CYP3A4 ihibitors should generally be avoided. Consider therapy modification

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Monitor therapy

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

Triazolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant moderate CYP3A4 inhibitors. Consider therapy modification

Ubrogepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and avoid a second dose for 24 hours when used with moderate CYP3A4 inhibitors. Consider therapy modification

Udenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil. Monitor therapy

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

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

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy

Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy

Zanubrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zanubrutinib. Management: Decrease the zanubrutinib dose to 80 mg twice daily during coadministration with a moderate CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details. Consider therapy modification

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Edema (11% to 14%)

Central nervous system: Fatigue (25% to 29%), headache (12%)

Dermatologic: Skin rash (27% to 31%)

Endocrine & metabolic: Hypophosphatemia (31%), hyponatremia (27% to 31%), hyperkalemia (26% to 31%), hypoalbuminemia (25% to 31%), hypocalcemia (23% to 25%), hypokalemia (10% to 20%), weight loss (11%)

Gastrointestinal: Colitis (≤57%), diarrhea (≤57%), increased serum lipase (36% to 37%), increased serum amylase (28% to 31%), nausea (23% to 24%), abdominal pain (16% to 18%), constipation (13% to 17%), vomiting (15% to 16%), mucositis (14%), decreased appetite (13% to 14%)

Hematologic & oncologic: Neutropenia (34% to 67%; grade ≥3: 30% to 49%; grade 4: 18% to 32%), anemia (20% to 55%; grade ≥3: 11% to 20%), thrombocytopenia (17% to 43%; grade ≥3: 10% to 16%; grade 4: 6% to 7%), lymphocytosis (30%; grade ≥3: 21% to 22%), leukopenia (29%; grade ≥3: 8%; grade 4: 2%), lymphocytopenia (21%; grade ≥3: 9%; grade 4: 3%)

Hepatic: Increased serum alanine aminotransferase (40% to 42%), increased serum aspartate aminotransferase (36% to 37%), decreased serum alkaline phosphatase (34%), increased serum alkaline phosphatase (27% to 29%), increased serum transaminases (11% to 15%)

Infection: Sepsis (≤58%), serious infection (31%)

Neuromuscular & skeletal: Musculoskeletal pain (17% to 20%)

Renal: Renal insufficiency (≤58%), increased serum creatinine (24% to 29%)

Respiratory: Upper respiratory tract infection (21% to 28%), pneumonia (21% to 27%), cough (23% to 25%), lower respiratory tract infection (10% to 18%), dyspnea (12%)

Miscellaneous: Fever (26% to 29%)

1% to 10%:

Dermatologic: Dermatological reaction (5%)

Infection: Cytomegalovirus disease (1%)

Neuromuscular & skeletal: Arthralgia (10%)

Respiratory: Pneumonitis (5%), pneumonia due to Pneumocystis jiroveci (1%)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia, thrombocytopenia, and/or anemia may occur. Grade 3 or 4 neutropenia has occurred at a median onset of 2 months (range: 3 days to 31 months), with most cases occurring within 4 months. Monitor ANC at least every 2 weeks for the first 2 months of treatment and at least weekly in patients with grade 3 or 4 neutropenia. Withhold duvelisib for grade 4 neutropenia and monitor until ANC is >500/mm³ and then resume duvelisib either at same dose (first occurrence) or at a reduced dose (subsequent occurrence).
• Dermatologic toxicity: [US Boxed Warning]: Fatal and/or serious cutaneous reactions occurred in 5% of duvelisib-treated patients. Withhold duvelisib. Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). The median time to onset of cutaneous reaction (any grade) was 3 months (range: 1 day to 29 months) and the median duration was 1 month (range: 1 day to 37 months). Serious dermatologic events generally presented with pruritic, erythematous, or maculo-papular features, although cases also presented with exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Patients should report any new or worsening cutaneous reactions. Review all concomitant medications and discontinue any medications potentially contributing to the event. For patients presenting with mild or moderate (grade 1 or 2) cutaneous reactions, continue duvelisib at the current dose and initiate supportive management with emollients, antihistamines (for pruritus), or topical corticosteroids, and monitor closely. Withhold duvelisib for severe (grade 3) cutaneous reaction until resolution; initiate supportive management with corticosteroids (topical or systemic) or antihistamines (for pruritus). Monitor at least weekly until resolved; upon resolution, restart duvelisib at a reduced dose. Discontinue duvelisib if severe cutaneous reaction does not improve, worsens, or recurs, or for life-threatening cutaneous reactions, or for any grade Stevens Johnson syndrome (SJS), TEN, or DRESS.
• Gastrointestinal toxicity: [US Boxed Warning]: Fatal and/or serious diarrhea or colitis occurred in 18% of duvelisib-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold duvelisib. The median time to onset of diarrhea or colitis (any grade) was 4 months (range: 1 day to 33 months), with a majority of cases occurring by 8 months. The median duration was 0.5 months (range: 1 day to 29 months). Patients should report any new or worsening diarrhea. Depending on the severity, non-infectious diarrhea or colitis may require supportive management (eg, antidiarrheals, enteric corticosteroids, or systemic corticosteroids), treatment interruption, additional monitoring, dose reduction, and/or discontinuation; may also require diagnostic work-up (including colonoscopy) to determine etiology.
• Hepatotoxicity: Grade 3 and 4 ALT and/or AST elevation has been observed in patients treated with duvelisib. Some patients had both an ALT or AST >3 times ULN and total bilirubin >2 times ULN. The median time to onset of transaminase elevation (any grade) was 2 months (range: 3 days to 26 months) and the median duration of 1 month (range: 1 day to 16 months). Monitor hepatic function during duvelisib treatment. Hepatotoxicity may require additional monitoring, treatment interruption, dose reduction, and/or discontinuation.
• Infection: [US Boxed Warning]: Fatal and/or serious infections occurred in duvelisib-treated patients. Monitor for signs/symptoms of infection. Withhold duvelisib if infection is suspected. The most common serious infections were pneumonia, sepsis, and lower respiratory infections. The median time to onset of infection (any grade) was 3 months (range: 1 day to 32 months), with a majority of the cases occurring within 6 months. Treat preexisting infections prior to initiation of duvelisib therapy. Patients should report any new or worsening infection signs/symptoms. For grade 3 or higher infection, withhold duvelisib until infection has resolved and then resume duvelisib at the same or reduced dose. Serious, including fatal, Pneumocystis jirovecii pneumonia (PCP) has been reported in patients taking duvelisib. Provide PCP prophylaxis during duvelisib treatment and continue PCP prophylaxis until the absolute CD4+ T cell count is >200 cells/microliter following duvelisib discontinuation. Withhold duvelisib if PCP (any grade) is suspected; permanently discontinue duvelisib if PCP is confirmed. CMV reactivation/infection has also been reported with duvelisib. Consider prophylactic antivirals to prevent CMV infection or reactivation during duvelisib treatment. For clinical CMV infection or viremia, withhold duvelisib until infection or viremia resolves. If duvelisib therapy is resumed, administer at the same or a reduced dose; monitor at least monthly for CMV reactivation with PCR or antigen test.
• Pulmonary toxicity: [US Boxed Warning]: Fatal and/or serious pneumonitis occurred in 5% of duvelisib-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold duvelisib. The median time to onset of pneumonitis (any grade) was 4 months (range: 9 days to 27 months), with most cases occurring within 9 months. The median duration of pneumonitis was 1 month, with the majority resolving by 2 months. Withhold treatment in patients who present with new or progressive pulmonary signs and symptoms (eg, cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or an oxygen saturation decline by >5%) and evaluate for etiology. If the pneumonitis is infectious, may restart duvelisib (at the previous dose) once the infection and pulmonary signs/symptoms resolve. For moderate non-infectious pneumonitis (grade 2), manage with systemic corticosteroids, and resume duvelisib (at a reduced dose) upon resolution. Discontinue duvelisib if non-infectious pneumonitis recurs or does not respond to corticosteroid steroid therapy; discontinue and manage with systemic corticosteroids for severe or life-threatening 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 CBC with differential (at least every 2 weeks for the first 2 months of treatment and at least weekly in patients with grade 3 or 4 neutropenia), hepatic function (ALT and AST during treatment). Pregnancy test in females of reproductive potential (to evaluate pregnancy status prior to treatment). Monitor for signs/symptoms of infection, including CMV infection or viremia (by PCR or antigen test) and PCP; if CMV develops on duvelisib therapy, monitor PCR or antigen test monthly for CMV reactivation upon therapy reinitiation. Monitor for signs/symptoms of dermatologic toxicity and gastrointestinal toxicity (colitis, diarrhea). Monitor for pulmonary symptoms and interstitial infiltrates. Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and adverse events observed in animal reproduction studies, fetal harm may occur if administered to a pregnant female.

Pregnancy status should be evaluated prior to treatment. Females of reproductive potential, and males with female partners of reproductive potential, should use effective contraception during therapy and for at least 1 month after the last duvelisib dose.

Patient Education

What is this drug used for?

• It is used to treat types of leukemia and lymphoma.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Abdominal pain
• Common cold symptoms
• Bone pain
• Joint pain
• Muscle pain
• Mouth irritation
• Mouth sores
• Constipation
• Lack of appetite
• Headache
• Weight loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Colitis like black, tarry, or bloody stools; diarrhea; or severe abdominal pain
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse
• 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; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Severe loss of strength and energy
• Swelling
• 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.