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|blackBoxWarningTitle=<b><span style="color:#FF0000;">FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION</span></b>
|blackBoxWarningTitle=<b><span style="color:#FF0000;">FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i>  
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i>  
*Fatal and/or serious hepatotoxicity occurred in 14% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.  
*Fatal and/or serious hepatotoxicity occurred in 14% of Idelalisib-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Idelalisib as recommended.  
*Fatal and/or serious and severe diarrhea or colitis occurred in 14% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.  
*Fatal and/or serious and severe diarrhea or colitis occurred in 14% of Idelalisib-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Idelalisib as recommended.  
*Fatal and serious pneumonitis can occur in Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.  
*Fatal and serious pneumonitis can occur in Idelalisib-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Idelalisib as recommended.  
*Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. *Discontinue Zydelig for intestinal perforation.
*Fatal and serious intestinal perforation can occur in Idelalisib-treated patients across clinical trials. *Discontinue Idelalisib for intestinal perforation.
|fdaLIADAdult=====Recommended Dose====
|fdaLIADAdult=====Recommended Dose====
*The recommended maximum starting dose of Zydelig is 150 mg administered orally twice daily.
*The recommended maximum starting dose of Idelalisib is 150 mg administered orally twice daily.
*Zydelig can be taken with or without food. Tablets should be swallowed whole.
*Idelalisib can be taken with or without food. Tablets should be swallowed whole.
*Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who receive treatment longer than several months is unknown.
*Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who receive treatment longer than several months is unknown.


====Dose Modification====
====Dose Modification====
*<i>See the table below for dose modification instructions for specific toxicities related to Zydelig.</i>
*<i>See the table below for dose modification instructions for specific toxicities related to Idelalisib.</i>
*For other severe or life-threatening toxicities related to Zydelig, withhold drug until toxicity is resolved. If resuming Zydelig after interruption for other severe or life-threatening toxicities, reduce the dose to 100 mg twice daily. Recurrence of other severe or life-threatening Zydelig-related toxicity upon rechallenge should result in permanent discontinuation of Zydelig.
*For other severe or life-threatening toxicities related to Idelalisib, withhold drug until toxicity is resolved. If resuming Idelalisib after interruption for other severe or life-threatening toxicities, reduce the dose to 100 mg twice daily. Recurrence of other severe or life-threatening Idelalisib-related toxicity upon rechallenge should result in permanent discontinuation of Idelalisib.


[[file:Dosage Idelalisib.png|none|350px]]
[[file:Dosage Idelalisib.png|none|350px]]
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|contraindications=*History of serious [[allergic reactions]] including [[anaphylaxis]] and [[toxic epidermal necrolysis]].
|contraindications=*History of serious [[allergic reactions]] including [[anaphylaxis]] and [[toxic epidermal necrolysis]].
|warnings=====Hepatotoxicity====
|warnings=====Hepatotoxicity====
*Fatal and/or serious [[hepatotoxicity]] occurred in 14% of patients treated with Zydelig. Elevations in [[ALT]] or [[AST]] greater than 5 times the upper limit of normal have occurred. 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]].
*Fatal and/or serious [[hepatotoxicity]] occurred in 14% of patients treated with Idelalisib. Elevations in [[ALT]] or [[AST]] greater than 5 times the upper limit of normal have occurred. 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 Idelalisib for recurrent [[hepatotoxicity]].
*Avoid concurrent use of Zydelig with other drugs that may cause liver toxicity.
*Avoid concurrent use of Idelalisib 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.
*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 Idelalisib 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.


====Severe Diarrhea or Colitis====
====Severe Diarrhea or Colitis====
*Severe [[diarrhea]] or [[colitis]] (Grade 3 or higher) occurred in 14% of Zydelig-treated patients across clinical trials. [[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]].  
*Severe [[diarrhea]] or [[colitis]] (Grade 3 or higher) occurred in 14% of Idelalisib-treated patients across clinical trials. [[Diarrhea]] can occur at any time. Avoid concurrent use of Idelalisib and other drugs that cause [[diarrhea]]. [[Diarrhea]] due to Idelalisib responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month across trials, following interruption of Idelalisib therapy and in some instances, use of [[corticosteroids]].  


====Pneumonitis====
====Pneumonitis====
*Fatal and serious [[pneumonitis]] occurred in patients treated with Zydelig. 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 should be evaluated for [[pneumonitis]]. If [[pneumonitis]] is suspected, interrupt Zydelig until the etiology of the pulmonary symptoms has been determined. Patients with [[pneumonitis]] thought to be caused by Zydelig have been treated with discontinuation of Zydelig and administration of [[corticosteroids]].
*Fatal and serious [[pneumonitis]] occurred in patients treated with Idelalisib. Patients taking Idelalisib 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 should be evaluated for [[pneumonitis]]. If [[pneumonitis]] is suspected, interrupt Idelalisib until the etiology of the pulmonary symptoms has been determined. Patients with [[pneumonitis]] thought to be caused by Idelalisib have been treated with discontinuation of Idelalisib and administration of [[corticosteroids]].


====Intestinal Perforation====
====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]].
*Fatal and serious [[intestinal perforation]] occurred in Idelalisib-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 Idelalisib permanently in patients who experience [[intestinal perforation]].


====Severe Cutaneous Reactions====
====Severe Cutaneous Reactions====
*One case of [[toxic epidermal necrolysis]] ([[TEN]]) occurred in a study of Zydelig in combination with [[rituximab]] and [[bendamustine]]. Other severe or life-threatening (Grade ≥3) cutaneous reactions, including [[dermatitis exfoliative]], [[rash]], [[erythematous rash]], [[generalized rash]], [[macular rash]], [[maculo-papular rash]], [[papular rash]], [[pruritic rash]], [[exfoliative rash]], and skin disorder, have been reported in Zydelig-treated patients. Monitor patients for the development of severe cutaneous reactions and discontinue Zydelig.
*One case of [[toxic epidermal necrolysis]] ([[TEN]]) occurred in a study of Idelalisib in combination with [[rituximab]] and [[bendamustine]]. Other severe or life-threatening (Grade ≥3) cutaneous reactions, including [[dermatitis exfoliative]], [[rash]], [[erythematous rash]], [[generalized rash]], [[macular rash]], [[maculo-papular rash]], [[papular rash]], [[pruritic rash]], [[exfoliative rash]], and skin disorder, have been reported in Idelalisib-treated patients. Monitor patients for the development of severe cutaneous reactions and discontinue Idelalisib.


====Anaphylaxis====
====Anaphylaxis====
*Serious [[allergic reactions]], including [[anaphylaxis]], have been reported in patients on Zydelig. In patients who develop serious [[allergic reactions]], discontinue Zydelig permanently and institute appropriate supportive measures.
*Serious [[allergic reactions]], including [[anaphylaxis]], have been reported in patients on Idelalisib. In patients who develop serious [[allergic reactions]], discontinue Idelalisib permanently and institute appropriate supportive measures.


====Neutropenia====
====Neutropenia====
*Treatment-emergent Grade 3 or 4 [[neutropenia]] occurred in 31% of Zydelig-treated patients across clinical trials. Monitor blood counts at least every two weeks for the first 3 months of therapy, and at least weekly in patients while [[neutrophil]] counts are less than 1.0 Gi/L.
*Treatment-emergent Grade 3 or 4 [[neutropenia]] occurred in 31% of Idelalisib-treated patients across clinical trials. Monitor blood counts at least every two weeks for the first 3 months of therapy, and at least weekly in patients while [[neutrophil]] counts are less than 1.0 Gi/L.


====Embryo-fetal Toxicity====
====Embryo-fetal Toxicity====
*Based on findings in animals, Zydelig may cause fetal harm when administered to a pregnant woman. Idelalisib is teratogenic in rats, at systemic exposures 12 times those reported in patients at the recommended dose of 150 mg twice daily. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
*Based on findings in animals, Idelalisib may cause fetal harm when administered to a pregnant woman. Idelalisib is teratogenic in rats, at systemic exposures 12 times those reported in patients at the recommended dose of 150 mg twice daily. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
*Advise females of reproductive potential to avoid becoming pregnant while taking Zydelig. If contraceptive methods are being considered, use effective contraception during treatment, and for at least 1 month after the last dose of Zydelig.
*Advise females of reproductive potential to avoid becoming pregnant while taking Idelalisib  If contraceptive methods are being considered, use effective contraception during treatment, and for at least 1 month after the last dose of Idelalisib.
|clinicalTrials=====Summary of Clinical Trials in Chronic Lymphocytic Leukemia====
|clinicalTrials=====Summary of Clinical Trials in Chronic Lymphocytic Leukemia====
*The safety data reflect subject exposure to Zydelig from Study 1, in which 218 subjects with relapsed CLL received up to 8 doses of [[rituximab]] with or without Zydelig 150 mg twice daily. The median duration of exposure to Zydelig was 5 months.
*The safety data reflect subject exposure to Idelalisib from Study 1, in which 218 subjects with relapsed CLL received up to 8 doses of [[rituximab]] with or without Idelalisib 150 mg twice daily. The median duration of exposure to Idelalisib was 5 months.
*Serious adverse reactions were reported in 54 (49%) subjects treated with Zydelig + rituximab. The most frequent (≥2%) serious adverse reactions reported for subjects treated with Zydelig were [[pneumonia]] (17%), [[pyrexia]] (9%), [[sepsis]] (8%), [[febrile neutropenia]] (5%) and [[diarrhea]] (5%). Adverse reactions that led to discontinuation of Zydelig occurred in 11 (10%) subjects. The most common adverse reactions that led to treatment discontinuations were [[hepatotoxicity]] and [[diarrhea]]/[[colitis]].
*Serious adverse reactions were reported in 54 (49%) subjects treated with Idelalisib + rituximab. The most frequent (≥2%) serious adverse reactions reported for subjects treated with Idelalisib were [[pneumonia]] (17%), [[pyrexia]] (9%), [[sepsis]] (8%), [[febrile neutropenia]] (5%) and [[diarrhea]] (5%). Adverse reactions that led to discontinuation of Idelalisib occurred in 11 (10%) subjects. The most common adverse reactions that led to treatment discontinuations were [[hepatotoxicity]] and [[diarrhea]]/[[colitis]].
*Thirty-nine subjects (35%) had dose interruptions and sixteen subjects (15%) had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose reductions were elevated [[transaminases]], [[diarrhea]] or [[colitis]], and [[rash]].
*Thirty-nine subjects (35%) had dose interruptions and sixteen subjects (15%) had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose reductions were elevated [[transaminases]], [[diarrhea]] or [[colitis]], and [[rash]].
*Table 2 and Table 3 summarize common adverse reactions and laboratory abnormalities reported for Zydelig + [[rituximab]] and [[placebo]] + [[rituximab]] arms.
*Table 2 and Table 3 summarize common adverse reactions and laboratory abnormalities reported for Idelalisib + [[rituximab]] and [[placebo]] + [[rituximab]] arms.


[[file:Idelalisib AR1.png|none|350px]]
[[file:Idelalisib AR1.png|none|350px]]


====Summary of Clinical Trials in Indolent Non-Hodgkin Lymphoma====
====Summary of Clinical Trials in Indolent Non-Hodgkin Lymphoma====
*The safety data reflect exposure to Zydelig in 146 adults with indolent [[non-Hodgkin lymphoma]] treated with Zydelig 150 mg twice daily in clinical trials. The median duration of exposure was 6.1 months (range 0.3 to 26.4 months).
*The safety data reflect exposure to Idelalisib in 146 adults with indolent [[non-Hodgkin lymphoma]] treated with Idelalisib 150 mg twice daily in clinical trials. The median duration of exposure was 6.1 months (range 0.3 to 26.4 months).
*Serious adverse reactions were reported in 73 (50%) subjects. The most frequent serious adverse reactions that occurred were [[pneumonia]] (15%), [[diarrhea]] (11%), and [[pyrexia]] (9%).
*Serious adverse reactions were reported in 73 (50%) subjects. The most frequent serious adverse reactions that occurred were [[pneumonia]] (15%), [[diarrhea]] (11%), and [[pyrexia]] (9%).
*Adverse reactions resulted in interruption or discontinuation for 78 (53%) subjects. The most common reasons for interruption or discontinuations were [[diarrhea]] (11%), [[pneumonia]] (11%), and elevated [[transaminases]] (10%).
*Adverse reactions resulted in interruption or discontinuation for 78 (53%) subjects. The most common reasons for interruption or discontinuations were [[diarrhea]] (11%), [[pneumonia]] (11%), and elevated [[transaminases]] (10%).


Table 4 provides the adverse reactions occurring in at least 10% of subjects receiving Zydelig monotherapy, and Table 5 provides the treatment-emergent laboratory abnormalities.
Table 4 provides the adverse reactions occurring in at least 10% of subjects receiving Idelalisib monotherapy, and Table 5 provides the treatment-emergent laboratory abnormalities.


[[file:Idelalisib AR2.png|none|350px]]
[[file:Idelalisib AR2.png|none|350px]]
|drugInteractions=====Effects of Other Drugs on Zydelig====
|drugInteractions=====Effects of Other Drugs on Idelalisib====
=====CYP3A Inducers=====
=====CYP3A Inducers=====
*The AUC of idelalisib was reduced by 75% when Zydelig was coadministered with a strong [[CYP3A inducer]]. Avoid coadministration of Zydelig with strong CYP3A inducers, such as [[rifampin]], [[phenytoin]], [[St. John's wort]], or [[carbamazepine]].  
*The AUC of idelalisib was reduced by 75% when Idelalisib was coadministered with a strong [[CYP3A inducer]]. Avoid coadministration of Idelalisib with strong CYP3A inducers, such as [[rifampin]], [[phenytoin]], [[St. John's wort]], or [[carbamazepine]].  


=====CYP3A Inhibitors=====
=====CYP3A Inhibitors=====
*The AUC of idelalisib was increased 1.8-fold when Zydelig was coadministered with a strong [[CYP3A]] inhibitor. If patients are taking concomitant strong [[CYP3A]] inhibitors, monitor for signs of Zydelig toxicity. Follow dose modifications for adverse reactions.  
*The AUC of idelalisib was increased 1.8-fold when Idelalisib was coadministered with a strong [[CYP3A]] inhibitor. If patients are taking concomitant strong [[CYP3A]] inhibitors, monitor for signs of Idelalisib toxicity. Follow dose modifications for adverse reactions.  


====Effects of Zydelig on Other Drugs====
====Effects of Idelalisib on Other Drugs====
=====CYP3A Substrates=====
=====CYP3A Substrates=====
*Zydelig is a strong [[CYP3A]] inhibitor. The AUC of a sensitive [[CYP3A]] substrate was increased 5.4-fold when Zydelig was coadministered with a sensitive [[CYP3A]] substrate. Avoid coadministration of Zydelig with [[CYP3A]] substrates.  
*Idelalisib is a strong [[CYP3A]] inhibitor. The AUC of a sensitive [[CYP3A]] substrate was increased 5.4-fold when Idelalisib was coadministered with a sensitive [[CYP3A]] substrate. Avoid coadministration of Idelalisib with [[CYP3A]] substrates.
|FDAPregCat=D
|FDAPregCat=D
|useInPregnancyFDA=*Based on findings in animals, Zydelig may cause fetal harm when administered to a pregnant woman. Idelalisib was teratogenic in animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
|useInPregnancyFDA=*Based on findings in animals, Idelalisib may cause fetal harm when administered to a pregnant woman. Idelalisib was teratogenic in animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
|useInNursing=*It is not known whether idelalisib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Zydelig, a decision should be made whether to discontinue nu
|useInNursing=*It is not known whether idelalisib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Idelalisib, a decision should be made whether to discontinue nu
|useInPed=*Safety and effectiveness of Zydelig in children less than 18 years of age have not been established.
|useInPed=*Safety and effectiveness of Idelalisib in children less than 18 years of age have not been established.
|useInGeri=*In clinical trials of Zydelig in patients with FL, SLL, and CLL, 131/208 (63%) patients were age 65 and older. No major differences in effectiveness were observed. In patients 65 years of age or older with indolent non-Hodgkin lymphoma in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 20%), higher incidence of serious adverse reactions (64% vs 37%), and higher incidence of death (11% vs 5%). In patients 65 years of age or older with CLL in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (11% vs 5%), higher incidence of serious adverse reactions (51% vs 43%), and higher incidence of death (3% vs 0%).
|useInGeri=*In clinical trials of Idelalisib in patients with FL, SLL, and CLL, 131/208 (63%) patients were age 65 and older. No major differences in effectiveness were observed. In patients 65 years of age or older with indolent non-Hodgkin lymphoma in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 20%), higher incidence of serious adverse reactions (64% vs 37%), and higher incidence of death (11% vs 5%). In patients 65 years of age or older with CLL in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (11% vs 5%), higher incidence of serious adverse reactions (51% vs 43%), and higher incidence of death (3% vs 0%).
|useInRenalImpair=*No dose adjustment of Zydelig is necessary for patients with [[creatinine clearance]] ([[CLcr]]) ≥ 15 mL/min
|useInRenalImpair=*No dose adjustment of Idelalisib is necessary for patients with [[creatinine clearance]] ([[CLcr]]) ≥ 15 mL/min
|useInHepaticImpair=*The AUC of idelalisib increased up to 1.7-fold in subjects with [[ALT]] or [[AST]] or [[bilirubin]] greater than the upper limit of normal (ULN) compared to healthy subjects with normal [[ALT]] or [[AST]] or [[bilirubin]] values. Safety and efficacy data are not available in patients with baseline [[ALT]] or [[AST]] values greater than 2.5 × ULN or [[bilirubin]] values greater than 1.5 × ULN, as these patients were excluded from Studies 1 and 2. Patients with baseline hepatic impairment should be monitored for signs of Zydelig toxicity. Follow dose modifications for adverse reactions  
|useInHepaticImpair=*The AUC of idelalisib increased up to 1.7-fold in subjects with [[ALT]] or [[AST]] or [[bilirubin]] greater than the upper limit of normal (ULN) compared to healthy subjects with normal [[ALT]] or [[AST]] or [[bilirubin]] values. Safety and efficacy data are not available in patients with baseline [[ALT]] or [[AST]] values greater than 2.5 × ULN or [[bilirubin]] values greater than 1.5 × ULN, as these patients were excluded from Studies 1 and 2. Patients with baseline hepatic impairment should be monitored for signs of Idelalisib toxicity. Follow dose modifications for adverse reactions
|useInReproPotential=====Contraception====
|useInReproPotential=====Contraception====
*Zydelig may cause fetal harm when administered during pregnancy. Advise females of reproductive potential to avoid becoming pregnant while taking Zydelig. If contraceptive methods are being considered, use effective contraception while taking Zydelig and for at least one month after taking the last dose of Zydelig. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Zydelig.
*Idelalisib may cause fetal harm when administered during pregnancy. Advise females of reproductive potential to avoid becoming pregnant while taking Idelalisib  If contraceptive methods are being considered, use effective contraception while taking Idelalisib and for at least one month after taking the last dose of Idelalisib  Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Idelalisib.
|drugBox={{Drugbox
|drugBox={{Drugbox
| IUPAC_name        = 5-Fluoro-3-phenyl-2-[(1''S'')-1-(7''H''-purin-6-ylamino)propyl]-4(3''H'')-quinazolinone
| IUPAC_name        = 5-Fluoro-3-phenyl-2-[(1''S'')-1-(7''H''-purin-6-ylamino)propyl]-4(3''H'')-quinazolinone
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<!-- Clinical data -->
<!-- Clinical data -->
| tradename        = Zydelig
| tradename        = Idelalisib
| Drugs.com        = {{Drugs.com|parent|zydelig}}
| Drugs.com        = {{Drugs.com|parent|Idelalisib}}
| MedlinePlus      =  
| MedlinePlus      =  
| pregnancy_AU      = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU      = <!-- A / B1 / B2 / B3 / C / D / X -->
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}}
}}
|mechAction=*Idelalisib is an inhibitor of PI3Kδ kinase, which is expressed in normal and malignant [[B-cells]]. Idelalisib induced [[apoptosis]] and inhibited proliferation in cell lines derived from malignant [[B-cells]] and in primary tumor cells. Idelalisib inhibits several cell signaling pathways, including [[B-cell receptor]] ([[BCR]]) signaling and the [[CXCR4]] and [[CXCR5]] signaling, which are involved in trafficking and homing of [[B-cells]] to the [[lymph nodes]] and [[bone marrow]]. Treatment of [[lymphoma cells]] with idelalisib resulted in inhibition of [[chemotaxis]] and [[adhesion]], and reduced cell viability.
|mechAction=*Idelalisib is an inhibitor of PI3Kδ kinase, which is expressed in normal and malignant [[B-cells]]. Idelalisib induced [[apoptosis]] and inhibited proliferation in cell lines derived from malignant [[B-cells]] and in primary tumor cells. Idelalisib inhibits several cell signaling pathways, including [[B-cell receptor]] ([[BCR]]) signaling and the [[CXCR4]] and [[CXCR5]] signaling, which are involved in trafficking and homing of [[B-cells]] to the [[lymph nodes]] and [[bone marrow]]. Treatment of [[lymphoma cells]] with idelalisib resulted in inhibition of [[chemotaxis]] and [[adhesion]], and reduced cell viability.
|structure=[[file:Idelalisib Structure.png|none|300px]]
|structure=*It has a molecular formula of C22H18FN7O and a molecular weight of 415.42 g/mol. Idelalisib has the following structural formula:
 
[[file:Idelalisib Structure.png|none|300px]]
|PD=====Electrocardiographic Effects====
|PD=====Electrocardiographic Effects====
*The effect of Zydelig (150 mg and 400 mg) on the [[QT]]/[[QTc]] interval was evaluated in a placebo- and positive-controlled ([[moxifloxacin]] 400 mg) crossover study in 46 healthy subjects. At a dose 2.7 times the maximum recommended dose, Zydelig did not prolong the [[QT]]/[[QTc interval]] (i.e., not greater than or equal to 10 ms).
*The effect of Idelalisib (150 mg and 400 mg) on the [[QT]]/[[QTc]] interval was evaluated in a placebo- and positive-controlled ([[moxifloxacin]] 400 mg) crossover study in 46 healthy subjects. At a dose 2.7 times the maximum recommended dose, Idelalisib did not prolong the [[QT]]/[[QTc interval]] (i.e., not greater than or equal to 10 ms).
|PK=====Absorption====
|PK=====Absorption====
*Following oral administration of a single dose of Zydelig in the fasted state, the median Tmax was observed at 1.5 hours.
*Following oral administration of a single dose of Idelalisib in the fasted state, the median Tmax was observed at 1.5 hours.
*Idelalisib exposure increased in a less than dose-proportional manner over a dose range of 50 mg to 350 mg twice daily in the fasted state.
*Idelalisib exposure increased in a less than dose-proportional manner over a dose range of 50 mg to 350 mg twice daily in the fasted state.
*Relative to fasting conditions, the administration of a single dose of Zydelig with a high-fat meal increased idelalisib AUC 1.4-fold. Zydelig can be administered without regard to food.
*Relative to fasting conditions, the administration of a single dose of Idelalisib with a high-fat meal increased idelalisib AUC 1.4-fold. Idelalisib can be administered without regard to food.


====Distribution====
====Distribution====
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*Toxicities observed in animals and not reported in patients include cardiac toxicity (cardiomyopathy, inflammation, and increased heart weight) and pancreatic findings (inflammation, hemorrhage, and low-incidence acinar degeneration and hyperplasia). These findings were observed in Sprague-Dawley rats in toxicology studies at exposures (AUCs) higher than those reported in patients at the recommended dose of 150 mg twice daily. Cardiac inflammation was mainly seen in a 28-day study in rats, the other findings were observed in the 13-week and/or 6-month studies.
*Toxicities observed in animals and not reported in patients include cardiac toxicity (cardiomyopathy, inflammation, and increased heart weight) and pancreatic findings (inflammation, hemorrhage, and low-incidence acinar degeneration and hyperplasia). These findings were observed in Sprague-Dawley rats in toxicology studies at exposures (AUCs) higher than those reported in patients at the recommended dose of 150 mg twice daily. Cardiac inflammation was mainly seen in a 28-day study in rats, the other findings were observed in the 13-week and/or 6-month studies.
|clinicalStudies=====Relapsed Chronic Lymphocytic Leukemia====
|clinicalStudies=====Relapsed Chronic Lymphocytic Leukemia====
Zydelig was evaluated in a randomized, double-blind, placebo-controlled study (Study 1) in 220 subjects with relapsed CLL who required treatment and were unable to tolerate standard chemoimmunotherapy due to coexisting medical conditions, reduced renal function as measured by creatinine clearance <60 mL/min, or NCI CTCAE Grade ≥3 neutropenia or Grade ≥3 thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents. Subjects were randomized 1:1 to receive 8 doses of rituximab (first dose at 375 mg/m2, subsequent doses at 500 mg/m2 every 2 weeks for 4 infusions and every 4 weeks for an additional 4 infusions) in combination with either an oral placebo twice daily or with Zydelig 150 mg taken twice daily until disease progression or unacceptable toxicity.
Idelalisib was evaluated in a randomized, double-blind, placebo-controlled study (Study 1) in 220 subjects with relapsed CLL who required treatment and were unable to tolerate standard chemoimmunotherapy due to coexisting medical conditions, reduced [[renal function]] as measured by [[creatinine clearance]] <60 mL/min, or NCI CTCAE Grade ≥3 [[neutropenia]] or Grade ≥3 [[thrombocytopenia]] resulting from myelotoxic effects of prior therapy with cytotoxic agents. Subjects were randomized 1:1 to receive 8 doses of [[rituximab]] (first dose at 375 mg/m2, subsequent doses at 500 mg/m2 every 2 weeks for 4 infusions and every 4 weeks for an additional 4 infusions) in combination with either an oral placebo twice daily or with Idelalisib 150 mg taken twice daily until disease progression or unacceptable toxicity.


In Study 1, the median age was 71 (range 47, 92) with 78% over 65, 66% were male, and 90% were Caucasian. The median time since diagnosis was 8.5 years. The median number of prior therapies was 3. Nearly all (96%) subjects had received prior anti-CD20 monoclonal antibodies. The most common (>15%) prior regimens were: bendamustine + rituximab (98 subjects, 45%), fludarabine + cyclophosphamide + rituximab (75 subjects, 34%), single-agent rituximab (67 subjects, 31%), fludarabine + rituximab (37 subjects, 17%), and chlorambucil (36 subjects, 16%).
*In Study 1, the median age was 71 (range 47, 92) with 78% over 65, 66% were male, and 90% were Caucasian. The median time since diagnosis was 8.5 years. The median number of prior therapies was 3. Nearly all (96%) subjects had received prior [[anti-CD20]] monoclonal antibodies. The most common (>15%) prior regimens were: [[bendamustine]] + [[rituximab]] (98 subjects, 45%), [[fludarabine]] + [[cyclophosphamide]] + [[rituximab]] (75 subjects, 34%), single-agent [[rituximab]] (67 subjects, 31%), [[fludarabine]] + [[rituximab]] (37 subjects, 17%), and [[chlorambucil]] (36 subjects, 16%).


The primary endpoint was progression free survival (PFS), as assessed by an independent review committee (IRC). The trial was stopped for efficacy following the first pre-specified interim analysis. Results of a second interim analysis continued to show a statistically significant improvement for Zydelig + rituximab over placebo + rituximab for the primary endpoint of PFS (HR: 0.18, 95% CI [0.10, 0.32], p < 0.0001). The efficacy results are shown in Table 6 and the Kaplan-Meier curve for PFS is shown in Figure 1.
*The primary endpoint was progression free survival (PFS), as assessed by an independent review committee (IRC). The trial was stopped for efficacy following the first pre-specified interim analysis. Results of a second interim analysis continued to show a statistically significant improvement for Idelalisib + [[rituximab]] over placebo + [[rituximab]] for the primary endpoint of PFS (HR: 0.18, 95% CI [0.10, 0.32], p < 0.0001). The efficacy results are shown in Table 6 and the Kaplan-Meier curve for PFS is shown in Figure 1.
 
[[file:Idelalisib CS1.png|none|350px]]
 
====Relapsed Follicular B-cell non-Hodgkin Lymphoma====
*The safety and efficacy of Idelalisib in patients with FL was evaluated in a single-arm, multicenter clinical trial which included 72 patients with follicular B-cell [[non-Hodgkin lymphoma]] who had relapsed within 6 months following [[rituximab]] and an alkylating agent and had received at least 2 prior treatments. The median age was 62 years (range 33 to 84), 54% were male, and 90% were Caucasian. At enrollment, 92% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 4.7 years and the median number of prior treatments was 4 (range 2 to 12). The most common prior combination regimens were [[R-CHOP]] (49%), BR (50%), and [[R-CVP]] (28%). At baseline, 33% of patients had extranodal involvement and 26% had [[bone marrow]] involvement.
 
*Patients received 150 mg of Idelalisib orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for [[malignant lymphoma]]. The primary endpoint was Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 7.
 
[[file:Idelalisib CS2.png|none|350px]]
 
====Relapsed Small Lymphocytic Lymphoma====
*The safety and efficacy of Idelalisib in patients with SLL was evaluated in a single-arm, multicenter clinical trial which included 26 patients with [[small lymphocytic lymphoma]] who had relapsed within 6 months following [[rituximab]] and an [[alkylating agent]] and had received at least 2 prior treatments. The median age was 65 years (range 50 to 87), 73% were male, and 81% were Caucasian. At enrollment, 96% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 6.7 years and the median number of prior treatments was 4 (range 2 to 9). The most common prior combination regimens were BR (81%), FCR (62%) and R-CHOP (35%). At baseline, 27% of patients had extranodal involvement.
 
*Subjects received 150 mg of Idelalisib orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 8.
 
[[file:Idelalisib CS3.png|none|350px]]
|howSupplied=Idelalisib tablets supplied as follows:
[[file:Idelalisib How Supplied.png|none|300px]]
|storage=Store between 20–30 °C (68–86 °F) with excursions permitted 15–30 ºC (59–86 ºF).
*Dispense only in original container.
*Do not use if seal over bottle opening is broken or missing.
|packLabel=[[file:Idelalisib Package1.png|none|300px]]
[[file:Idelalisib Package2.png|none|300px]]
[[file:Idelalisib Appearance.png|none|400px]]
|alcohol=Alcohol-Idelalisib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=Alcohol-Idelalisib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*[[Zydelig]]
}}
}}
[[Category:Drug]]
[[Category:Chemotherapeutic agents]]

Latest revision as of 16:29, 20 August 2015

Idelalisib
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

Disclaimer

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Black Box Warning

FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION
See full prescribing information for complete Boxed Warning.
Condition Name:
  • Fatal and/or serious hepatotoxicity occurred in 14% of Idelalisib-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Idelalisib as recommended.
  • Fatal and/or serious and severe diarrhea or colitis occurred in 14% of Idelalisib-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Idelalisib as recommended.
  • Fatal and serious pneumonitis can occur in Idelalisib-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Idelalisib as recommended.
  • Fatal and serious intestinal perforation can occur in Idelalisib-treated patients across clinical trials. *Discontinue Idelalisib for intestinal perforation.

Overview

Idelalisib is an antineoplastic agent that is FDA approved for the treatment of relapsed chronic lymphocytic leukemia, relapsed follicular b-cell non-hodgkin lymphoma and relapsed small lymphocytic lymphoma. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hyperglycemia, hypertriglyceridemia, abdominal pain, nausea, neutropenia, cough, fatigue, fever and shivering.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Recommended Dose

  • The recommended maximum starting dose of Idelalisib is 150 mg administered orally twice daily.
  • Idelalisib can be taken with or without food. Tablets should be swallowed whole.
  • Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who receive treatment longer than several months is unknown.

Dose Modification

  • See the table below for dose modification instructions for specific toxicities related to Idelalisib.
  • For other severe or life-threatening toxicities related to Idelalisib, withhold drug until toxicity is resolved. If resuming Idelalisib after interruption for other severe or life-threatening toxicities, reduce the dose to 100 mg twice daily. Recurrence of other severe or life-threatening Idelalisib-related toxicity upon rechallenge should result in permanent discontinuation of Idelalisib.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Idelalisib in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Idelalisib in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Idelalisib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Idelalisib in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Idelalisib in pediatric patients.

Contraindications

Warnings

FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION
See full prescribing information for complete Boxed Warning.
Condition Name:
  • Fatal and/or serious hepatotoxicity occurred in 14% of Idelalisib-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Idelalisib as recommended.
  • Fatal and/or serious and severe diarrhea or colitis occurred in 14% of Idelalisib-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Idelalisib as recommended.
  • Fatal and serious pneumonitis can occur in Idelalisib-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Idelalisib as recommended.
  • Fatal and serious intestinal perforation can occur in Idelalisib-treated patients across clinical trials. *Discontinue Idelalisib for intestinal perforation.

Hepatotoxicity

  • Fatal and/or serious hepatotoxicity occurred in 14% of patients treated with Idelalisib. Elevations in ALT or AST greater than 5 times the upper limit of normal have occurred. 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 Idelalisib for recurrent hepatotoxicity.
  • Avoid concurrent use of Idelalisib 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 Idelalisib 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.

Severe Diarrhea or Colitis

  • Severe diarrhea or colitis (Grade 3 or higher) occurred in 14% of Idelalisib-treated patients across clinical trials. Diarrhea can occur at any time. Avoid concurrent use of Idelalisib and other drugs that cause diarrhea. Diarrhea due to Idelalisib responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month across trials, following interruption of Idelalisib therapy and in some instances, use of corticosteroids.

Pneumonitis

  • Fatal and serious pneumonitis occurred in patients treated with Idelalisib. Patients taking Idelalisib 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 should be evaluated for pneumonitis. If pneumonitis is suspected, interrupt Idelalisib until the etiology of the pulmonary symptoms has been determined. Patients with pneumonitis thought to be caused by Idelalisib have been treated with discontinuation of Idelalisib and administration of corticosteroids.

Intestinal Perforation

Severe Cutaneous Reactions

Anaphylaxis

Neutropenia

  • Treatment-emergent Grade 3 or 4 neutropenia occurred in 31% of Idelalisib-treated patients across clinical trials. Monitor blood counts at least every two weeks for the first 3 months of therapy, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L.

Embryo-fetal Toxicity

  • Based on findings in animals, Idelalisib may cause fetal harm when administered to a pregnant woman. Idelalisib is teratogenic in rats, at systemic exposures 12 times those reported in patients at the recommended dose of 150 mg twice daily. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
  • Advise females of reproductive potential to avoid becoming pregnant while taking Idelalisib If contraceptive methods are being considered, use effective contraception during treatment, and for at least 1 month after the last dose of Idelalisib.

Adverse Reactions

Clinical Trials Experience

Summary of Clinical Trials in Chronic Lymphocytic Leukemia

  • The safety data reflect subject exposure to Idelalisib from Study 1, in which 218 subjects with relapsed CLL received up to 8 doses of rituximab with or without Idelalisib 150 mg twice daily. The median duration of exposure to Idelalisib was 5 months.
  • Serious adverse reactions were reported in 54 (49%) subjects treated with Idelalisib + rituximab. The most frequent (≥2%) serious adverse reactions reported for subjects treated with Idelalisib were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%) and diarrhea (5%). Adverse reactions that led to discontinuation of Idelalisib occurred in 11 (10%) subjects. The most common adverse reactions that led to treatment discontinuations were hepatotoxicity and diarrhea/colitis.
  • Thirty-nine subjects (35%) had dose interruptions and sixteen subjects (15%) had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose reductions were elevated transaminases, diarrhea or colitis, and rash.
  • Table 2 and Table 3 summarize common adverse reactions and laboratory abnormalities reported for Idelalisib + rituximab and placebo + rituximab arms.

Summary of Clinical Trials in Indolent Non-Hodgkin Lymphoma

  • The safety data reflect exposure to Idelalisib in 146 adults with indolent non-Hodgkin lymphoma treated with Idelalisib 150 mg twice daily in clinical trials. The median duration of exposure was 6.1 months (range 0.3 to 26.4 months).
  • Serious adverse reactions were reported in 73 (50%) subjects. The most frequent serious adverse reactions that occurred were pneumonia (15%), diarrhea (11%), and pyrexia (9%).
  • Adverse reactions resulted in interruption or discontinuation for 78 (53%) subjects. The most common reasons for interruption or discontinuations were diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).

Table 4 provides the adverse reactions occurring in at least 10% of subjects receiving Idelalisib monotherapy, and Table 5 provides the treatment-emergent laboratory abnormalities.

Postmarketing Experience

There is limited information regarding Idelalisib Postmarketing Experience in the drug label.

Drug Interactions

Effects of Other Drugs on Idelalisib

CYP3A Inducers
CYP3A Inhibitors
  • The AUC of idelalisib was increased 1.8-fold when Idelalisib was coadministered with a strong CYP3A inhibitor. If patients are taking concomitant strong CYP3A inhibitors, monitor for signs of Idelalisib toxicity. Follow dose modifications for adverse reactions.

Effects of Idelalisib on Other Drugs

CYP3A Substrates
  • Idelalisib is a strong CYP3A inhibitor. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when Idelalisib was coadministered with a sensitive CYP3A substrate. Avoid coadministration of Idelalisib with CYP3A substrates.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

  • Based on findings in animals, Idelalisib may cause fetal harm when administered to a pregnant woman. Idelalisib was teratogenic in animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Idelalisib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Idelalisib during labor and delivery.

Nursing Mothers

  • It is not known whether idelalisib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Idelalisib, a decision should be made whether to discontinue nu

Pediatric Use

  • Safety and effectiveness of Idelalisib in children less than 18 years of age have not been established.

Geriatic Use

  • In clinical trials of Idelalisib in patients with FL, SLL, and CLL, 131/208 (63%) patients were age 65 and older. No major differences in effectiveness were observed. In patients 65 years of age or older with indolent non-Hodgkin lymphoma in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 20%), higher incidence of serious adverse reactions (64% vs 37%), and higher incidence of death (11% vs 5%). In patients 65 years of age or older with CLL in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (11% vs 5%), higher incidence of serious adverse reactions (51% vs 43%), and higher incidence of death (3% vs 0%).

Gender

There is no FDA guidance on the use of Idelalisib with respect to specific gender populations.

Race

There is no FDA guidance on the use of Idelalisib with respect to specific racial populations.

Renal Impairment

Hepatic Impairment

  • The AUC of idelalisib increased up to 1.7-fold in subjects with ALT or AST or bilirubin greater than the upper limit of normal (ULN) compared to healthy subjects with normal ALT or AST or bilirubin values. Safety and efficacy data are not available in patients with baseline ALT or AST values greater than 2.5 × ULN or bilirubin values greater than 1.5 × ULN, as these patients were excluded from Studies 1 and 2. Patients with baseline hepatic impairment should be monitored for signs of Idelalisib toxicity. Follow dose modifications for adverse reactions

Females of Reproductive Potential and Males

Contraception

  • Idelalisib may cause fetal harm when administered during pregnancy. Advise females of reproductive potential to avoid becoming pregnant while taking Idelalisib If contraceptive methods are being considered, use effective contraception while taking Idelalisib and for at least one month after taking the last dose of Idelalisib Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Idelalisib.

Immunocompromised Patients

There is no FDA guidance one the use of Idelalisib in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Idelalisib Administration in the drug label.

Monitoring

There is limited information regarding Idelalisib Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Idelalisib and IV administrations.

Overdosage

There is limited information regarding Idelalisib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

Idelalisib
Clinical data
Trade namesIdelalisib
SynonymsGS-1101, CAL-101
AHFS/Drugs.comIdelalisib
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration		Oral
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
ChEBI
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC22H18FN7O
Molar mass415.42 g/mol
3D model (JSmol)

Mechanism of Action

  • Idelalisib is an inhibitor of PI3Kδ kinase, which is expressed in normal and malignant B-cells. Idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B-cells and in primary tumor cells. Idelalisib inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion, and reduced cell viability.

Structure

  • It has a molecular formula of C22H18FN7O and a molecular weight of 415.42 g/mol. Idelalisib has the following structural formula:

Pharmacodynamics

Electrocardiographic Effects

  • The effect of Idelalisib (150 mg and 400 mg) on the QT/QTc interval was evaluated in a placebo- and positive-controlled (moxifloxacin 400 mg) crossover study in 46 healthy subjects. At a dose 2.7 times the maximum recommended dose, Idelalisib did not prolong the QT/QTc interval (i.e., not greater than or equal to 10 ms).

Pharmacokinetics

Absorption

  • Following oral administration of a single dose of Idelalisib in the fasted state, the median Tmax was observed at 1.5 hours.
  • Idelalisib exposure increased in a less than dose-proportional manner over a dose range of 50 mg to 350 mg twice daily in the fasted state.
  • Relative to fasting conditions, the administration of a single dose of Idelalisib with a high-fat meal increased idelalisib AUC 1.4-fold. Idelalisib can be administered without regard to food.

Distribution

  • Idelalisib is greater than 84% bound to human plasma proteins with no concentration dependence. The mean blood-to-plasma ratio was 0.7. The population apparent central volume of distribution at steady state is 23 L.

Metabolism and Elimination

  • Idelalisib is metabolized to its major metabolite GS-563117 via aldehyde oxidase and CYP3A. GS-563117 is inactive against PI3Kδ in vitro. Idelalisib undergoes minor metabolism by UGT1A4.
  • The population apparent systemic clearance at steady-state is 14.9 L/hr. The population terminal elimination half-life of idelalisib is 8.2 hours. Following a single dose of 150 mg of [14C] idelalisib, 78% and 14% of the radioactivity was excreted in feces and urine, respectively. GS-563117 accounted for 49% of the radioactivity in the urine and 44% in the feces.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

  • Carcinogenicity studies with idelalisib have not been conducted.
  • Idelalisib did not induce mutations in the bacterial mutagenesis (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay using human peripheral blood lymphocytes. Idelalisib was genotoxic in males in the in vivo rat micronucleus study at a high dose of 2000 mg/kg.
  • Idelalisib may impair fertility in humans. In a fertility study, treated male rats (25, 50, or 100 mg/kg/day of idelalisib) were mated with untreated females. Decreased epididymidal and testicular weights were observed at all dose levels and reduced sperm concentration at the mid- and high doses; however, there were no adverse effects on fertility parameters. The low dose in males resulted in an exposure (AUC) that is approximately 50% of the exposure in patients at the recommended dose of 150 mg twice daily.
  • In a separate fertility study, treated female rats (25, 50, or 100 mg/kg/day of idelalisib) were mated with untreated males. There were no adverse effects on fertility parameters; however, there was a decrease in the number of live embryos at the high dose. The high dose in females resulted in an exposure (AUC) that is approximately 17-fold the exposure in patients at the recommended dose of 150 mg twice daily.

Animal Pharmacology and/or Toxicology

  • Toxicities observed in animals and not reported in patients include cardiac toxicity (cardiomyopathy, inflammation, and increased heart weight) and pancreatic findings (inflammation, hemorrhage, and low-incidence acinar degeneration and hyperplasia). These findings were observed in Sprague-Dawley rats in toxicology studies at exposures (AUCs) higher than those reported in patients at the recommended dose of 150 mg twice daily. Cardiac inflammation was mainly seen in a 28-day study in rats, the other findings were observed in the 13-week and/or 6-month studies.

Clinical Studies

Relapsed Chronic Lymphocytic Leukemia

Idelalisib was evaluated in a randomized, double-blind, placebo-controlled study (Study 1) in 220 subjects with relapsed CLL who required treatment and were unable to tolerate standard chemoimmunotherapy due to coexisting medical conditions, reduced renal function as measured by creatinine clearance <60 mL/min, or NCI CTCAE Grade ≥3 neutropenia or Grade ≥3 thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents. Subjects were randomized 1:1 to receive 8 doses of rituximab (first dose at 375 mg/m2, subsequent doses at 500 mg/m2 every 2 weeks for 4 infusions and every 4 weeks for an additional 4 infusions) in combination with either an oral placebo twice daily or with Idelalisib 150 mg taken twice daily until disease progression or unacceptable toxicity.

  • In Study 1, the median age was 71 (range 47, 92) with 78% over 65, 66% were male, and 90% were Caucasian. The median time since diagnosis was 8.5 years. The median number of prior therapies was 3. Nearly all (96%) subjects had received prior anti-CD20 monoclonal antibodies. The most common (>15%) prior regimens were: bendamustine + rituximab (98 subjects, 45%), fludarabine + cyclophosphamide + rituximab (75 subjects, 34%), single-agent rituximab (67 subjects, 31%), fludarabine + rituximab (37 subjects, 17%), and chlorambucil (36 subjects, 16%).
  • The primary endpoint was progression free survival (PFS), as assessed by an independent review committee (IRC). The trial was stopped for efficacy following the first pre-specified interim analysis. Results of a second interim analysis continued to show a statistically significant improvement for Idelalisib + rituximab over placebo + rituximab for the primary endpoint of PFS (HR: 0.18, 95% CI [0.10, 0.32], p < 0.0001). The efficacy results are shown in Table 6 and the Kaplan-Meier curve for PFS is shown in Figure 1.

Relapsed Follicular B-cell non-Hodgkin Lymphoma

  • The safety and efficacy of Idelalisib in patients with FL was evaluated in a single-arm, multicenter clinical trial which included 72 patients with follicular B-cell non-Hodgkin lymphoma who had relapsed within 6 months following rituximab and an alkylating agent and had received at least 2 prior treatments. The median age was 62 years (range 33 to 84), 54% were male, and 90% were Caucasian. At enrollment, 92% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 4.7 years and the median number of prior treatments was 4 (range 2 to 12). The most common prior combination regimens were R-CHOP (49%), BR (50%), and R-CVP (28%). At baseline, 33% of patients had extranodal involvement and 26% had bone marrow involvement.
  • Patients received 150 mg of Idelalisib orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 7.

Relapsed Small Lymphocytic Lymphoma

  • The safety and efficacy of Idelalisib in patients with SLL was evaluated in a single-arm, multicenter clinical trial which included 26 patients with small lymphocytic lymphoma who had relapsed within 6 months following rituximab and an alkylating agent and had received at least 2 prior treatments. The median age was 65 years (range 50 to 87), 73% were male, and 81% were Caucasian. At enrollment, 96% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 6.7 years and the median number of prior treatments was 4 (range 2 to 9). The most common prior combination regimens were BR (81%), FCR (62%) and R-CHOP (35%). At baseline, 27% of patients had extranodal involvement.
  • Subjects received 150 mg of Idelalisib orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 8.

How Supplied

Idelalisib tablets supplied as follows:

Storage

Store between 20–30 °C (68–86 °F) with excursions permitted 15–30 ºC (59–86 ºF).

  • Dispense only in original container.
  • Do not use if seal over bottle opening is broken or missing.

Images

Drug Images

{{#ask: Page Name::Idelalisib |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Idelalisib |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Idelalisib Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Idelalisib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

There is limited information regarding Idelalisib Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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