IDELALISIB Drug Interactions: What You Need to Know

INTERACTIONS Strong CYP3A Inhibitors : Additional monitoring required if alternative therapy is not available. ( 7.1 ) Strong CYP3A Inducers : Avoid coadministration of strong CYP3A inducers. ( 7.1 ) CYP3A Substrates : Avoid coadministration of sensitive CYP3A substrates. ( 7.2 )

7.1 Effects of Other Drugs on Zydelig Table 6 lists the potential effects of the coadministration of strong CYP3A modulators on Zydelig.

Table

6 Drug Interactions with Zydelig that affect Idelalisib Concentrations Strong CYP3A Inhibitors Clinical Impact Coadministration with strong CYP3A inhibitors may increase idelalisib concentrations [see Clinical Pharmacology (12.3) ] . Increased idelalisib concentrations may increase the risk of exposure related adverse reactions. Prevention or Management Use other drugs that are not strong CYP3A inhibitors. If unable to use alternative drugs, monitor patients more frequently for Zydelig adverse reactions [see Adverse Reactions (6.1) ] . Strong CYP3A Inducers Clinical Impact Coadministration with strong CYP3A inducers may decrease idelalisib concentrations [see Clinical Pharmacology (12.3) ] . Decreased idelalisib concentrations may reduce efficacy. Prevention or Management Avoid coadministration of Zydelig with strong CYP3A4 inducers.

7.2 Effects of Zydelig on Other Drugs The coadministration of Zydelig with a CYP3A substrate may increase the concentrations of this CYP3A substrate. Avoid coadministration of Zydelig with sensitive CYP3A substrates <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

Zydelig is contraindicated in patients with a history of serious hypersensitivity reactions to idelalisib, including anaphylaxis, or patients with a history of toxic epidermal necrolysis with any drug [see Warnings and Precautions (5.6 , 5.7) ] . History of serious hypersensitivity reactions to idelalisib, including anaphylaxis, or history of toxic epidermal necrolysis with any drug. ( 4 )

AND PRECAUTIONS Severe Cutaneous Reactions : Monitor patients for the development of severe cutaneous reactions. Permanently discontinue Zydelig if confirmed. ( 2.2 , 5.6 )

Hypersensitivity

Reactions : Permanently discontinue Zydelig and institute appropriate supportive measures. ( 2.2 , 5.7 ) Neutropenia : Monitor blood counts.

Interrupt

Zydelig until resolution and resume at reduced dose. ( 2.2 , 5.8 ) Embryo-fetal Toxicity : May cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.9 , 8.1 , 8.3 )

5.1 Hepatotoxicity Fatal and/or serious hepatotoxicity occurred in 16% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. Elevations in ALT or AST greater than 5 times the upper limit of normal have occurred <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. These findings were generally observed within the first 12 weeks of treatment and were reversible with dose interruption. After resumption of treatment at a lower dose, 26% of patients had recurrence of ALT and AST elevations.

Discontinue

Zydelig for recurrent hepatotoxicity. Avoid concurrent use of Zydelig with other drugs that may cause liver toxicity. Monitor ALT and AST in all patients every 2 weeks for the first 3 months of treatment, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter. Monitor weekly for liver toxicity if the ALT or AST rises above 3 times the upper limit of normal until resolved.

Withhold

Zydelig if the ALT or AST is greater than 5 times the upper limit of normal, and continue to monitor AST, ALT and total bilirubin weekly until the abnormality is resolved [see Dosage and Administration (2.2) ].

5.2 Severe Diarrhea or Colitis Severe diarrhea or colitis (Grade 3 or higher) occurred in 20% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Diarrhea can occur at any time. Avoid concurrent use of Zydelig and other drugs that cause diarrhea. Diarrhea due to Zydelig responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month across trials, following interruption of Zydelig therapy and in some instances, use of corticosteroids <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span>.

5.3 Pneumonitis Fatal and serious pneumonitis occurred in patients treated with Zydelig <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Clinical manifestations included interstitial infiltrates and organizing pneumonia. In randomized clinical trials of combination therapies, pneumonitis occurred in 4% of patients treated with Zydelig compared to 1% on the comparator arms. Time to onset of pneumonitis ranged from &lt;1 to 15 months. Monitor patients on Zydelig for pulmonary symptoms. In patients taking Zydelig who present with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation, 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

5.4 Infections Fatal and/or serious infections occurred in 48% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . The most common infections were pneumonia, sepsis, and febrile neutropenia. Treat infections prior to initiation of Zydelig therapy. Monitor patients on Zydelig for signs and symptoms of infection, and interrupt Zydelig for Grade 3 or higher infection <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . Serious or fatal Pneumocystis jirovecii pneumonia (PJP) or cytomegalovirus (CMV) occurred in &lt;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 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 [see Dosage and Administration (2.2) ] .

5.5 Intestinal Perforation Fatal and serious intestinal perforation occurred in Zydelig-treated patients. At the time of perforation, some patients had moderate to severe diarrhea. 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.

5.6 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . Zydelig is contraindicated in patients with a history of toxic epidermal necrolysis <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>. If SJS, TEN, or DRESS is suspected, interrupt Zydelig until the etiology of the reaction has been determined. If SJS, TEN, or DRESS is confirmed, permanently discontinue Zydelig <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . Other severe or life-threatening (Grade ≥3) cutaneous reactions, including dermatitis exfoliative, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, exfoliative rash, and skin disorder, have been reported in patients treated with Zydelig. Monitor patients for the development of other severe or life-threatening cutaneous reactions and permanently discontinue Zydelig <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

5.7 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 <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>. In patients who develop serious hypersensitivity reactions, permanently discontinue Zydelig <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> and institute appropriate supportive measures.

5.8 Neutropenia Grade 3 or 4 neutropenia occurred in 58% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Monitor blood counts at least every 2 weeks for the first 6 months of therapy, 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 [see Dosage and Administration (2.2) ].

5.9 Embryo-fetal Toxicity Based on findings in animals and its mechanism of action, Zydelig may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of idelalisib to pregnant rats during organogenesis caused decreased fetal weight and congenital malformations at systemic exposures 12 times those reported in patients at the recommended dose of 150 mg twice daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Zydelig and for 1 month after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span> .