Idelalisib

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# Black Box Warning

# 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.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-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.

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

# Contraindications
- History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.

# Warnings

### 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
- 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
- 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
- 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
- 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
- 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.
- 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
- 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
- No dose adjustment of Idelalisib is necessary for patients with creatinine clearance (CLcr)  15 mL/min

### 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

## Mechanism of Action
- Idelalisib is an inhibitor of PI3K 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 PI3K 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  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 , 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 2030 C (6886 F) with excursions permitted 1530 oC (5986 oF).
- Dispense only in original container.
- Do not use if seal over bottle opening is broken or missing.

# Images

## Drug Images

## Package and Label Display Panel

# 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
- Zydelig

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

# Drug Shortage Status

# Price