ZYDELIG® (idelalisib) Important Safety Information

IMPORTANT SAFETY INFORMATION

BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, AND INTESTINAL PERFORATION

Fatal and/or serious hepatotoxicity occurred in 16% of ZYDELIG®-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG.
Fatal and/or serious and severe diarrhea or colitis occurred in 20% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG.
Fatal and/or serious pneumonitis occurred in 4% of ZYDELIG-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG.
Fatal and/or serious infections occurred in 48% of ZYDELIG-treated patients. Monitor for signs and symptoms of infection. Interrupt ZYDELIG if infection is suspected.
Fatal and serious intestinal perforation can occur in ZYDELIG-treated patients. Discontinue ZYDELIG if intestinal perforation is suspected.

Contraindications

History of serious hypersensitivity reactions to idelalisib, including anaphylaxis, or patients with a history of toxic epidermal necrolysis (TEN) with any drug.

Warnings and Precautions

Hepatotoxicity: Fatal and/or serious hepatotoxicity occurred in 16% of patients treated with ZYDELIG in combination with rituximab or with unapproved combination therapies. Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3x upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5x ULN, withhold ZYDELIG and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs.
Severe diarrhea or colitis: Severe diarrhea or colitis (Grade ≥3) occurred in 20% of patients treated with ZYDELIG in combination with rituximab or with unapproved combination therapies. Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea.
Pneumonitis: Fatal and serious pneumonitis occurred in 4% of patients treated with ZYDELIG compared to 1% on the comparator arms in randomized clinical trials of combination therapies. Time to onset of pneumonitis ranged from <1 to 15 months. Clinical manifestations included interstitial infiltrates and organizing pneumonia. Monitor patients on ZYDELIG for pulmonary symptoms. In patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by>5%, interrupt ZYDELIG until the etiology has been determined. If symptomatic pneumonitis or organizing pneumonia is diagnosed, initiate appropriate treatment with corticosteroids and permanently discontinue ZYDELIG.
Infections: Fatal and/or serious infections occurred in 48% of patients treated with ZYDELIG in combination with rituximab or with unapproved combination therapies. The most common infections were pneumonia, sepsis, and febrile neutropenia. Treat infections prior to initiation of ZYDELIG therapy and interrupt ZYDELIG for Grade 3 or higher infection. Serious or fatal Pneumocystis jirovecii pneumonia (PJP) or cytomegalovirus (CMV) occurred in <1% of patients treated with ZYDELIG. Provide PJP prophylaxis during treatment with ZYDELIG. Interrupt ZYDELIG in patients with suspected PJP infection of any grade, and permanently discontinue ZYDELIG if PJP infection of any grade is confirmed. Regular clinical and laboratory monitoring for CMV infection is recommended in patients with a history of CMV infection or positive CMV serology at the start of treatment with ZYDELIG. Interrupt ZYDELIG in the setting of positive CMV PCR or antigen test until the viremia has resolved. If ZYDELIG is subsequently resumed, patients should be monitored (by PCR or antigen test) for CMV reactivation at least monthly.
Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Discontinue ZYDELIG permanently in patients who experience intestinal perforation.
Severe cutaneous reactions: Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have occurred in patients treated with ZYDELIG. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have also occurred. If suspected, interrupt ZYDELIG until the etiology of the reaction has been determined. If SJS, TEN, or DRESS is confirmed, permanently discontinue ZYDELIG. Other severe or life-threatening (Grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and permanently discontinue ZYDELIG.
Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients on ZYDELIG. ZYDELIG is contraindicated in patients with a history of serious hypersensitivity reactions to idelalisib, including anaphylaxis. Permanently discontinue ZYDELIG and institute appropriate supportive measures if a reaction occurs.
Neutropenia: Grade 3-4 neutropenia occurred in 58% of patients treated with ZYDELIG in combination with rituximab or with unapproved combination therapies. Monitor blood counts at least every 2 weeks for the first 6 months, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L. Interrupt ZYDELIG until resolution and resume at reduced dose.
Embryo-fetal toxicity: ZYDELIG may cause fetal harm. Females who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during and for 1 month after treatment with ZYDELIG.

Adverse Reactions

Most common adverse reactions (incidence ≥30%) in patients treated with ZYDELIG in combination trials were diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea.
Most frequent serious adverse reactions (SAR) in clinical studies in combination with rituximab were pneumonia (23%), diarrhea (10%), pyrexia (9%), sepsis (8%) and febrile neutropenia (5%); SAR were reported in 59% of patients, and 17% discontinued therapy due to adverse reactions.
Most common lab abnormalities were neutropenia, ALT and AST elevations, and leukopenia.

Drug Interactions

CYP3A inducers: Avoid coadministration with strong CYP3A inducers.
CYP3A inhibitors: Avoid coadministration with strong CYP3A inhibitors. If unable to use alternative drugs, monitor patients more frequently for ZYDELIG adverse reactions.
CYP3A substrates: Avoid coadministration with sensitive CYP3A substrates.

Dosage and Administration

Recommended Dosage: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown.
Dose modification: Consult the ZYDELIG full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: ALT/AST elevations, bilirubin elevations, diarrhea, pneumonitis, infections, intestinal perforation, severe cutaneous reactions, hypersensitivity reactions, neutropenia, and thrombocytopenia. For other severe or life-threatening adverse reactions, withhold ZYDELIG until resolution. If resuming ZYDELIG after interruption for other severe or life-threatening toxicities, reduce the dosage to 100 mg twice daily. Permanently discontinue ZYDELIG for recurrence of other severe or life-threatening ZYDELIG-related toxicity upon rechallenge.

INDICATION

ZYDELIG (idelalisib) is indicated for the treatment of relapsed chronic lymphocytic leukemia (CLL) in combination with rituximab in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities.

Limitations of use: ZYDELIG is not indicated and is not recommended for first-line treatment of any patient, including patients with CLL, small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other indolent non-Hodgkin lymphomas.

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

Please see full Prescribing Information, including BOXED WARNING.