Duvelisib (Monograph)

Brand name: Copiktra
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Phosphatidylinositol-3-Kinase Inhibitors
- Phosphoinositide-3-Kinase Inhibitors
- PI3K Inhibitors
Chemical name: 1(2H)-Isoquinolinone, 8-chloro-2-phenyl-3-[(1S)-1-(9H-purin-6-ylamino)ethyl]
Molecular formula: C₂₂H₁₇ClN₆O
CAS number: 1201438-56-3

Medically reviewed by Drugs.com on Feb 25, 2023. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity mainly against PI3K-δ and PI3K-γ isoforms.

Uses for Duvelisib

Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Treatment of relapsed or refractory CLL or SLL in patients who previously received ≥2 therapies (designated an orphan drug by FDA for these cancers).

Duvelisib Dosage and Administration

General

Pretreatment Screening

• The manufacturer recommends testing for pregnancy prior to starting duvelisib.

Patient Monitoring

• Monitor hepatic function during treatment. For patients who develop abnormal AST or ALT elevations during therapy, the manufacturer has specific monitoring recommendations based on the severity. (See Dosage Modification for Toxicity in Dosage.)

• Monitor blood counts (e.g., absolute neutrophil count [ANC], platelets) during treatment. For patients who develop abnormal blood count results during therapy, the manufacturer has specific monitoring recommendations based on the severity. (See Dosage Modification for Toxicity in Dosage.)

• Monitor for signs and symptoms of infection during treatment. The manufacturer recommends monitoring patients who develop CMV infection or viremia during therapy for CMV reactivation at least monthly if duvelisib is resumed. (See Dosage Modification for Toxicity in Dosage.)

• Monitor for severe diarrhea or colitis during treatment. For patients who develop diarrhea or colitis during therapy, the manufacturer has specific monitoring recommendations based on the severity. (See Dosage Modification for Toxicity in Dosage.)

• Monitor for cutaneous reactions during treatment. For patients who develop cutaneous reactions during therapy, the manufacturer has specific monitoring recommendations based on the severity. (See Dosage Modification for Toxicity in Dosage.)

• Monitor for pulmonary symptoms and interstitial infiltrates during treatment.

• Monitor for drug-drug interactions. Patients may require a dosage increase or decrease of duvelisib if given with CYP3A4 inducers or inhibitors, respectively.

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.

• Consider giving antiviral prophylaxis to minimize the risk of cytomegalovirus (CMV) infection and/or reactivation.

REMS

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

Other General Considerations

• Advise females of reproductive potential and male partners of females of reproductive potential to use effective contraception during duvelisib therapy and for 1 month after their last dose.

Administration

Oral Administration

Administer orally twice daily without regard to meals. Swallow capsules whole; do not open, break, or chew.

Dosage

Adults

CLL or SLL

Relapsed or Refractory CLL or SLL

Oral

25 mg twice daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

May need to interrupt therapy, reduce dosage to 15 mg twice daily, and/or permanently discontinue duvelisib if toxicity occurs. If a reduced dosage of 15 mg twice daily is not tolerated, permanently discontinue duvelisib.

Infections

If grade 3 or 4 infection occurs, withhold duvelisib until infection resolves, then resume duvelisib at previous dosage or at reduced dosage.

If CMV infection or viremia (confirmed by polymerase chain reaction [PCR] or antigen assay) occurs, withhold duvelisib until infection or viremia resolves, then resume duvelisib at previous dosage or at reduced dosage. After resuming therapy, monitor for reactivation of CMV infection at least monthly.

If PJP (any grade) is suspected, withhold duvelisib. If PJP is confirmed, permanently discontinue duvelisib.

Noninfectious Diarrhea or Colitis

If mild or moderate diarrhea (grade 1 or 2; ≤6 stools per day over baseline) responsive to antidiarrheal therapy or asymptomatic (grade 1) colitis occurs, continue duvelisib at the same dosage and monitor patient at least weekly until diarrhea or colitis resolves.

If mild or moderate diarrhea is not responsive to antidiarrheal therapy, withhold duvelisib, initiate supportive therapy with enteric-acting corticosteroid (e.g., budesonide), and monitor patient at least weekly; when diarrhea resolves, resume therapy at reduced dosage.

If severe diarrhea (grade 3; >6 stools per day over baseline), abdominal pain, blood or mucus in stools, change in bowel habits, or peritoneal signs occur, withhold duvelisib, initiate supportive therapy with enteric-acting (e.g., budesonide) or systemic corticosteroids, and monitor patient at least weekly; when diarrhea or colitis resolves, resume therapy at reduced dosage.

If recurrent severe diarrhea or recurrent colitis of any grade occurs, permanently discontinue duvelisib.

If life-threatening diarrhea or colitis occurs, permanently discontinue duvelisib.

Dermatologic Toxicity

If grade 1 or 2 dermatologic reactions occur, continue duvelisib at the same dosage, initiate supportive care (e.g., emollients, antihistamines for relief of pruritus, topical corticosteroids) and monitor patient closely.

If severe (grade 3) dermatologic reactions occur, withhold duvelisib, initiate supportive care (e.g., emollients, antihistamines for relief of pruritus, topical or systemic corticosteroids), and monitor patient at least weekly; when toxicity resolves, resume therapy at reduced dosage. If severe toxicity does not improve, worsens, or recurs, permanently discontinue duvelisib.

If life-threatening dermatologic toxicity occurs, permanently discontinue duvelisib.

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

Noninfectious Pneumonitis

If grade 2 noninfectious pneumonitis occurs, withhold duvelisib and initiate systemic corticosteroid therapy. When symptoms resolve to grade 1 or less, resume therapy at reduced dosage. If noninfectious pneumonitis recurs or does not respond to corticosteroid therapy, permanently discontinue duvelisib.

If severe (grade 3) or life-threatening noninfectious pneumonitis occurs, permanently discontinue duvelisib and initiate systemic corticosteroid therapy.

Hepatotoxicity

For grade 2 ALT and/or AST elevations (3–5 times the ULN), continue duvelisib at the same dosage and monitor liver function tests at least weekly until ALT and AST concentrations return to <3 times the ULN.

For first occurrence of grade 3 ALT and/or AST elevations (>5 to 20 times the ULN), withhold duvelisib and monitor liver function tests at least weekly; when ALT and AST concentrations return to <3 times the ULN, resume duvelisib at the previous dosage. If grade 3 toxicity recurs, withhold duvelisib and monitor liver function at least weekly; when ALT and AST concentrations return to <3 times the ULN, resume duvelisib at reduced dosage.

For grade 4 ALT and/or AST elevations (>20 times the ULN), permanently discontinue duvelisib.

Hematologic Toxicity

For grade 3 neutropenia (ANC 500–1000/mm³), continue duvelisib at the same dosage and monitor ANC at least weekly.

For first occurrence of grade 4 neutropenia (ANC <500/mm³), withhold duvelisib and monitor ANC; when ANC is ≥500/mm³, resume therapy at previous dosage. If grade 4 neutropenia recurs, withhold duvelisib; when ANC is ≥500/mm³, resume duvelisib at reduced dosage.

For grade 3 thrombocytopenia (platelet count 25,000 to <50,000/mm³) with grade 1 bleeding, continue duvelisib at the same dosage and monitor platelet counts at least weekly.

For first occurrence of grade 3 thrombocytopenia with grade 2 bleeding, withhold duvelisib and monitor platelet counts; when platelet count is ≥25,000/mm³ and bleeding resolves, resume duvelisib at the previous dosage. If toxicity recurs, withhold duvelisib; when platelet count is ≥25,000/mm³, resume duvelisib at reduced dosage.

For first occurrence of grade 4 thrombocytopenia (platelet count <25,000/mm³) withhold duvelisib and monitor platelet counts; when platelet count is ≥25,000/mm³, resume duvelisib at previous dosage. If toxicity recurs, withhold duvelisib; when platelet count is ≥25,000/mm³, resume duvelisib at reduced dosage.

Concomitant Use with Drugs Affecting Microsomal Enzymes

If concomitant use of potent CYP3A4 inhibitors cannot be avoided, reduce duvelisib dosage to 15 mg twice daily.

Avoid concomitant use of potent CYP3A4 inducers. If concomitant use of moderate CYP3A4 inducers cannot be avoided, increase duvelisib dosage on the 12th day of concomitant use according to the initial duvelisib dosage:

• Initial dosage: 25 mg twice daily – increase to duvelisib 40 mg twice daily

• Initial dosage: 15 mg twice daily – increase to duvelisib 25 mg twice daily

Resume the previous duvelisib dosage after at least 14 days from when the CYP3A4 inducers was discontinued.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Duvelisib

Contraindications

• No known contraindications.

Warnings/Precautions

Warnings

Infectious Complications

Serious infections (most commonly pneumonia, sepsis, and lower respiratory infections), including fatalities, reported.

Serious, sometimes fatal PJP reported. PJP prophylaxis is recommended. If PJP is suspected, withhold duvelisib. If PJP is confirmed, permanently discontinue duvelisib.

CMV infection and/or reactivation also reported; consider antiviral prophylaxis during duvelisib therapy. If CMV infection or viremia occurs, interrupt duvelisib therapy; when infection or viremia resolves, resume at previous dosage or at reduced dosage and monitor for CMV reactivation at least monthly with PCR or antigen assay.

Treat infections prior to initiating duvelisib therapy.

Monitor for signs and symptoms of infection. If grade 3 or greater infection occurs, withhold duvelisib.

Diarrhea or Colitis

Serious, sometimes fatal, diarrhea or colitis reported.

Monitor for development of severe diarrhea or colitis.

If diarrhea or colitis occurs, provide supportive therapy (e.g., antidiarrheal agents, corticosteroids) and monitor patients at least weekly until diarrhea or colitis resolves. Perform diagnostic evaluation, including colonoscopy, if diarrhea is severe or manifestations include abdominal pain, blood or mucus in stool, change in bowel habits, or peritoneal signs. May need to interrupt therapy, reduce dosage, and/or permanently discontinue duvelisib depending on severity of diarrhea or colitis.

Dermatologic Effects

Severe dermatologic reactions, including erythroderma, exfoliative dermatitis, desquamation, pruritus, keratinocyte necrosis, and rash (e.g., exanthem; erythematous, papular, or maculopapular rash), reported. Fatal dermatologic reactions, including toxic epidermal necrolysis and DRESS, also reported.

If dermatologic reactions occur, evaluate concomitant therapy and discontinue drugs that may be contributing to dermatologic reactions. Initiate supportive care (e.g., emollients, antihistamines for relief of pruritus, topical or systemic corticosteroids) and monitor patients closely. May need to interrupt therapy, reduce dosage, and/or permanently discontinue duvelisib depending on severity of dermatologic toxicity.

Pneumonitis

Serious, sometimes fatal, noninfectious pneumonitis reported.

Monitor for respiratory symptoms and presence of interstitial infiltrates. If new or progressive respiratory manifestations (e.g., cough, dyspnea, hypoxia, interstitial infiltrates, >5% decrease in oxygen saturation) occur, interrupt therapy and evaluate etiology.

If infectious pneumonitis is confirmed, resume duvelisib at previous dosage when infection and respiratory manifestations resolve.

For grade 2 or greater noninfectious pneumonitis, initiate systemic corticosteroid therapy. May need to interrupt therapy, reduce dosage, and/or permanently discontinue duvelisib depending on severity and persistence of pneumonitis.

Other Warnings and Precautions

Hepatotoxicity

ALT or AST elevations of >5 times the ULN reported. Concomitant total bilirubin elevations also reported.

Monitor liver function tests, including ALT and AST concentrations, periodically during therapy. If hepatotoxicity occurs, monitor liver function tests more frequently. May need to interrupt therapy, reduce dosage, and/or permanently discontinue duvelisib depending on severity of hepatotoxicity.

Neutropenia

Severe (grade 3 or 4) neutropenia reported.

Monitor ANC at least every 2 weeks during the first 2 months of therapy. If ANC <1000/mm³, monitor ANC at least every week. May need to interrupt therapy and/or reduce dosage depending on severity of neutropenia.

Fetal/Neonatal Morbidity and Mortality

Based on its mechanism of action and animal findings, duvelisib may cause fetal harm. Embryofetal toxicity and teratogenicity demonstrated in animals.

Perform pregnancy test prior to initiating duvelisib therapy in women of childbearing potential. Avoid pregnancy during therapy and for 1 month after drug discontinuance. Women of childbearing potential and men who are partners of such women should use effective contraception while receiving the drug and for 1 month after discontinuance of therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Impairment of Fertility

Results of animal studies suggest duvelisib may impair male fertility.

Risk of Death and Serious Side Effects

The 5-year safety analysis of the DUO trial showed a possible association of duvelisib with an increased risk of death and association with a higher rate of serious side effects. The FDA issued a safety communication in 2022 regarding these potential risks. The incidence of death with duvelisib was numerically higher (50%) than with ofatumumab (44%). 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. Serious side effects included diarrhea, infections, inflammation of the intestine and lungs, liver enzyme elevations, and skin reactions. The FDA is evaluating whether duvelisib should continue to be used in patients. Assess the risks and benefits of continuing to use duvelisib and advise patients on duvelisib regarding the potential for increased risk of death and the higher rate of serious adverse events.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether duvelisib distributes into milk, affects milk production, or affects nursing infants.

Women should not breast-feed during therapy and for 1 month following drug discontinuance.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

In clinical studies evaluating duvelisib, 61% of patients were ≥65 years of age and 24% were ≥75 years of age. No overall differences in safety or efficacy between geriatric patients (≥65 years of age) and younger adults.

Hepatic Impairment

Systemic exposure not altered in patients with hepatic impairment (Child-Pugh class A, B, or C).

Renal Impairment

Systemic exposure not altered in patients with Cl_cr ≥23 mL/minute.

Common Adverse Effects

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

Drug Interactions

Metabolized principally by CYP3A4.

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro.

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 in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased systemic exposure to duvelisib) and increased risk of toxicity. If concomitant use cannot be avoided, reduce duvelisib dosage from 25 mg twice daily to 15 mg twice daily.

Mild or moderate inhibitors of CYP3A: Pharmacokinetic simulations suggest no effect on duvelisib exposure.

Potent and moderate inducers of CYP3A4: Potential pharmacokinetic interaction (decreased systemic exposure to duvelisib) and decreased therapeutic efficacy. Avoid concomitant use with potent inducers. If concomitant use with moderate inducers cannot be avoided, increase the duvelisib dosage on the 12th day of concomitant use according to the initial duvelisib dosage:

• Initial dosage: 25 mg twice daily – increase to duvelisib 40 mg twice daily

• Initial dosage: 15 mg twice daily – increase to duvelisib 25 mg twice daily

Resume the previous duvelisib dosage after at least 14 days from when the CYP3A4 inducers was discontinued. (See Specific Drugs under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Potential pharmacokinetic interaction (increased systemic exposure to CYP3A4 substrate) and increased adverse effects. Monitor for toxicity; consider reducing CYP3A4 substrate dosage. (See Specific Drugs under Interactions.)

Specific Drugs

Duvelisib Pharmacokinetics

Absorption

Bioavailability

Systemic exposure to duvelisib increases in a dose-proportional manner over a dosage range of 8–75 mg twice daily.

Absolute oral bioavailability is 42%.

Peak plasma concentrations achieved within 1–2 hours.

Food

Administration with high-fat meal decreases peak plasma concentrations and AUC by 37 and 6%, respectively, compared with administration in the fasted state.

Distribution

Extent

Not known whether duvelisib is distributed into human milk.

Plasma Protein Binding

>98%.

Elimination

Metabolism

Principally metabolized by CYP3A4.

Elimination Route

Eliminated in feces (79% [11% as unchanged drug]) and urine (14% [<1% as unchanged drug]).

Half-life

Mean terminal half-life: 4.7 hours.

Special Populations

In a pharmacokinetic population analysis, age (18–90 years), gender, race, body weight, hepatic impairment (Child-Pugh class A, B, or C), and renal impairment (Cl_cr ≥ 23 mL/minute) did not have clinically important effects on duvelisib pharmacokinetics.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C). Store and dispense in original packaging.

Actions

• Inhibits phosphatidylinositol-3-kinase (PI3K). Phosphatidylinositol-3-kinases are lipid kinases consisting of a catalytic subunit that exists in 4 different isoforms (α, β, γ, δ).

• Predominantly active against 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.

• Induces apoptosis and inhibits proliferation of primary malignant B-cell lines.

• Inhibits several important cell signaling pathways, including B-cell receptor (BCR) signaling and CXCR12-mediated chemotaxis of malignant B cells. Also, inhibits CXCL12-induced T-cell migration and macrophage colony-stimulating factor (M-CSF)- and interleukin-4 (IL-4)-driven M2 polarization of macrophages.

Advice to Patients

• Importance of instructing patients to read the manufacturer's patient information (medication guide) before initiating duvelisib therapy and each time the prescription is refilled.

• Importance of advising patients to take duvelisib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by their clinician. Importance of advising patients to swallow duvelisib capsules whole and not to open, break, or chew the capsules.

• Importance of advising 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.

• Risk of serious infections such as pneumonia. Importance of immediately reporting fever or any other signs of infection.

• Risk of severe diarrhea or colitis. Importance of immediately informing clinician if mucus or blood is present in stool or if abdominal pain or new or worsening diarrhea occurs.

• Risk of severe dermatologic reactions. 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.

• Risk of pneumonitis. Importance of informing clinician if new or worsening respiratory symptoms (e.g., cough, dyspnea) occur.

• Risk of hepatotoxicity; importance of regular liver function test monitoring. Importance of immediately informing clinician if possible signs or symptoms of hepatotoxicity (e.g., abdominal pain, jaundice, bruising, bleeding diathesis) occur.

• Risk of neutropenia; importance of periodic monitoring of blood cell counts during duvelisib therapy. Importance of immediately informing clinician if fever or other signs of infection occur.

• Risk of fetal harm. Necessity of advising women of childbearing potential to avoid pregnancy and to use effective contraceptive methods while receiving duvelisib and for one month following discontinuance of therapy. Importance of advising 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. Importance of women informing clinicians immediately if they become pregnant during therapy or think they may be pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.

• Importance of advising women to avoid breast-feeding while receiving duvelisib and for one month after discontinuance of therapy.

• 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.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Duvelisib can only be obtained through designated specialty pharmacies. Contact manufacturer or consult the Copiktra website ([Web]) for specific availability information.

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Frequently asked questions

• What type of drug is Copiktra?

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