Idelalisib (Monograph)

Brand name: Zydelig
Drug class: Antineoplastic Agents
- Phosphoinositide 3-kinase δ inhibitor
- PI3Kδ inhibitor
Chemical name: 5-Fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-(3H)-quinazolinone
Molecular formula: C₂₂H₁₈FN₇O
CAS number: 870281-82-6

Medically reviewed by Drugs.com on Jan 30, 2023. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of phosphoinositide 3-kinase isoform delta (PI3Kδ).

Uses for Idelalisib

Chronic Lymphocytic Leukemia (CLL)

Used in combination with rituximab for treatment of relapsed CLL in patients in whom monotherapy with rituximab would be considered appropriate therapy due to other comorbidities (designated an orphan drug by FDA for this use).

Not indicated and not recommended for first-line treatment, including in patients with CLL, small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other indolent non-Hodgkin's lymphomas.

Not indicated and not recommended in combination with bendamustine and rituximab, or in combination with rituximab, for treatment of patients with FL, SLL, and other indolent non-Hodgkin's lymphomas.

Idelalisib Dosage and Administration

General

Pretreatment Screening

• Perform liver function tests at baseline.

• Verify pregnancy status in females of reproductive potential.

• Treat infections prior to initiation of idelalisib.

Patient Monitoring

• Monitor liver function tests every 2 weeks during the first 3 months of therapy, every 4 weeks during the next 3 months, and then every 1–3 months thereafter. Monitor more frequently if ALT and/or AST concentrations increase to >3 times the ULN.

• Monitor for severe diarrhea or colitis. If moderate or severe diarrhea occurs, monitor at least weekly until diarrhea resolves.

• Monitor for pulmonary symptoms.

• Monitor for signs and symptoms of infection.

• Monitor for signs or symptoms of Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PJP).

• In patients with a history of cytomegalovirus (CMV) infection or positive CMV serology at the start of treatment with idelalisib, regular clinical and laboratory monitoring for CMV infection is recommended.

• If idelalisib is resumed in patients who developed clinical CMV infection or viremia during therapy, monitor for CMV reactivation by polymerase chain reaction (PCR) or antigen test at least monthly.

• Monitor for severe dermatologic reactions.

• Monitor CBC at least every 2 weeks during the first 6 months of therapy. If neutropenia occurs, monitor more frequently.

• In patients with preexisting hepatic impairment, monitor for signs of idelalisib toxicity.

Premedication and Prophylaxis

• Administer prophylaxis for PJP during therapy.

Administration

Oral Administration

Administer orally twice daily without regard to meals. Swallow tablets whole.

Dosage

Adults

CLL

Relapsed CLL

Oral

150 mg twice daily in combination with rituximab. Continue therapy until disease progression or unacceptable toxicity occurs. Manufacturer states safety and efficacy of use beyond several months not established; in phase 3 study, median duration of exposure to idelalisib was 5 months.

Dosage Modification for Toxicity

May need to interrupt therapy, reduce dosage, and/or permanently discontinue idelalisib if severe hepatotoxicity, diarrhea, pneumonitis, infection, intestinal perforation, severe cutaneous reaction, serious hypersensitivity reaction, or myelosuppression occurs.

If other severe or life-threatening toxicities occur, withhold idelalisib until toxicity resolves. If clinically appropriate, resume therapy at reduced dosage of 100 mg twice daily. If severe or life-threatening toxicities recur at dosage of 100 mg twice daily, permanently discontinue idelalisib.

Hepatotoxicity

If ALT and/or AST concentrations increase to >3–5 times the ULN or bilirubin concentrations increase to >1.5–3 times the ULN, continue idelalisib at the same dosage; monitor liver function tests at least weekly until ALT, AST, and bilirubin concentrations return to within normal limits.

If ALT and/or AST concentrations increase to >5–20 times the ULN or bilirubin concentrations increase to >3–10 times the ULN, withhold idelalisib; monitor liver function tests at least weekly. When ALT, AST, and bilirubin concentrations return to within normal limits, resume therapy at reduced dosage of 100 mg twice daily.

If ALT and/or AST concentrations increase to >20 times the ULN or bilirubin concentrations increase to >10 times ULN, permanently discontinue idelalisib.

Diarrhea

If moderate diarrhea (4–6 stools per day over baseline) occurs, continue idelalisib at the same dosage and monitor patient at least weekly until diarrhea resolves.

If severe diarrhea (≥7 stools per day over baseline) or diarrhea requiring hospitalization occurs, withhold idelalisib and monitor patient at least weekly; when diarrhea resolves, resume therapy at reduced dosage of 100 mg twice daily.

If life-threatening diarrhea occurs, permanently discontinue idelalisib.

Pneumonitis

If any severity of symptomatic pneumonitis or organizing pneumonia occurs, permanently discontinue idelalisib.

Infection

In patients who develop grade 3 or higher sepsis or pneumonia, withhold idelalisib therapy until infection has resolved.

In patients with evidence of active CMV infection of any grade or viremia (positive PCR or antigen test), withhold idelalisib therapy until viremia has resolved. If idelalisib is resumed, monitor patients at least monthly by PCR or antigen test for CMV reactivation.

In patients with suspected PJP infection of any grade, withhold idelalisib therapy. If PJP infection is confirmed, permanently discontinue idelalisib.

Intestinal Perforation

In patients who develop intestinal perforation, permanently discontinue idelalisib.

Hypersensitivity Reactions

In patients who develop serious hypersensitivity reactions, permanently discontinue idelalisib.

Dermatologic Reactions

In patients with suspected Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS), withhold idelalisib therapy until the etiology of the reaction has been determined.

In patients with confirmed SJS, TEN, DRESS, or other severe or life-threatening (i.e., grade ≥3) cutaneous reactions, permanently discontinue idelalisib.

Myelosuppression

If ANC is 1000 to <1500/mm³ or platelet count is 50,000 to <75,000/mm³, continue idelalisib at the same dosage.

If ANC is 500 to <1000/mm³ or platelet count is 25,000 to <50,000/mm³, continue idelalisib at the same dosage; monitor ANC and platelet count at least weekly.

If ANC is <500/mm³ or platelet count is <25,000/mm³, withhold idelalisib; monitor ANC and platelet count at least weekly. When ANC is ≥500/mm³ and platelet count is ≥25,000/mm³, resume therapy at reduced dosage of 100 mg twice daily.

Lymphocytosis

No dosage modifications required in patients who develop lymphocytosis.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time; however, monitor for signs of toxicity and adjust dosage as appropriate.

Renal Impairment

Cl_cr ≥15 mL/minute: No dosage adjustment needed.

Geriatric Patients

No specific dosage recommendations at this time.

Related/similar drugs

prednisone, methotrexate, dexamethasone, Decadron, rituximab, cyclophosphamide, Revlimid

Cautions for Idelalisib

Contraindications

• History of serious hypersensitivity reactions, including anaphylaxis.

• History of toxic epidermal necrolysis with any drug.

Warnings/Precautions

Warnings

Hepatotoxicity

Serious and/or fatal hepatotoxicity reported with idelalisib in combination with rituximab or other drugs.

ALT or AST elevations of >5 times the ULN reported; elevations generally occurred during initial 12 weeks of therapy. ALT or AST elevations reversible following temporary interruption of therapy; however, recurrence reported in 26% of patients following resumption of idelalisib therapy at reduced dosage.

Monitor serum ALT and AST concentrations at baseline, every 2 weeks during the first 3 months of therapy, every 4 weeks during the next 3 months, and then every 1–3 months thereafter. If hepatotoxicity occurs, monitor liver function tests more frequently until levels return to within normal limits. May need to interrupt therapy, reduce dosage, and/or permanently discontinue idelalisib depending on severity of hepatotoxicity.

Discontinue therapy if hepatotoxicity recurs.

Avoid concomitant use with drugs that may cause hepatotoxicity.

Diarrhea or Colitis

Severe (≥grade 3) diarrhea or colitis reported with idelalisib in combination with rituximab or other drugs.

Diarrhea can occur at any time and responds poorly to antimotility agents.

Diarrhea resolves within a median of 1 week to 1 month following temporary interruption of therapy and, in some instances, use of corticosteroids.

Monitor for development of severe diarrhea or colitis. If moderate or severe diarrhea occurs, monitor patients at least weekly until diarrhea resolves. May need to interrupt therapy, reduce dosage, and/or permanently discontinue idelalisib depending on severity of diarrhea. If life-threatening diarrhea occurs, permanently discontinue idelalisib.

Avoid concomitant use with drugs that may cause diarrhea.

Pneumonitis

Serious or fatal pneumonitis reported; onset <1 to 15 months.

Evaluate patients for possible pneumonitis if pulmonary manifestations (e.g., cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, >5% decrease in oxygen saturation) occur. If pneumonitis is suspected, withhold therapy until etiology of pulmonary symptoms has been determined.

If symptomatic pneumonitis or organizing pneumonia is confirmed, initiate appropriate treatment with corticosteroids and permanently discontinue idelalisib.

Infection

Serious and/or fatal infection reported with idelalisib in combination with rituximab or other drugs.

Monitor for signs and symptoms of infection. If infection is suspected, interrupt idelalisib therapy. In patients who develop ≥grade 3 sepsis or pneumonia, interrupt idelalisib therapy until infection has resolved.

Serious or fatal PJP or CMV reported. Provide appropriate PJP prophylaxis during therapy. Interrupt idelalisib therapy in patients with suspected PJP infection of any grade; if PJP infection of any grade is confirmed, permanently discontinue idelalisib.

Monitor for CMV infection in patients with history of CMV infection or positive CMV serology at the start of treatment. In case of a positive CMV PCR or antigen test, interrupt idelalisib therapy until the viremia has resolved. If idelalisib is resumed in patients who developed clinical CMV infection or viremia during therapy, monitor for CMV reactivation by PCR or antigen test at least monthly.

Intestinal Perforation

Severe and fatal intestinal perforation reported. At the time of perforation, some patients had moderate to severe diarrhea.

If intestinal perforation occurs, permanently discontinue idelalisib.

Sensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, reported. If severe hypersensitivity reaction occurs, permanently discontinue idelalisib and institute supportive treatment.

Other Warnings and Precautions

Dermatologic Effects

Fatal cases of SJS and TEN reported. Cases of DRESS also reported.

If SJS, TEN, or DRESS is suspected, interrupt idelalisib until etiology determined. If SJS, TEN, or DRESS confirmed, permanently discontinue idelalisib.

Other severe or life-threatening dermatologic reactions, including exfoliative dermatitis, rash (i.e., erythematous, generalized, macular, maculopapular, papular, pruritic, and exfoliative rash), and toxic skin reactions also reported.

Monitor patients for development of severe dermatologic reactions. If severe dermatologic reactions occur, permanently discontinue idelalisib.

Neutropenia

Severe (grade 3 or 4) neutropenia reported with idelalisib in combination with rituximab or other drugs.

Monitor CBC at least every 2 weeks during the first 6 months of therapy. If ANC decreases to <1000/mm³, monitor CBC more frequently. May need to interrupt therapy and reduce dosage depending on severity of neutropenia.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Teratogenicity and embryofetal toxicity demonstrated in animals receiving dosages equivalent to 12–30 times human exposure. Advise females of reproductive potential to use effective contraception during therapy and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during therapy and for 3 months after the last dose. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm. Appropriate contraceptive measures required.

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Lactation

Not known whether distributed into milk; effects on milk production or on the breast-fed infant also not known. Avoid breast-feeding during therapy and for 1 month after the last dose.

Females and Males of Reproductive Potential

Verify pregnancy status of females of reproductive potential prior to starting idelalisib therapy. Advise females of reproductive potential to use effective contraception during therapy and for 1 month after the last dose.

Advise males with female partners of reproductive potential to use effective contraception during therapy and for 3 months after the last dose.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Higher incidences of serious adverse reactions, death, or discontinuance of idelalisib due to adverse reactions observed in patients ≥65 years of age or older with CLL compared with younger adults.

Hepatic Impairment

Increased systemic exposure in patients with elevated ALT, AST, or bilirubin concentrations. Monitor for adverse effects.

Limited data available on idelalisib exposure in patients with baseline ALT or AST concentrations >2.5 times the ULN or bilirubin concentrations >1.5 times the ULN.

Renal Impairment

Systemic exposure not affected by renal impairment (Cl_cr ≥15 mL/minute).

Common Adverse Effects

Common adverse effects (≥30%) in patients with relapsed CLL receiving idelalisib in combination with rituximab or other drugs: Diarrhea, pneumonia, pyrexia, fatigue, rash, cough, nausea. Common laboratory abnormalities (≥28%): Neutropenia, elevated aminotransferase (ALT or AST) concentrations.

Drug Interactions

Metabolized by aldehyde oxidase, CYP3A and, to a lesser extent, uridine diphosphate-glucuronosyl transferase (UGT) 1A4.

Idelalisib: Substrate of CYP3A, aldehyde oxidase, UGT1A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Not a substrate of organic anion transport protein (OATP) 1B1, OATP1B3, renal organic anion transporter (OAT) 1, OAT3, or organic cation transporter (OCT) 2. Inhibits CYP isoenzymes 2C8, 2C19, and 3A; also inhibits UGT1A1. Induces CYP isoenzyme 2B6.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A: Potential pharmacokinetic interaction (increased systemic exposure to idelalisib). If possible, avoid concomitant use; if concomitant use is necessary, monitor frequently for signs of toxicity. May need to interrupt therapy and reduce dosage if severe adverse effects occur.

Potent inducers of CYP3A: Potential pharmacokinetic interaction (decreased systemic exposure to idelalisib). Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Potential pharmacokinetic interaction (increased systemic exposure of CYP3A substrate). Avoid concomitant use with sensitive CYP3A substrates.

Drugs Affecting the P-glycoprotein Transport System

Potential pharmacokinetic interaction (increased systemic exposure to idelalisib).

P-gp inducer: Potential pharmacokinetic interaction (decreased systemic exposure to idelalisib).

Substrates of P-glycoprotein or OATP Transport Systems

Substrates of hepatic uptake transport proteins OATP1B1 or OATP1B3: Pharmacokinetic interaction not observed to date.

Substrates of P-gp: Pharmacokinetic interaction not observed to date.

Specific Drugs

Idelalisib Pharmacokinetics

Absorption

Bioavailability

Systemic exposure to idelalisib increases in a less than dose-proportional manner over a dosage range of 50–350 mg twice daily.

Food

Systemic exposure to idelalisib increased by 1.4-fold following administration of a single dose of the drug with a high-fat meal compared with administration in the fasted state.

Special Populations

In patients with ALT, AST, or bilirubin concentrations above the ULN, systemic exposure to idelalisib increased by 1.7-fold compared with individuals with normal hepatic function.

In patients with severe renal impairment (Cl_cr 15–29 mL/minute), systemic exposure to idelalisib was unaffected following administration of a single 150-mg dose of idelalisib.

Distribution

Extent

Not known whether idelalisib is distributed into human milk.

Plasma Protein Binding

≥84%.

Elimination

Metabolism

Metabolized by aldehyde oxidase and CYP3A. Metabolized to a minor extent by UGT1A4.

Elimination Route

Eliminated in feces (78%) and urine (14%).

Half-life

Mean terminal half-life: 8.2 hours.

Stability

Storage

Oral

Tablets

20–30°C (may be exposed to 15–30°C).

Actions

• Selectively inhibits phosphoinositide 3-kinase isoform delta (PI3Kδ).

• PI3Kδ is highly expressed in hematopoietic cells and mediates B-cell receptor (BCR) signaling critical for B-cell homeostasis and function.

• Oversignaling of PI3K, particularly the delta isoform (PI3Kδ), implicated in development of lymphoid malignancies.

• Idelalisib blocks constitutive PI3K/Akt signaling which results in apoptosis.

• Inhibits several other cell signaling pathways, including BCR, CXCR4, and CXCR5, which are involved in the migration of B-cells to lymph nodes and bone marrow.

• Induces apoptosis and inhibits proliferation in cell lines derived from malignant B-cells and in primary tumor cells.

• Inhibits chemotaxis and adhesion, and reduces viability, of lymphoma cells.

Advice to Patients

• Importance of instructing patients to read the manufacturer's patient information before starting idelalisib therapy and each time their prescription is refilled.

• Importance of advising patients to take idelalisib 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 idelalisib tablets whole.

• If a dose is missed, importance of advising patients to take it as soon as they remember unless the dose was missed by >6 hours, in which case they should not take the missed dose.

• Risk of hepatotoxicity; importance of regular liver function test monitoring. Importance of advising patients to immediately report possible symptoms of hepatotoxicity (e.g., abdominal pain [especially right upper quadrant pain], jaundice, dark urine, bruising, bleeding diathesis) to their clinician.

• Risk of severe diarrhea or colitis. Importance of immediately informing clinician if frequency of bowel movements increases by ≥6 within a day.

• Risk of intestinal perforation. Importance of immediately informing clinician if new or worsening abdominal pain, chills, fever, nausea, or vomiting occurs.

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

• Risk of serious, potentially fatal, infection. Importance of immediately informing clinician if symptoms of infection (e.g., pyrexia) occur.

• Risk of anaphylaxis or severe dermatologic reactions. Importance of immediately informing clinician if anaphylaxis or severe dermatologic reactions occur.

• Risk of neutropenia. Importance of periodically monitoring CBC during idelalisib therapy. Importance of immediately informing clinician if signs of infection (e.g., fever) occur.

• Risk of fetal harm. Necessity of advising women of childbearing potential to avoid pregnancy and to use effective contraceptive methods while receiving idelalisib and for 1 month following discontinuance of therapy. Advise males with female partners of reproductive potential to use effective contraception while receiving idelalisib and for 3 months after the last dose. 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 idelalisib therapy and for 1 month after the final dose.

• 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 (e.g., hepatic impairment).

• 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.

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Frequently asked questions

• What is Zydelig used for and how does it work?

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