Zydelig: Package Insert and Label Information

ZYDELIG- idelalisib tablet, film coated
Gilead Sciences, Inc.

1 INDICATIONS AND USAGE

Zydelig is indicated, in combination with rituximab, for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.

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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of Zydelig is 150 mg administered orally twice daily with or without food until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who receive treatment longer than several months is unknown.

Swallow tablets whole.

If a planned dose of Zydelig is missed by less than 6 hours, take the missed dose as soon as possible and take the next dose as usual. If a dose of Zydelig is missed by more than 6 hours, skip the missed dose and take the next dose at the usual time.

2.2 Dosage Modifications for Adverse Reactions

Table 1 presents the dosage modification for specific adverse reactions.

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 orally twice daily. Permanently discontinue Zydelig for recurrence of other severe or life-threatening Zydelig-related toxicity upon rechallenge.

Table 1 Dosage Modifications for Adverse Reactions

Abbreviations: ANC: absolute neutrophil count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; ULN, upper limit of normal; CMV, cytomegalovirus; DRESS, drug reaction with eosinophilia and systemic symptoms; PCR: polymerase chain reaction; PJP: Pneumocystis jirovecii pneumonia; SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis
* Moderate diarrhea: increase of 4–6 stools per day over baseline; severe diarrhea: increase of ≥7 stools per day over baseline.
ALT/AST	>3–5 × ULN	>5–20 × ULN	>20 × ULN
[see Warnings and Precautions (5.1)]	Maintain Zydelig dose. Monitor at least weekly until ≤1 × ULN.	Withhold Zydelig.Monitor at least weekly until ALT/AST are ≤1 × ULN, then may resume Zydelig at 100 mg BID.	Discontinue Zydelig permanently.
Bilirubin	>1.5–3 × ULN	>3–10 × ULN	>10 × ULN
[see Warnings and Precautions (5.1)]	Maintain Zydelig dose. Monitor at least weekly until ≤1 × ULN.	Withhold Zydelig.Monitor at least weekly until bilirubin is ≤1 × ULN, then may resume Zydelig at 100 mg BID.	Discontinue Zydelig permanently.
Diarrhea *	Moderate diarrhea	Severe diarrhea or hospitalization	Life-threatening diarrhea
[see Warnings and Precautions (5.2)]	Maintain Zydelig dose. Monitor at least weekly until resolved.	Withhold Zydelig.Monitor at least weekly until resolved, then may resume Zydelig at 100 mg BID.	Discontinue Zydelig permanently.
Pneumonitis	Any symptomatic pneumonitis
[see Warnings and Precautions (5.3)]	Discontinue Zydelig in patients with any severity of symptomatic pneumonitis.
Infections	Grade 3 or higher sepsis or pneumonia
[see Warnings and Precautions (5.4)]	Interrupt Zydelig until infection has resolved.
	Evidence of CMV infection or viremia
	Interrupt Zydelig in patients with evidence of active CMV infection of any grade or viremia (positive PCR or antigen test) until the viremia has resolved. If Zydelig is resumed, monitor patients by PCR or antigen test for CMV reactivation at least monthly.
	Evidence of PJP infection
	Interrupt Zydelig in patients with suspected PJP infection of any grade.Permanently discontinue Zydelig if PJP infection is confirmed.
Intestinal Perforation	Evidence of intestinal perforation
[see Warnings and Precautions (5.5)]	Permanently discontinue Zydelig in patients who experience intestinal perforation.
Severe Cutaneous Reactions	Suspected/Confirmed SJS, TEN, DRESS, or other severe or life-threatening (Grade ≥3) cutaneous reactions
[see Warnings and Precautions (5.6)]	Interrupt Zydelig in patients with suspected SJS, TEN, or DRESS until the etiology of the reaction has been determined.Permanently discontinue Zydelig in patients with confirmed SJS, TEN, or DRESS, or other severe or life-threatening (Grade ≥3) cutaneous reactions.
Hypersensitivity Reactions	Evidence of hypersensitivity reactions
[see Warnings and Precautions (5.7)]	Permanently discontinue Zydelig in patients who develop serious hypersensitivity reactions.
Neutropenia	ANC 1.0 to <1.5 Gi/L	ANC 0.5 to <1.0 Gi/L	ANC <0.5 Gi/L
[see Warnings and Precautions (5.8)]	Maintain Zydelig dose.	Maintain Zydelig dose. Monitor ANC at least weekly.	Interrupt Zydelig. Monitor ANC at least weekly until ANC ≥0.5 Gi/L, then may resume Zydelig at 100 mg BID.
Thrombocytopenia	Platelets 50 to <75 Gi/L	Platelets 25 to <50 Gi/L	Platelets <25 Gi/L
[see Adverse Reactions (6.1)]	Maintain Zydelig dose.	Maintain Zydelig dose. Monitor platelet counts at least weekly.	Interrupt Zydelig. Monitor platelet count at least weekly. May resume Zydelig at 100 mg BID when platelets ≥25 Gi/L.

No dosage modification is recommended for lymphocytosis, which has been observed in some patients taking Zydelig. This observed lymphocytosis is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings.

3 DOSAGE FORMS AND STRENGTHS

Tablets:

• 100 mg: orange, oval-shaped, film-coated tablet debossed with “GSI” on one side and “100” on the other side.
• 150 mg: pink, oval-shaped, film-coated tablet debossed with “GSI” on one side and “150” on the other side.

4 CONTRAINDICATIONS

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)].

5 WARNINGS AND PRECAUTIONS

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 [see Adverse Reactions (6.1)]. 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 [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.2)].

5.3 Pneumonitis

Fatal and serious pneumonitis occurred in patients treated with Zydelig [see Adverse Reactions (6.1)]. 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 <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 [see Dosage and Administration (2.2)].

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 [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.2)].

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 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.