idelalisib (Rx)

Brand and Other Names:Zydelig
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet

  • 100mg
  • 150mg

Chronic Lymphocytic Leukemia

Indicated, in combination with rituximab, for relapsed chronic lymphocytic leukemia (CLL) in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities

Starting dose: 150 mg PO BID; continue treatment until disease progression or unacceptable toxicity

Follicular B-cell Non-Hodgkin Lymphoma

Accelerated approval for relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least 2 prior systemic therapies

Starting dose: 150 mg PO BID; continue treatment until disease progression or unacceptable toxicity

Small Lymphocytic Lymphoma

Accelerated approval for relapsed small lymphocytic lymphoma (SLL) in patients who have received at least 2 prior systemic therapies

Starting dose: 150 mg PO BID; continue treatment until disease progression or unacceptable toxicity

Dosage Modifications

Pneumonitis: Discontinue with any severity of symptomatic pneumonitis

CrCl ≥15 mL/min: No dose adjustment required

ALT/AST

  • >3-5 x ULN: Maintain dose; monitor at least weekly until ≤1 x ULN
  • >5-20 x ULN: Withhold idelalisib; monitor ALT/AST at least weekly until ≤1 x ULN, then resume at 100 mg BID
  • >20 x ULN: Permanently discontinue

Bilirubin

  • >1.5-3 x ULN: Maintain dose; monitor at least weekly until≤1 x ULN
  • >3-10 x ULN: Withhold idelalisib; monitor bilirubin at least weekly until ≤1 x ULN, then resume at 100 mg BID
  • >10 x ULN: Permanently discontinue

Diarrhea

  • Moderate: Maintain dose; monitor at least weekly until resolved
  • Severe or hospitalization: Withhold idelalisib; monitor at least weekly until resolved, then resume dose at 100 mg BID
  • Life-threatening: Permanently discontinue

Neutropenia

  • ANC 1 to <1.5 Gi/L: Maintain dose
  • ANC 0.5 to <1 Gi/L: Maintain dose; monitor ANC at least weekly
  • ANC <0.5 Gi/L: Withhold idelalisib; monitor ANC at least weekly until ANC ≥0.5 Gi/L, then resume at 100 mg BID

Thrombocytopenia

  • Platelets 50 to <75 Gi/L: Maintain dose
  • Platelets 25 to <5 Gi/L: Maintain dose; monitor platelets at least weekly
  • Platelets <25 Gi/L: Withhold idelalisib; monitor platelets at least weekly until platelets ≥25 Gi/L, then resume at 100 mg BID

Infections

  • Evidence of CMV infection or viremia
    • Interrupt idelalisib in patients with evidence of active CMV infection of any grade or viremia (positive PCR or antigen test) until the viremia has resolved
    • If idelalisib is resumed, monitor patients by PCR or antigen test for CMV reactivation at least monthly
  • Grade ≥3 sepsis or pneumonia
    • Interrupt idelalisib with until infection has resolved
  • Evidence of PJP infection
    • Interrupt idelalisib in patients with suspected PJP infection of any grade
    • Permanently discontinue idelalisib if PJP infection is confirmed

Other severe or life-threatening toxicities

  • Withhold drug until toxicity is resolved
  • If resuming treatment after interruption for other severe or life-threatening toxicities, reduce dose to 100 mg twice daily
  • Discontinue idelalisib permanently for recurrence of other severe or life-threatening idelalisib-related toxicity upon rechallenge

Dosing Considerations

Traditional (full) FDA approval for chronic lymphocytic leukemia (CLL)

Accelerated approval for relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL)

FDA accelerated approval program: Allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients; this program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials

Limitation of use

  • Not indicated or recommended for first-line treatment of any patients with CLL, FL, or SLL
  • Not indicated or recommended in combination with bendamustine and/or rituximab for the treatment of FL

Safety and efficacy not established

See Adult Dosing

No major differences in effectiveness were observed

Indolent non-Hodgkin lymphoma: Older patients (≥65 yr) had a higher incidence of discontinuation due to an adverse reaction (28% vs 20%), higher incidence of serious adverse reactions (64% vs 37%), and higher incidence of death (11% vs 5%)

CLL: Older patients (≥65 yr) had a higher incidence of discontinuation due to an adverse reaction (11% vs 5%), higher incidence of serious adverse reactions (51% vs 43%), and higher incidence of death (3% vs 0%)

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Interactions

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            Adverse Effects

            >10% (with rituximab for CLL)

            Decreased ANC, Grade 3-4 (37%)

            Pyrexia (3-35%)

            Neutropenia, Grade 3 or 4 (31%)

            Nausea (27%)

            Pneumonia (16-23%)

            Chills (2-21%)

            Diarrhea, any grade (32%)

            Diarrhea or colitis, >Grade 3 (14-19%)

            Increased lymphocyte count, Grade 3-4 (18%)

            Rash (4-18%)

            Hepatotoxicity, fatal/serious (14%)

            Vomiting (13%)

            Hypoglycemia, any grade (11%)

            >10% (monotherapy for indolent non-Hodgkin lymphoma)

            Pneumonia, Grade ≥3 (16%)

            Diarrhea, Grade ≥3 (14%)

            ANC decreased, Grade 3-4 (11-14%)

            ALT increased, Grade 3-4 (5-14%)

            1-10% (with rituximab for CLL)

            Headache (1-10%)

            Decreased lymphocyte count, Grade 3-4 (9%)

            ALT increased, Grade 3-4 (8%)

            Sinusitis (8%)

            Sepsis (7-8%)

            Pain (7%)

            Arthralgia (1-7%)

            GERD (6%)

            Stomatitis (6%)

            Bronchitis (1-6%)

            AST increased, Grade 3-4 (5%)

            Postmarketing Reports

            Skin and subcutaneous disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis

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            Warnings

            Black Box Warnings

            Fatal and/or serious hepatotoxicity occurred in 16-18% of treated patients; monitor hepatic function before and during treatment; interrupt and then reduce or discontinue as recommended (see Dosage Modifications)

            Fatal and/or serious diarrhea, or colitis occurred in 14-20% of treated patients; monitor prior to and during treatment; interrupt and then reduce or discontinue idelalisib if symptoms/laboratory evidence appears (see Dosage Modifications)

            Fatal and serious pneumonitis reported in 4% of treated patients; monitor for pulmonary symptoms and bilateral interstitial infiltrates; interrupt or discontinue idelalisib if pneumonitis suspected (see Dosage Modifications)

            Fatal and/or serious infections occurred in 21-48% of treated patients; monitor for signs and symptoms of infection; interrupt if infection is suspected (see Dosage modifications)

            Fatal and serious intestinal perforation reported; discontinue if intestinal perforation is suspected

            Contraindications

            History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis

            Cautions

            Fatal and/or serious hepatotoxicity reported (see Black Box Warnings and Dosage Modifications)

            Avoid concurrent use with other drugs that may cause hepatotoxicity

            Severe diarrhea or colitis reported (see Black Box Warnings and Dosage Modifications)

            Fatal and serious pneumonitis reported; evaluate patients with pulmonary symptoms (eg, cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic examination, or oxygen saturation decline of >5%); if symptomatic pneumonitis or organizing pneumonia is diagnosed, initiate appropriate treatment with corticosteroids and permanently discontinue therapy (See Black Box Warnings and Dosage Modifications)

            Fatal and/or serious infections occurred in 21% of patients treated with monotherapy and 36% of patients treated in combination trials; the most common infections were pneumonia, sepsis, and febrile neutropenia; monitor for signs and symptoms of infection and interrupt for ≥Grade 3 infection; serious or fatal Pneumocystis jirovecii pneumonia (PJP) or cytomegalovirus (CMV) occurred in <1% of patients treated; regular clinical and laboratory monitoring for CMV infection is recommended in patients with history of CMV infection or positive CMV serology at start of treatment (see Black Box Warnings and Dosage Modifications)

            Fatal and serious intestinal perforation reported; advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting (See Black Box Warnings)

            Severe cutaneous reactions occurred in clinical trials, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS); other severe or life-threatening (Grade ≥3) cutaneous reactions reported include dermatitis, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, and skin disorder

            Serious allergic reactions, including anaphylaxis, reported; discontinue permanently if allergic reaction occurs

            Neutropenia requiring treatment (Grade 3 or 4) reported; monitor blood counts at least q2wk for first 3 months of treatment and at least weekly if neutrophil count <1 Gi/L

            May cause fetal harm when administered pregnant women (see Pregnancy)

            Drug interactions overview

            • Idelalisib is predominantly metabolized by CYP3A; avoid coadministration with strong CYP3A inducers
            • Strong CYP3A inhibitors are known to increase idelalisib AUC; monitor for signs of idelalisib toxicity (see Dosage Modifications)
            • Idelalisib is a strong CYP3A inhibitor; avoid coadministration with CYP3A substrates
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            Pregnancy & Lactation

            Pregnancy

            There are no available data in pregnant women to inform the drug-associated risk In animal reproduction studies, administration of idelalisib to pregnant rats during organogenesis resulted in decreased fetal weight and congenital malformations in rats at maternal exposures (AUC) 12 times those reported in patients at the recommended dose of 150 mg twice daily

            Females of reproductive potential should have a pregnancy test prior to starting treatment

            Contraception

            • Females
              • Based on animal studies, idelalisib can cause fetal harm when administered to a pregnant woman
              • Advise females of reproductive potential to use effective contraception during treatment with idelalisib and for at least 1 month after the last dose
            • Males
              • Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose

            Lactation

            No data are available regarding the presence of idelalisib or its metabolites in human milk or its effects on the breastfed child or on milk production

            Owing to the potential for serious adverse reactions from idelalisib in a breastfed child, advise lactating women not to breastfeed while taking idelalisib and for at least 1 month after the last dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Phosphoinositide 3-kinase (PI3K) delta inhibitor

            PI3K delta kinase is expressed in normal and malignant B cells

            Idelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B cells and in primary tumor cells; also inhibits several cell-signaling pathways, including B cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B cells to the lymph nodes and bone marrow

            Treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion, as well as reduced cell viability

            Absorption

            Peak plasma time: 1.5 hr (single dose, fasting)

            AUC increased 1.4-fold when administered with a high-fat meal

            Distribution

            Protein bound: 84%

            Vd: 23 L

            Metabolism

            Metabolized to its major metabolite GS-563117 (inactive) via aldehyde oxidase and CYP3A

            Idelalisib undergoes minor metabolism by UGT1A4

            Elimination

            Half-life: 8.2 hr

            Systemic clearance: 14.9 L/hr

            Excretion: 78% feces; 14% urine; ~45-50% excreted as metabolite in both urine and feces

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            Administration

            Oral Administration

            Swallow tablet whole; do not chew, crush, or break

            May take with or without food

            Missed dose

            • Missed dose <6 hr: Take missed dose right away and take the next dose as usual
            • Missed by >6 hr: Wait and take the next dose at the usual time

            Storage

            Tablets: Store between 20–30°C (68–86°F) with excursions permitted 15–30ºC (59–86ºF)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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