AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Duvelisib

Duvelisib, an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity mainly against PI3K-δ and PI3K-γ isoforms, is an antineoplastic agent.1,  2,  3,  5,  6,  7,  8

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Duvelisib is used for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients who previously received at least 2 therapies;1,  2 duvelisib has been designated an orphan drug by FDA for the treatment of these cancers.4

Duvelisib is not indicated or recommended for the treatment of any patients with CLL or SLL as initial or second line treatment due to an increased treatment-related mortality risk.1

Clinical Experience

The current indication for duvelisib in the treatment of relapsed or refractory CLL and SLL is based principally on the results for a subset of patients enrolled in a randomized, open-label phase 3 study (DUO) evaluating duvelisib compared with ofatumumab in 319 patients with CLL or SLL that had progressed during or had relapsed following at least one prior therapy;1,  2 the subset analysis included 196 patients in the study who had previously received at least 2 therapies for CLL or SLL.1,  10 In this study, patients were randomized in a 1:1 ratio to receive either duvelisib (25 mg orally twice daily) or ofatumumab (300 mg administered by IV infusion initially, followed one week later by 2 g by IV infusion once weekly for 7 doses and then every 4 weeks for an additional 4 doses).1,  2 Patients received duvelisib until disease progression or unacceptable toxicity occurred.1,  2 Patients who had received prior therapy with a phosphatidylinositol-3-kinase (PI3K) inhibitor or Bruton tyrosine kinase inhibitor, had undergone prior allogeneic stem-cell transplantation, had undergone autologous stem-cell transplantation within the previous 6 months, or had a history of Richter transformation were excluded from the study.1,  2 The primary end point of this study was progression-free survival as assessed by an independent review committee; secondary end points included overall response rate as assessed using 2008 updated International Workshop on CLL (IWCLL) National Cancer Institute-sponsored Working Group Guidelines or the 2007 revised International Working Group (IWG) criteria for malignant lymphoma, with modification for treatment-related lymphocytosis.1,  2

In the DUO study, the median age of patients who had received at least 2 prior therapies for CLL or SLL was 69 years (range: 40-90 years); 59% of these patients were male, 97% had CLL, 88% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 54% had received at least 3 prior therapies, 52% had at least one tumor measuring at least 5 cm, and 22% had tumors harboring the 17p deletion chromosomal abnormality.1,  10 The median duration of duvelisib treatment in patients who had received at least 2 prior therapies was 13 months;1,  10 80 or 52% of these patients received duvelisib for at least 6 or 12 months, respectively.1 In the subset of patients who had received at least 2 prior therapies, patients who received duvelisib had longer median progression-free survival compared with those who received ofatumumab (16.4 versus 9.1 months).1 The overall response rates for duvelisib and ofatumumab were 78 and 39%, respectively; there were no complete responses in either treatment group.1 Although duvelisib provided a modest progression-free survival benefit compared with ofatumumab in the overall study population (13.3 versus 9.9 months),2,  10 duvelisib is associated with serious, sometimes fatal adverse effects; therefore, FDA considered the benefit-to-risk ratio to be more favorable in patients with CLL or SLL who had received at least 2 prior therapies.1,  10

In the 5-year safety analysis of the DUO trial required by the FDA to assess long-term safety, duvelisib was found to be possibly associated with an increased risk of death and associated with a higher rate of serious side effects.11 These findings prompted the FDA to issue a safety communication in 2022 regarding these potential risks.11 Results of the study in 319 patients with CLL or SLL revealed a higher incidence of death (50%) in patients receiving duvelisib compared with those receiving ofatumumab (44%; hazard ratio 1.09; 95% confidence interval 0.79-1.51).11 There was also a higher rate of serious adverse events, grades ≥3 adverse events, treatment modifications due to adverse events, and deaths due to adverse events in patients who received duvelisib.11 Serious side effects included diarrhea, infections, inflammation of the intestine and lungs, liver enzyme elevations, and skin reactions.11 These safety events were similar for other drugs in the PI3K inhibitor class.11 The FDA is evaluating whether duvelisib should continue to be used in patients.11 In the meantime, health care providers should assess the risks and benefits of continuing to use duvelisib and should advise patients on duvelisib regarding the potential for increased risk of death and the higher rate of serious adverse events.11

General

Pretreatment Screening

• Verify pregnancy status prior to initiation of therapy.1

Patient Monitoring

• Monitor hepatic function during treatment.1 For patients who develop abnormal AST or ALT elevations during therapy, the manufacturer has specific monitoring recommendations based on the severity.1 (See Dosage Modification for Toxicity in Dosage.)
• Monitor blood counts (e.g., absolute neutrophil count [ANC], platelets) during treatment.1 For patients who develop abnormal blood count results during therapy, the manufacturer has specific monitoring recommendations based on the severity.1 (See Dosage Modification for Toxicity in Dosage.)
• Monitor for signs and symptoms of infection during treatment.1 The manufacturer recommends monitoring patients who develop CMV infection or viremia during therapy for CMV reactivation at least monthly if duvelisib is resumed.1 (See Dosage Modification for Toxicity in Dosage.)
• Monitor for severe diarrhea or colitis during treatment.1 For patients who develop diarrhea or colitis during therapy, the manufacturer has specific monitoring recommendations based on the severity.1 (See Dosage Modification for Toxicity in Dosage.)
• Monitor for cutaneous reactions during treatment.1 For patients who develop cutaneous reactions during therapy, the manufacturer has specific monitoring recommendations based on the severity.1 (See Dosage Modification for Toxicity in Dosage.)
• Monitor for pulmonary symptoms and interstitial infiltrates during treatment.1
• Monitor for drug-drug interactions.1 Patients may require a dosage increase or decrease of duvelisib if given with CYP3A4 inducers or inhibitors, respectively.1

Premedication and Prophylaxis

• Give anti-infectives for Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PJP) prophylaxis when starting duvelisib and continue until completion of therapy and until the CD4⁺ T-cell count exceeds 200 cells/mm³.1
• Consider giving antiviral prophylaxis to minimize the risk of cytomegalovirus (CMV) infection and/or reactivation.1

REMS

• The FDA approved a REMS for duvelisib to ensure that the benefits outweigh the risks. The REMS consists of a communication plan.([Web])

Administration

Duvelisib is administered orally twice daily without regard to meals.1 The capsules should be swallowed whole and should not be opened, broken, or chewed.1 Duvelisib capsules should be stored at 20-25°C (excursions permitted to 15-30°C).1

Dosage

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

For the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in patients who have received at least 2 prior therapies, the recommended adult dosage of duvelisib is 25 mg twice daily.1 In the phase 3 study (DUO) in patients with relapsed or refractory CLL or SLL, therapy was continued until disease progression or unacceptable toxicity occurred;1 the median duration of duvelisib therapy in patients who had received at least 2 prior therapies was 13 months.1,  10

Dosage Modification for Toxicity

Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of duvelisib may be necessary in patients experiencing certain adverse effects.1

When dosage modification is necessary, the dosage of duvelisib should be reduced from 25 mg twice daily to 15 mg twice daily; if a dosage of 15 mg twice daily is not tolerated, duvelisib should be discontinued.1

Infections

If grade 3 or 4 infection occurs, duvelisib therapy should be withheld until the infection resolves.1 Duvelisib may then be resumed at the previous dosage or at a reduced dosage of 15 mg twice daily.1

If CMV infection or viremia (confirmed by polymerase chain reaction [PCR] or antigen assay) occurs, duvelisib therapy should be withheld until the infection or viremia resolves.1 Duvelisib may then be resumed at the previous dosage or at a reduced dosa following resumption of therapy, patients should be monitored at least monthly for reactivation of CMV infection by PCR or antigen assay.1

If PJP of any grade is suspected, duvelisib therapy should be withheld.1 If PJP is confirmed, duvelisib should be permanently discontinued.1

Noninfectious Diarrhea or Colitis

In patients with mild or moderate noninfectious diarrhea (grade 1 or 2; up to 6 stools per day over baseline) that is responsive to antidiarrheal therapy or in those with asymptomatic (grade 1) colitis, duvelisib therapy may be continued at the same dosage, and patients should be monitored at least weekly until diarrhea or colitis resolves.1 If mild or moderate noninfectious diarrhea is not responsive to antidiarrheal therapy, duvelisib therapy should be withheld, supportive therapy with enteric-acting corticosteroids (e.g., budesonide) should be initiated, and patients should be monitored at least weekly.1 When diarrhea resolves, duvelisib therapy may be resumed at a reduced dosage.1

In patients with severe noninfectious diarrhea (grade 3; more than 6 stools per day over baseline), abdominal pain, blood or mucus in stools, change in bowel habits, or peritoneal signs, duvelisib therapy should be withheld, supportive therapy with enteric-acting (e.g., budesonide) or systemic-acting corticosteroids should be initiated, and patients should be monitored at least weekly.1 When diarrhea or colitis resolves, duvelisib may be resumed at a reduced dosage.1 In patients with recurrent severe diarrhea or recurrent colitis of any grade, therapy with duvelisib should be permanently discontinued.1

In patients with life-threatening diarrhea or colitis, therapy with duvelisib should be permanently discontinued.1

Dermatologic Toxicity

If grade 1 or 2 dermatologic reactions occur, duvelisib therapy may be continued at the same dosage, supportive care (e.g., emollients, antihistamines for relief of pruritus, topical corticosteroids) should be initiated, and patients should be monitored closely.1

If severe (grade 3) dermatologic reactions occur, duvelisib therapy should be withheld until toxicity resolves, supportive care (e.g., emollients, antihistamines for relief of pruritus, topical or systemic corticosteroids) should be initiated, and patients should be monitored at least weekly.1 When toxicity resolves, duvelisib may be resumed at a reduced dosage.1 If severe toxicity does not improve, worsens, or recurs, duvelisib therapy should be permanently discontinued.1

If life-threatening dermatologic toxicity occurs, duvelisib therapy should be permanently discontinued.1

If Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (DRESS) occurs, duvelisib therapy should be permanently discontinued.1

Noninfectious Pneumonitis

If grade 2 noninfectious pneumonitis occurs, duvelisib therapy should be withheld and systemic corticosteroid therapy should be initiated.1 When symptoms resolve to grade 1 or less, duvelisib may be resumed at a reduced dosage.1 If noninfectious pneumonitis recurs or is not responsive to corticosteroid therapy, duvelisib should be permanently discontinued.1

If grade 3 or life-threatening noninfectious pneumonitis occurs, duvelisib should be permanently discontinued and systemic corticosteroid therapy should be initiated.1

Hepatotoxicity

For grade 2 serum aminotransferase (ALT and/or AST) elevations (i.e., concentrations 3-5 times the upper limit of normal [ULN]), duvelisib therapy may be continued at the same dosage.1 Liver function tests should be monitored at least weekly until ALT and AST concentrations return to less than 3 times the ULN.1

For the first occurrence of grade 3 ALT and/or AST elevations (i.e., concentrations exceeding 5 times but not exceeding 20 times the ULN), therapy with duvelisib should be withheld and liver function tests should be monitored at least weekly until ALT and AST concentrations return to less than 3 times the ULN; duvelisib may then be resumed at the previous dosage.1 If grade 3 toxicity recurs, therapy with duvelisib should be withheld again and liver function tests should be monitored at least weekly until ALT and AST concentrations return to less than 3 times the ULN; duvelisib may then be resumed at a reduced dosage.1

For grade 4 ALT and/or AST elevations (i.e., concentrations exceeding 20 times the ULN), therapy with duvelisib should be permanently discontinued.1

Hematologic Toxicity

In patients with grade 3 neutropenia (i.e., absolute neutrophil count [ANC] of 500-1000/mm³), duvelisib therapy may be continued at the same dosage, and ANC should be monitored at least weekly.1

For the first occurrence of grade 4 neutropenia (i.e., ANC less than 500/mm³), therapy with duvelisib should be withheld and ANC should be monitored.1 When ANC reaches or exceeds 500/mm³, duvelisib may be resumed at the previous dosage.1 If grade 4 neutropenia recurs, duvelisib should be withheld again; when ANC reaches or exceeds 500/mm³, the drug may be resumed at a reduced dosage.1

In patients with grade 3 thrombocytopenia (i.e., platelet counts of 25,000/mm³ to less than 50,000/mm³) and grade 1 bleeding, duvelisib therapy may be continued at the same dosage, and platelet counts should be monitored at least weekly.1

For the first occurrence of grade 3 thrombocytopenia and grade 2 bleeding, therapy with duvelisib should be withheld and platelet counts should be monitored.1 When platelet counts reach or exceed 25,000/mm³ and bleeding resolves, duvelisib may be resumed at the previous dosage.1 If toxicity recurs, therapy with duvelisib should be withheld again.1 When platelet counts reach or exceed 25,000/mm³, duvelisib may be resumed at a reduced dosage.1

For the first occurrence of grade 4 thrombocytopenia (i.e., platelet counts less than 25,000/mm³), therapy with duvelisib should be withheld and platelet counts should be monitored.1 When platelet counts reach or exceed 25,000/mm³, duvelisib may be resumed at the previous dosage.1 If grade 4 thrombocytopenia recurs, therapy with duvelisib should be withheld again.1 When platelet counts reach or exceed 25,000/mm³, duvelisib may be resumed at a reduced dosage.1

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of duvelisib and drugs that are potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 may result in increased duvelisib exposure and may increase the risk of toxicity.1 If concomitant use of duvelisib and potent CYP3A4 inhibitors cannot be avoided, the manufacturer recommends that the duvelisib dosage be reduced to 15 mg twice daily.1 Concomitant use of duvelisib and drugs that induce CYP3A4 may result in decreased duvelisib exposure and reduced efficacy.1 Avoid concomitant use of duvelisib and potent CYP3A4 inducers.1 If concomitant use of duvelisib and moderate CYP3A4 inducers cannot be avoided, the manufacturer recommends that the duvelisib dosage be increased on day 12 of coadministration with the inducer according to the initial duvelisib dosage.1 For an initial dosage of 25 mg twice daily, increase the duvelisib dose to 40 mg twice daily; for an initial dosage of 15 mg twice daily, increase the duvelisib dose to 25 mg twice daily.1 If the inducer is discontinued during duvelisib therapy, resume the previous duvelisib dosage after at least 14 days from when the inducer was discontinued.1

Special Populations

The manufacturer makes no specific dosage recommendations for geriatric patients; however, 61% of patients enrolled in clinical studies of the drug were 65 years of age or older.1 The manufacturer also makes no specific dosage recommendations for patients with renal or hepatic impairment.1

Contraindications

• None.1

Warnings/Precautions

Warnings

Treatment-related Mortality

Duvelisib therapy was associated with an increase in treatment-related mortality in a randomized controlled study in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1 A boxed warning about the risk of treatment-related mortality is included in the prescribing information for duvelisib.1 With a median follow-up of 63 months, treatment-related deaths occurred in 23 (15%) of 158 patients in the overall population.1 For patients administered duvelisib according to the approved indication for use, treatment-related mortality occurred in 13 (14%) of 93 patients.1 The most common cause of treatment-related deaths were infections, which occurred in 9% and 11% of patients with relapsed or refractory CLL following at least one or two prior systemic therapies, respectively.1 Duvelisib is not indicated for use and is not recommended for any patients in the initial or second-line treatment setting.1

Infectious Complications

Serious infections, sometimes fatal, have been reported in 31% of patients receiving duvelisib in clinical trials.1 A boxed warning about the risk of infectious complications is included in the prescribing information for duvelisib.1 Pneumonia, sepsis, and lower respiratory infections were the most frequently reported serious infections.1 The median time to occurrence of infection of any grade was 3 months (range: 1 day to 32 months); 75% of infections occurred within 6 months.1

Serious Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PJP), sometimes fatal, has been reported in 1% of patients receiving duvelisib in clinical trials.1 PJP prophylaxis is recommended for all patients during duvelisib therapy; after duvelisib therapy is discontinued, PJP prophylaxis should be continued until the absolute CD4⁺ T-cell count exceeds 200/mm³.1,  2 The drug should be withheld in patients with suspected PJP of any grade.1 If PJP is confirmed, duvelisib should be permanently discontinued.1

Cytomegalovirus [CMV] infection and/or reactivation has been reported in 1% of patients receiving duvelisib in clinical trials.1 Antiviral prophylaxis should be considered during duvelisib therapy to prevent CMV infection and/or reactivation.1 If CMV infection or viremia occurs, duvelisib treatment should be interrupted until infection or viremia resolves.1 Duvelisib may then be resumed at the previous dosage or at a reduced dosage, and patients should be monitored at least monthly for CMV reactivation by polymerase chain reaction (PCR) or antigen assay.1

Preexisting infections should be treated prior to initiating duvelisib therapy.1 Patients receiving duvelisib should be monitored for signs and symptoms of infection.1 The drug should be withheld in those who develop grade 3 or greater infection.1

Diarrhea or Colitis

Serious diarrhea or colitis, sometimes fatal, has been reported in 18% of patients receiving duvelisib in clinical trials.1 A boxed warning about the risk of GI effects is included in the prescribing information for duvelisib.1 The median time to occurrence of diarrhea or colitis was 4 months (range: 1 day to 33 months); 75% of cases of diarrhea or colitis occurred within 8 months of initiation of therapy, and the median duration was 0.5 month (range: 1 day to 29 months).1

Patients receiving duvelisib should be monitored for the development of severe diarrhea or colitis.1 If mild or moderate noninfectious diarrhea or asymptomatic colitis occurs, duvelisib may be continued at the same dosage, antidiarrheal therapy should be initiated as needed, and patients should be monitored at least weekly until diarrhea or colitis resolves.1 If diarrhea is not responsive to antidiarrheal therapy, temporary interruption of therapy, supportive therapy with enteric-acting corticosteroids, and/or dosage reduction may be necessary.1

If severe diarrhea (grade 3 or greater) or colitis with abdominal pain, blood or mucus in stool, change in bowel habits, or peritoneal signs occurs, duvelisib treatment should be interrupted, supportive therapy with enteric-acting or systemic corticosteroids should be initiated, and a diagnostic evaluation, including colonoscopy, should be performed to determine the etiology.1 Patients should be monitored at least weekly until diarrhea or colitis resolves.1 Dosage reduction or discontinuance of the drug may be necessary.1

Dermatologic Effects

Serious dermatologic reactions, sometimes fatal, have been reported in 5% of patients receiving duvelisib in clinical trials.1 A boxed warning about the risk of dermatologic effects is included in the prescribing information for duvelisib.1 Serious dermatologic reactions have included erythroderma, exfoliative dermatitis, desquamation, pruritus, keratinocyte necrosis, and rash (including exanthem and erythematous, papular, or maculopapular rash); fatal dermatologic reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis, have been reported.1 The median time to occurrence of dermatologic reactions of any grade was 3 months (range: 1 day to 29 months), and the median duration was 1 month (range: 1 day to 37 months).1

If dermatologic reactions occur, all concomitant therapy should be reviewed and drugs that may be contributing to dermatologic reactions should be discontinued.1 Supportive care (e.g., emollients, antihistamines for relief of pruritus, topical or systemic corticosteroids) should be initiated, and patients should be monitored closely.1 Temporary interruption of duvelisib therapy and/or dosage reduction or discontinuance of therapy may be necessary depending on the severity of dermatologic reactions.1

Pneumonitis

Serious noninfectious pneumonitis, sometimes fatal, has been reported in 5% of patients receiving duvelisib in clinical trials.1 A boxed warning about the risk of pneumonitis is included in the prescribing information for duvelisib.1 The median time to occurrence of noninfectious pneumonitis was 4 months (range: 9 days to 27 months); 75% of cases of noninfectious pneumonitis occurred within 9 months.1 The median duration of noninfectious pneumonitis was 1 month; 75% of the cases of noninfectious pneumonitis resolved within 2 months.1

Patients receiving duvelisib should be monitored for respiratory symptoms and presence of interstitial infiltrates.1 If new or progressive respiratory signs and symptoms (e.g., cough, dyspnea, hypoxia, interstitial infiltrates, decrease in oxygen saturation of more than 5%) occur, duvelisib therapy should be interrupted and the etiology should be evaluated.1 If infectious pneumonitis is confirmed, duvelisib therapy may be resumed at the previous dosage when infection and respiratory manifestations resolve.1 For grade 2 or greater noninfectious pneumonitis, systemic corticosteroid therapy should be initiated; temporary interruption of duvelisib therapy and/or dosage reduction or discontinuance of therapy may be necessary depending on the severity and persistence of pneumonitis.1

Other Warnings and Precautions

Hepatotoxicity

Grade 3 or 4 elevations in aminotransferases (ALT and/or AST) have been reported in 8 or 2%, respectively, of patients receiving duvelisib in clinical trials.1 Elevations in both aminotransferase (ALT or AST) and total bilirubin concentrations exceeding 3 and 2 times the upper limit of normal (ULN), respectively, have been reported in 2% of patients receiving duvelisib.1 The median time to occurrence of elevated ALT or AST concentrations of any grade was 2 months (range: 3 days to 26 months); the median duration was 1 month (range: 1 day to 16 months).1

Liver function tests, including ALT and AST concentrations, should be monitored periodically during therapy, with more frequent monitoring in patients who develop aminotransferase elevations during therapy.1 Temporary interruption of duvelisib therapy and/or dosage reduction or discontinuance of therapy may be necessary depending on the severity of hepatotoxicity.1

Neutropenia

Severe (grade 3 or 4) neutropenia has been reported in 42% of patients receiving duvelisib in clinical trials; grade 4 neutropenia has been reported in 24% of patients receiving the drug.1 The median time to onset of severe neutropenia was 2 months (range: 3 days to 31 months); 75% of cases of severe neutropenia occurred within 4 months.1

Absolute neutrophil count (ANC) should be monitored at least every 2 weeks during the first 2 months of therapy.1 If ANC decreases to less than 1000/mm³, ANC should be monitored at least every week.1 Temporary interruption of duvelisib therapy and/or dosage reduction may be necessary depending on the severity of neutropenia.1

Fetal/Neonatal Morbidity and Mortality

Data are lacking on use of duvelisib in pregnant women; however, based on its mechanism of action and animal findings, duvelisib may cause fetal harm.1 Embryofetal death, teratogenicity (e.g., fetal malformations), and decreased fetal weight have been demonstrated in rats and rabbits receiving duvelisib at dosages approximately 10 and 39 times, respectively, the maximum recommended human dosage.1

Pregnancy should be avoided during duvelisib therapy.1 The manufacturer states that a pregnancy test should be performed prior to initiation of duvelisib therapy in women of childbearing potential and that such women and men who are partners of such women should be advised to use effective contraceptive methods while receiving duvelisib and for one month after discontinuance of therapy.1 If duvelisib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1

Specific Populations

Pregnancy

Duvelisib may cause fetal harm if administered to pregnant women based on animal findings and its mechanism of action.1

Lactation

It is not known whether duvelisib and/or its metabolites distribute into human milk or if the drug has any effect on milk production or on the nursing infant.1 Because of the potential for serious adverse reactions to duvelisib in nursing infants, women should be advised not to breast-feed while receiving the drug and for one month after the drug is discontinued.1

Females and Males of Reproductive Potential

A pregnancy test should be performed prior to initiation of duvelisib therapy in women of childbearing potential and such women and men who are partners of such women should be advised to use effective contraceptive methods while receiving duvelisib and for one month after the last dose.1

Results of animal studies suggest that duvelisib may impair male fertility.1 In repeat-dose toxicity studies, testicular and epididymal changes (i.e., seminiferous epithelial atrophy, decreased testicular weight, soft testes, small epididymis, oligospermia, aspermia) were observed in male rats.1

Pediatric Use

Safety and efficacy of duvelisib have not been established in pediatric patients.1

Geriatric Use

In clinical studies evaluating duvelisib, 61% of patients were 65 years of age or older, while 24% were 75 years of age or older.1 No substantial differences in efficacy or safety were observed between geriatric patients and younger adults.1

Hepatic Impairment

Systemic exposure to duvelisib does not appear to be altered in patients with hepatic impairment (Child-Pugh class A, B, or C).1

Renal Impairment

Systemic exposure to duvelisib does not appear to be altered in patients with creatinine clearance of at least 23 mL/minute.1

Common Adverse Effects

The most common adverse effects (≥20%) are diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia.1

Duvelisib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1

In vitro, duvelisib is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1 In vitro studies indicate that duvelisib does not inhibit renal organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transport protein (OATP) 1B1, OATP1B3, BCRP, or P-gp.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4 Isoenzyme

Concomitant use of duvelisib with potent inhibitors of CYP3A4 may increase systemic exposure to duvelisib and increase the risk of toxicity.1 When the potent CYP3A4 inhibitor ketoconazole (200 mg orally once daily for 5 days) was administered concomitantly with duvelisib (single 10-mg oral dose) in healthy individuals, area under the plasma concentration-time curve (AUC) and peak plasma concentration of duvelisib were increased by 4- and 1.7-fold, respectively.1 Simulations suggest that concomitant use of duvelisib and a potent CYP3A4 inhibitor (e.g., ketoconazole) would result in a twofold increase in exposure to duvelisib at steady state.1 Simulations also suggest that concomitant use of duvelisib with mild or moderate inhibitors of CYP3A4 would not affect systemic exposure to duvelisib.1

If duvelisib is used concomitantly with a potent CYP3A4 inhibitor (e.g., ketoconazole), the manufacturer recommends that the dosage of duvelisib be reduced from 25 mg twice daily to 15 mg twice daily.1

Inducers of CYP3A4 Isoenzyme

Concomitant use of duvelisib with moderate or potent inducers of CYP3A4 may result in decreased systemic exposure to duvelisib and decrease therapeutic efficacy of the drug.1 When the potent CYP3A4 inducer rifampin (600 mg once daily for 7 days) was administered concomitantly with duvelisib (single 25-mg oral dose) in healthy individuals, AUC and peak plasma concentration of duvelisib were decreased by 82 and 66%, respectively.1 Concomitant use of duvelisib with potent CYP3A inducers (e.g., rifampin) should be avoided.1 When the moderate CYP3A4 inducer etravirine (200 mg twice daily for 12 days) was administered concomitantly with duvelisib (single 25-mg oral dose) in healthy individuals, AUC and peak plasma concentration of duvelisib were decreased by 35% and 16%, respectively.1 If duvelisib is used concomitantly with a moderate CYP3A4 inducer (e.g., etravirine), the manufacturer recommends that the dosage of duvelisib be increased on day 12 of coadministration with the inducer according to the initial duvelisib dosage.1 For an initial dosage of 25 mg twice daily, increase the duvelisib dose to 40 mg twice daily; for an initial dosage of 15 mg twice daily, increase the duvelisib dose to 25 mg twice daily.1 If the inducer is discontinued during duvelisib therapy, resume the previous duvelisib dosage after at least 14 days from when the inducer was discontinued.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4 Isoenzyme

Duvelisib may increase systemic exposure to and risk of adverse effects of other drugs metabolized by CYP3A4.1 When the CYP3A4 substrate midazolam (single 2-mg oral dose) was administered concomitantly with duvelisib (25 mg twice daily for 5 days) in healthy individuals, AUC and peak plasma concentration of midazolam were increased by 4.3- and 2.2-fold, respectively.1 If duvelisib is used concomitantly with a CYP3A4 substrate (e.g., midazolam), reduction in the dosage of the CYP3A4 substrate should be considered, and the patient should be monitored for CYP3A4 substrate-related toxicity.1

Description

Duvelisib, an inhibitor of phosphatidylinositol-3-kinase (PI3K), is an antineoplastic agent.1,  2,  3,  5,  6,  7,  8 Phosphatidylinositol-3-kinases are lipid kinases consisting of a catalytic subunit that exists in 4 different isoforms (α, β, γ, δ).6,  7,  8,  9 Duvelisib is predominantly active against the PI3K-δ and PI3K-γ isoforms, which are expressed in hematopoietic cells and mediate B-cell and T-cell receptor signaling critical for B-cell and T-cell homeostasis and function.2,  5,  6,  7,  8,  9,  10 Duvelisib has been shown to induce tumor cell death by apoptosis and to inhibit proliferation of primary malignant B-cell lines.5,  6,  7,  8,  9,  10 Duvelisib has demonstrated inhibition of several important cell signaling pathways, including B-cell receptor (BCR) signaling and CXCR12-mediated chemotaxis of malignant B cells.1,  5,  9,  10 The drug also has demonstrated inhibition of CXCL12-induced T-cell migration and macrophage colony-stimulating factor- and interleukin-4-driven M2 polarization of macrophages.1,  9,  10

Systemic exposure to duvelisib increases in a dose-proportional manner over a dosage range of 8-75 mg twice daily.1 Following oral administration of a single 25-mg dose of duvelisib, the absolute oral bioavailability was 42%; peak plasma concentrations of the drug were achieved within 1-2 hours.1 Administration of a single dose of duvelisib with a high-fat meal decreased peak plasma concentrations and area under the concentration-time curve (AUC) of the drug by 37 and 6%, respectively, compared with administration in the fasted state.1 Duvelisib is more than 98% bound to plasma proteins.1 Duvelisib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1 The mean terminal half-life of duvelisib is 4.7 hours.1 Following oral administration of a single 25-mg dose of radiolabeled duvelisib, 79% of the dose was recovered in feces (11% as unchanged drug) and 14% was recovered in urine (less than 1% as unchanged drug).1

Advice to Patients

• Instruct patients to read the manufacturer's patient information (medication guide) before initiating duvelisib therapy and each time the prescription is refilled.1
• Advise patients to take duvelisib exactly as prescribed and to not alter the dosage or discontinue therapy unless advised to do so by their clinician.1 Advise patients to swallow duvelisib capsules whole and not to open, break, or chew the capsules.1
• Advise patients to take a missed dose as soon as it is remembered unless the dose was missed by more than 6 hours, in which case they should not take the missed dose.1
• Risk of treatment-related mortality.1 Inform patients that duvelisib has been associated with increased death due to adverse effects of therapy (mainly infection).1
• Risk of serious infections such as pneumonia.1 Stress importance of immediately reporting fever or any other signs of infection.1
• Risk of severe diarrhea or colitis.1 Stress importance of immediately informing clinician if mucus or blood is present in stool or if abdominal pain or new or worsening diarrhea occurs.1
• Risk of severe dermatologic reactions.1 Stress importance of immediately informing clinician if dermatologic reactions (e.g., new or worsening rash; rash accompanied by itching or peeling skin, blisters, or fever; painful sores) occur.1
• Risk of pneumonitis.1 Inform clinician if new or worsening respiratory symptoms (e.g., cough, dyspnea) occur.1
• Risk of hepatotoxicity; stress importance of regular liver function test monitoring.1 Immediately inform clinician if possible signs or symptoms of hepatotoxicity (e.g., abdominal pain, jaundice, bruising, bleeding diathesis) occur.1
• Risk of neutropenia; stress importance of periodic monitoring of blood cell counts during duvelisib therapy.1 Immediately inform clinician if fever or other signs of infection occur.1
• Risk of fetal harm.1 Advise women of childbearing potential to avoid pregnancy and to use effective contraceptive methods while receiving duvelisib and for one month following discontinuance of therapy.1 Advise men who are partners of such women that they should use effective methods of contraception while receiving the drug and for one month after the drug is discontinued.1 Stress importance of women informing clinicians immediately if they become pregnant during therapy or think they may be pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1
• Advise patients to avoid breast-feeding while receiving duvelisib and for one month after discontinuance of therapy.1
• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

1. Secura Bio, Inc. Copiktra^® (duvelisib) capsules prescribing information. Las Vegas, NV; 2024 July.

2. Flinn IW, Hillmen P, Montillo M et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood . 2018; 132:2446-55.

3. Flinn IW, Miller CB, Ardeshna KM et al. DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma. J Clin Oncol . 2019; 37:912-922. [PubMed 30742566]

4. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2025 Jan 17. [Web]

5. Vangapandu HV, Jain N, Gandhi V. Duvelisib: A phosphoinositide-3 Kinase δ/γ Inhibitor for Chronic Lymphocytic Leukemia. Expert Opin Investig Drugs . 2017; 26:625-32.

6. Lampson BL, Brown JR. PI3Kδ-Selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma. Expert Opin Investig Drugs . 2017; 26:1267-79.

7. Zhao W, Yuling Q, Kong D. Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy. Acta Pharm Sin B . 2017; 7:27-37.

8. Faia K, White K, Murphy E et al. The phosphoinositide-3 kinase (PI3K)-δ/γ inhibitor, duvelisib shows preclinical synergy with multiple targeted therapies in hematologic malignancies. PLos One . 2018; 13:1-14.

9. Balakrishnan K, Peluso MK, Rosin NY et al. The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL. Leukemia . 2015; 29(9):1811-22.

10. US Food and Drug Administration. Center for Drug Evaluation and Research. Application numbers 211155Orig1s000 and 211155Orig2s000: Multi-discipline review. From FDA website. [Web]

11. Food and Drug Administration. Drug safety communication: FDA warns about possible increased risk of death and serious side effects with cancer drug Copiktra (duvelisib). 2022 Jun 30. From FDA website. [Web]

12. Secura Bio. Copiktra website. Accessed 2025 Jan 17. [Web]