Duvelisib

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
Brands: Copiktra

Medically reviewed by Drugs.com. Last updated on Sep 30, 2019.

• Uses
• Dosage
• Cautions
• Interactions
• Pharmacokinetics
• Patient advice
• Preparations
• FAQ

Introduction

Antineoplastic agent; an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity mainly against PI3K-δ and PI3K-γ isoforms.^{1 2 3 5 6 7 8}

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^{1 2} (designated an orphan drug by FDA for these cancers).⁴

Follicular Lymphoma

Treatment of relapsed or refractory follicular lymphoma in patients who previously received ≥2 systemic therapies^{1 3} (designated an orphan drug by FDA for this cancer).⁴

Accelerated approval based on overall response rate.¹ Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.¹

Duvelisib Dosage and Administration

General

• Prophylaxis against Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP) recommended.¹ Initiate prophylaxis upon initiation of duvelisib and continue until completion of therapy and until CD4⁺ T-cell count >200/mm³.¹ (See Infectious Complications under Cautions.)

• Consider antiviral prophylaxis against cytomegalovirus (CMV) infection and/or reactivation.¹ (See Infectious Complications under Cautions.)

Administration

Oral Administration

Administer orally twice daily without regard to meals.¹ Swallow capsules whole; do not open, break, or chew.¹

Dosage

Adults

CLL or SLL

Relapsed or Refractory CLL or SLL

Oral

25 mg twice daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Follicular Lymphoma

Relapsed or Refractory Follicular Lymphoma

Oral

25 mg twice daily.¹ Continue therapy until disease progression or unacceptable toxicity occurs.¹

Dosage Modification for Toxicity

May need to interrupt therapy, reduce dosage to 15 mg twice daily, and/or permanently discontinue duvelisib if toxicity occurs.¹ If a reduced dosage of 15 mg twice daily is not tolerated, permanently discontinue duvelisib.¹

Infections

If grade 3 or 4 infection occurs, withhold duvelisib until infection resolves, then resume duvelisib at previous dosage or at reduced dosage.¹ (See Infectious Complications under Cautions.)

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.¹ After resuming therapy, monitor for reactivation of CMV infection at least monthly.¹

If PCP (any grade) is suspected, withhold duvelisib.¹ If PCP is confirmed, permanently discontinue duvelisib.¹

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.¹

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.¹

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.¹

If recurrent severe diarrhea or recurrent colitis of any grade occurs, permanently discontinue duvelisib.¹

If life-threatening diarrhea or colitis occurs, permanently discontinue duvelisib.¹

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.¹

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.¹ If severe toxicity does not improve, worsens, or recurs, permanently discontinue duvelisib.¹

If life-threatening dermatologic toxicity occurs, permanently discontinue duvelisib.¹ (See Dermatologic Effects under Cautions.)

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

Noninfectious Pneumonitis

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

If severe (grade 3) or life-threatening noninfectious pneumonitis occurs, permanently discontinue duvelisib and initiate systemic corticosteroid therapy.¹ (See Pneumonitis under Cautions.)

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.¹

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.¹ 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.¹

For grade 4 ALT and/or AST elevations (>20 times the ULN), permanently discontinue duvelisib.¹

Hematologic Toxicity

For grade 3 neutropenia (ANC 500–1000/mm³), continue duvelisib at the same dosage and monitor ANC at least weekly.¹ (See Neutropenia under Cautions.)

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.¹ If grade 4 neutropenia recurs, withhold duvelisib; when ANC is ≥500/mm³, resume duvelisib at reduced dosage.¹

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.¹

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.¹ If toxicity recurs, withhold duvelisib; when platelet count is ≥25,000/mm³, resume duvelisib at reduced dosage.¹

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.¹ If toxicity recurs, withhold duvelisib; when platelet count is ≥25,000/mm³, resume duvelisib at reduced dosage.¹

Concomitant Use with Drugs Affecting Microsomal Enzymes

If concomitant use of potent CYP3A inhibitors cannot be avoided, reduce duvelisib dosage to 15 mg twice daily.¹ (See Interactions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.¹

Renal Impairment

No specific dosage recommendations at this time.¹

Geriatric Patients

No specific dosage recommendations at this time.¹ (See Geriatric Use under Cautions.)

Cautions for Duvelisib

Contraindications

• No known contraindications.¹

Warnings/Precautions

Warnings

Infectious Complications

Serious infections (most commonly pneumonia, sepsis, and lower respiratory infections), including fatalities, reported.¹

Serious, sometimes fatal PCP reported.¹ PCP prophylaxis is recommended.^{1 2} (See General under Dosage and Administration.) If PCP is suspected, withhold duvelisib.¹ If PCP is confirmed, permanently discontinue duvelisib.¹

CMV infection and/or reactivation also reported; consider antiviral prophylaxis during duvelisib therapy.¹ 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.¹

Treat infections prior to initiating duvelisib therapy.¹

Monitor for signs and symptoms of infection.¹ If grade 3 or greater infection occurs, withhold duvelisib.¹ (See Infections under Dosage and Administration.)

Diarrhea or Colitis

Serious, sometimes fatal, diarrhea or colitis reported.¹

Monitor for development of severe diarrhea or colitis.¹

If diarrhea or colitis occurs, provide supportive therapy (e.g., antidiarrheal agents, corticosteroids) and monitor patients at least weekly until diarrhea or colitis resolves.¹ 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.¹ May need to interrupt therapy, reduce dosage, and/or permanently discontinue duvelisib depending on severity of diarrhea or colitis.¹ (See Noninfectious Diarrhea or Colitis under Dosage and Administration.)

Dermatologic Effects

Severe dermatologic reactions, including erythroderma, exfoliative dermatitis, desquamation, pruritus, keratinocyte necrosis, and rash (e.g., exanthem; erythematous, papular, or maculopapular rash), reported.¹ Fatal dermatologic reactions, including toxic epidermal necrolysis and DRESS, also reported.¹

If dermatologic reactions occur, evaluate concomitant therapy and discontinue drugs that may be contributing to dermatologic reactions.¹ Initiate supportive care (e.g., emollients, antihistamines for relief of pruritus, topical or systemic corticosteroids) and monitor patients closely.¹ May need to interrupt therapy, reduce dosage, and/or permanently discontinue duvelisib depending on severity of dermatologic toxicity.¹ (See Dermatologic Toxicity under Dosage and Administration.)

Pneumonitis

Serious, sometimes fatal, noninfectious pneumonitis reported.¹

Monitor for respiratory symptoms and presence of interstitial infiltrates.¹ If new or progressive respiratory manifestations (e.g., cough, dyspnea, hypoxia, interstitial infiltrates, >5% decrease in oxygen saturation) occur, interrupt therapy and evaluate etiology.¹

If infectious pneumonitis is confirmed, resume duvelisib at previous dosage when infection and respiratory manifestations resolve.¹

For grade 2 or greater noninfectious pneumonitis, initiate systemic corticosteroid therapy.¹ May need to interrupt therapy, reduce dosage, and/or permanently discontinue duvelisib depending on severity and persistence of pneumonitis.¹ (See Noninfectious Pneumonitis under Dosage and Administration.)

Other Warnings and Precautions

Hepatotoxicity

ALT or AST elevations of >5 times the ULN reported.¹ Concomitant total bilirubin elevations also reported.¹

Monitor liver function tests, including ALT and AST concentrations, periodically during therapy.¹ If hepatotoxicity occurs, monitor liver function tests more frequently.¹ May need to interrupt therapy, reduce dosage, and/or permanently discontinue duvelisib depending on severity of hepatotoxicity.¹ (See Hepatotoxicity under Dosage and Administration.)

Neutropenia

Severe (grade 3 or 4) neutropenia reported.¹

Monitor ANC at least every 2 weeks during the first 2 months of therapy.¹ If ANC <1000/mm³, monitor ANC at least every week.¹ May need to interrupt therapy and/or reduce dosage depending on severity of neutropenia.¹ (See Hematologic Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

Based on its mechanism of action and animal findings, duvelisib may cause fetal harm.¹ Embryofetal toxicity and teratogenicity demonstrated in animals.¹

Perform pregnancy test prior to initiating duvelisib therapy in women of childbearing potential.¹ Avoid pregnancy during therapy and for ≥1 month after drug discontinuance.¹ 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.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Impairment of Fertility

Results of animal studies suggest duvelisib may impair male fertility.¹

Specific Populations

Pregnancy

May cause fetal harm.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether duvelisib distributes into milk, affects milk production, or affects nursing infants.¹

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

Pediatric Use

Safety and efficacy not established in pediatric patients.¹

Geriatric Use

In clinical studies evaluating duvelisib, 61% of patients were ≥65 years of age and 24% were ≥75 years of age.¹ No overall differences in safety or efficacy between geriatric patients (≥65 years of age) and younger adults.¹

Hepatic Impairment

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

Renal Impairment

Systemic exposure not altered in patients with Cl_cr ≥23 mL/minute.¹

Common Adverse Effects

Diarrhea or colitis,^{1 2 3} rash,^{1 2 3} pyrexia,^{1 2 3} fatigue,^{1 2 3} upper or lower respiratory tract infection,^{1 2} pneumonia,^{1 2} cough,^{1 2 3} nausea,^{1 2 3} musculoskeletal pain,¹ abdominal pain,^{1 2 3} vomiting,^{1 2 3} constipation,^{1 2 3} decreased appetite,^{1 2 3} edema,^{1 3} mucositis,¹ dyspnea,^{1 2} headache,^{1 3} decreased weight,^{1 2} arthralgia,^{1 3} neutropenia,^{1 2 3} anemia,^{1 2 3} thrombocytopenia,¹ elevated aminotransferase (ALT, AST) and alkaline phosphatase concentrations,¹ elevated lipase and amylase concentrations,¹ hypophosphatemia,¹ lymphocytosis,¹ hyponatremia,¹ hyperkalemia,¹ hypoalbuminemia,¹ elevated S_cr,¹ leukopenia,¹ hypocalcemia,¹ lymphopenia,¹ hypokalemia.¹

Interactions for Duvelisib

Metabolized principally by CYP3A4.¹

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro.¹

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.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A: Potential pharmacokinetic interaction (increased systemic exposure to duvelisib) and increased risk of toxicity.¹ If concomitant use cannot be avoided, reduce duvelisib dosage from 25 mg twice daily to 15 mg twice daily.¹

Mild or moderate inhibitors of CYP3A: Pharmacokinetic simulations suggest no effect on duvelisib exposure.¹

Potent inducers of CYP3A: Potential pharmacokinetic interaction (decreased systemic exposure to duvelisib) and decreased therapeutic efficacy.¹ Avoid concomitant use.¹ (See Specific Drugs under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Potential pharmacokinetic interaction (increased systemic exposure to CYP3A substrate) and increased adverse effects.¹ Monitor for toxicity; consider reducing CYP3A substrate dosage.¹ (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.¹

Absolute oral bioavailability is 42%.¹

Peak plasma concentrations achieved within 1–2 hours.¹

Food

Administration with high-fat meal decreases peak plasma concentrations and AUC by 37 and 6%, respectively, compared with administration in the fasted state.¹

Distribution

Extent

Not known whether duvelisib is distributed into human milk.¹

Plasma Protein Binding

>98%.¹

Elimination

Metabolism

Principally metabolized by CYP3A4.¹

Elimination Route

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

Half-life

Mean terminal half-life: 4.7 hours.¹

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.¹

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).¹ Store and dispense in original packaging.¹

Actions

• Inhibits phosphatidylinositol-3-kinase (PI3K).^{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}

• 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.^{2 5 6 7 8 9 10}

• Induces apoptosis and inhibits proliferation of primary malignant B-cell lines.^{5 6 7 8 9 10}

• Inhibits several important cell signaling pathways, including B-cell receptor (BCR) signaling and CXCR12-mediated chemotaxis of malignant B cells.^{1 5 9 10} Also, inhibits CXCL12-induced T-cell migration and macrophage colony-stimulating factor (M-CSF)- and interleukin-4 (IL-4)-driven M2 polarization of macrophages.^{1 9 10}

Advice to Patients

• Importance of reading the manufacturer's patient information (medication guide) before initiating duvelisib therapy and each time the prescription is refilled.¹

• Importance of taking duvelisib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by clinician.¹ Importance of swallowing duvelisib capsules whole and not opening, breaking, or chewing the capsules.¹

• Importance of taking a missed dose as soon as it is remembered unless the dose was missed by >6 hours, in which case the missed dose should not be taken.¹

• Risk of serious infections such as pneumonia.¹ Importance of immediately reporting fever or any other signs of infection.¹

• Risk of severe diarrhea or colitis.¹ Importance of immediately informing clinician if mucus or blood is present in stool or abdominal pain or new or worsening diarrhea occurs.¹

• Risk of severe dermatologic reactions.¹ 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 Importance of informing clinician if new or worsening respiratory symptoms (e.g., cough, dyspnea) occur.¹

• Risk of hepatotoxicity; importance of regular liver function test monitoring.¹ Importance of immediately informing clinician if possible signs or symptoms of hepatotoxicity (e.g., abdominal pain, jaundice, bruising, bleeding diathesis) occur.¹

• Risk of neutropenia; importance of periodic monitoring of blood cell counts.¹ Importance of immediately informing clinician if fever or other signs of infection occur.¹

• Risk of fetal harm.¹ Necessity of advising women of childbearing potential to avoid pregnancy and to use effective contraceptive methods while receiving duvelisib and for ≥1 month following discontinuance of therapy.¹ Importance of advising men who are partners of such women that they should use effective methods of contraception while receiving the drug and for ≥1 month after the drug is discontinued.¹ 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

• Importance of advising women to avoid breast-feeding while receiving duvelisib and for ≥1 month after discontinuance of therapy.¹

• 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

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

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.

Frequently asked questions

• What type of drug is Copiktra?

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