Dosing and uses of Zydelig (idelalisib)
Adult dosage forms and 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
Not indicated and is not recommended for first line treatment of CLL
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
Not indicated and is not recommended for first line treatment of FL
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
Not indicated and is not recommended for first line treatment of SLL
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 with evidence of CMV infection of any grade or viremia (positive PCR or antigen test) until the infection has resolved
- If treatment resumed, monitor patients (by PCR or antigen test) for CMV reactivation at least monthly
- Evidence of PJP infection
- Interrupt idelalisib with suspected PJP infection of any grade
- Permanently discontinue drug if PJP infection is confirmed
Dosing Considerations
Traditional (full) FDA approval for chronic lymphocytic leukemia (CLL)
Accelerated approval for 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
Pediatric dosage forms and strengths
Safety and efficacy not established
Geriatric dosage forms and strengths
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%)
Zydelig (idelalisib) adverse (side) 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
Warnings
Black box warnings
Fatal and/or serious hepatotoxicity occurred in 11-18% 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 14-19% 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 21-36% 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%) (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 (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
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
May cause fetal harm when administered pregnant women
Pregnancy and lactation
Pregnancy category: d
Women should use effective contraception during treatment and for 1 month following discontinuation
Lactation: Unknown if distributed in human breast milk; a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
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.
Pharmacology of Zydelig (idelalisib)
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
Administration
Oral Administration
Swallow tablet whole; do not chew, crush, or break
May take with or without food
