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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% to 18% 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 14% to 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 21% to 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 allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN).

Warnings and Precautions

Hepatotoxicity: Fatal and/or serious hepatotoxicity occurred in 18% of patients treated with ZYDELIG monotherapy and 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 14% of patients treated with ZYDELIG monotherapy and 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 21% of patients treated with ZYDELIG monotherapy and 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.
Severe cutaneous reactions: Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have occurred. If suspected, interrupt ZYDELIG until the etiology of the reaction has been determined. If SJS or TEN is confirmed, discontinue ZYDELIG. Other severe or life-threatening (Grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and discontinue ZYDELIG.
Anaphylaxis: Serious allergic reactions, including anaphylaxis, have been reported. Discontinue ZYDELIG permanently and institute appropriate supportive measures if a reaction occurs.
Neutropenia: Treatment-emergent Grade 3-4 neutropenia occurred in 25% of patients treated with monotherapy and 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.
Embryo-fetal toxicity: ZYDELIG may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking ZYDELIG and to use effective contraception during and at least 1 month after treatment with ZYDELIG.

Adverse Reactions

Most common adverse reactions in patients treated with ZYDELIG in combination trials (incidence ≥30%, all grades) were diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea; and in the monotherapy trial (incidence ≥20%, all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash.
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 frequent SAR in clinical studies when used alone were pneumonia (15%), diarrhea (11%), and pyrexia (9%); SAR were reported in 50% of patients, and 53% discontinued due to adverse reactions.
Most common lab abnormalities include neutropenia, ALT elevations, and AST elevations.

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

Adult starting dose: 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: pneumonitis, ALT/AST elevations, bilirubin elevations, diarrhea, neutropenia, thrombocytopenia, and infections. For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce the dose to 100 mg twice daily upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, ZYDELIG should be permanently discontinued.

INDICATIONS

ZYDELIG 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
Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies
Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies
Accelerated approval was granted for follicular lymphoma and SLL based on overall response rate. An improvement in patient survival or disease-related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.

ZYDELIG is not indicated or recommended for first-line treatment of any patient or in combination with bendamustine and/or rituximab for the treatment of FL.

Please see full Prescribing Information, including BOXED WARNING.