Dosage & Administration
Recommended dosage: 150 mg orally twice daily.
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Zydelig Prescribing Information
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 as recommended [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].
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 as recommended [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].
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 [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].
Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig for intestinal perforation [see Warnings and Precautions (5.5)].
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.
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.
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.
| 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 | |||
| |||
| 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.
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.
Pregnancy
Risk Summary
Based on findings in animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], Zydelig may cause fetal harm when administered to a pregnant woman.
There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of idelalisib to pregnant rats during organogenesis resulted in decreased fetal weight and congenital malformations in rats at maternal exposures (AUC) 12 times those reported in patients at the recommended dosage of 150 mg twice daily (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies 2–4% and 15–20%, respectively.
Data
Animal Data
In an embryo-fetal development study in rats, pregnant animals receiving oral doses of idelalisib during the period of organogenesis (implantation to closure of the hard palate), embryo-fetal toxicities were observed at the mid- and high-doses that also resulted in maternal toxicity, based on reductions in maternal body weight gain. Adverse findings at idelalisib doses ≥ 75 mg/kg/day included decreased fetal weights, external malformations (short tail), and skeletal variations (delayed ossification and/or unossification of the skull, vertebrae, and sternebrae). Additional findings were observed at 150 mg/kg/day dose of idelalisib and included urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, and microphthalmia/anophthalmia). The dose of 75 and 150 mg/kg/day of idelalisib in rats resulted in exposures (AUC) of approximately 12 and 30 times, respectively, the human exposure at the recommended dose of 150 mg twice daily.
Lactation
Risk Summary
There are no data on the presence of idelalisib or its metabolites in human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Zydelig and for 1 month after the last dose.
Females and Males of Reproductive Potential
Zydelig may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy
Pregnancy testing is recommended for females of reproductive potential prior to starting Zydelig.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with Zydelig and for 1 month after the last dose.
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with Zydelig and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].
Pediatric Use
Safety and effectiveness of Zydelig in pediatric patients have not been established.
Geriatric Use
Of the 490 patients with relapsed CLL who were treated with Zydelig in combination trials, 271 (55%) were 65 years of age and older. When comparing patients 65 years of age or older to younger patients with CLL, older patients had a higher incidence of discontinuation due to an adverse reaction (36% vs 28%), higher incidence of serious adverse reactions (73% vs 67%), and higher incidence of death (13% vs 9%).
Hepatic Impairment
No dose adjustment is recommended for patients with ALT or AST or bilirubin > upper limit of normal (ULN); however, limited safety and efficacy data are available for patients with baseline AST or ALT > 2.5 × ULN or bilirubin > 1.5 × ULN. Monitor patients with baseline hepatic impairment for adverse reactions [see Warnings and Precautions (5)]. Follow dosage modifications for adverse reactions [see Dosage and Administration (2.2)].
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)] .