Idelalisib

Idelalisib is a prescription medication used to treat certain types of leukemia and lymphoma. Idelalisib belongs to a group of drugs called phosphoinositide 3-kinase (PI3K) delta inhibitors.

PI3K delta signaling is active in many B-cell leukemias and lymphomas, and by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell ability to live. 

This medication comes in tablet form and is taken typically 2 times a day, with or without food. Do not chew, divide, or break idelalisib tablets. Swallow idelalisib tablets whole.

Common side effects of idelalisib include diarrhea, fever, fatigue, nausea, cough, pneumonia, abdominal pain, chills and rash.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Idelalisib falls into category 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 aware of the potential hazard to the fetus.

Women should avoid pregnancy during treatment with idelalisib. If contraceptive methods are being considered, women should use adequate contraception during therapy and for at least one month after completing therapy.

• Store idelalisib between 20–30°C (68–86°F).

• Keep this and all medicines out of the reach of children.

Idelalisib can cause serious harm to your liver, lungs, or intestines. Some of these conditions may lead to fatal complications. You will need frequent medical tests to be sure idelalisib is not causing harmful effects.

You may have severe or life-threatening diarrhea while taking idelalisib. Idelalisib can also cause a perforation (a hole or tear) in your intestines. Call your doctor at once if you have diarrhea that is watery or bloody, if you have bloody or tarry stools, or if you cough up blood that looks like coffee grounds.

You should not use idelalisib if you have ever had a serious allergic reaction.

To make sure idelalisib is safe for you, tell your doctor if you have:

• liver disease;

• an intestinal disorder such as ulcerative colitis; or

• lung disease.

FDA pregnancy category D. Do not use idelalisib if you are pregnant. It could harm the unborn baby. Use effective birth control while you are using this medicine and for at least 1 month after your treatment ends.

It is not known whether idelalisib passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Do not give this medicine to anyone under 18 years old without medical advice.

Idelalisib is usually taken twice per day. Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

You may take idelalisib with or without food.

Do not crush, chew, or break an idelalisib tablet. Swallow it whole.

While using idelalisib, you will need frequent medical tests to be sure idelalisib is not causing harmful effects. Your cancer treatments may be delayed based on the results of these tests.

Do not stop using idelalisib without your doctor's advice.

Store this medicine in the original container at room temperature, away from moisture and heat.

General

• Monitor liver function tests prior to initiation of therapy, every 2 weeks during the first 3 months of therapy, every 4 weeks during the next 3 months, and then every 1–3 months thereafter.1 More frequent monitoring recommended in patients who develop elevated ALT, AST, or bilirubin concentrations during therapy.1 (See Hepatotoxicity under Dosage and Administration.)

• Monitor CBC at least every 2 weeks during the first 3 months of therapy.1 More frequent monitoring recommended in patients who develop myelosuppression during therapy.1 (See Myelosuppression under Dosage and Administration.)

• Because idelalisib may cause hepatotoxicity or severe diarrhea, avoid concomitant use with drugs that may cause hepatotoxicity or diarrhea.1 (See Hepatotoxicity and also Diarrhea or Colitis under Cautions.)

Administration

Oral Administration

Administer orally twice daily without regard to meals.1 Swallow tablets whole.1

Dosage

Adults

150 mg twice daily in combination with rituximab.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 Manufacturer states safety and efficacy of use beyond several months not established; in phase 3 study, median duration of exposure to idelalisib was 5 months.1

150 mg twice daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 Manufacturer states safety and efficacy of use beyond several months not established; in single-arm study, median duration of exposure to idelalisib was 6.1 months.1

150 mg twice daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 Manufacturer states safety and efficacy of use beyond several months not established.1

May need to interrupt therapy, reduce dosage, and/or permanently discontinue idelalisib if severe hepatotoxicity, diarrhea, or myelosuppression occurs.1

If other severe or life-threatening toxicities occur, withhold idelalisib until toxicity resolves.1 If clinically appropriate, resume therapy at reduced dosage of 100 mg twice daily.1 If severe or life-threatening toxicities recur at dosage of 100 mg twice daily, permanently discontinue idelalisib.1

If ALT and/or AST concentrations increase to >3–5 times the ULN or bilirubin concentrations increase to >1.5–3 times the ULN, continue idelalisib at the same dosage; monitor liver function tests at least weekly until ALT, AST, and bilirubin concentrations return to within normal limits.1

If ALT and/or AST concentrations increase to >5–20 times the ULN or bilirubin concentrations increase to >3–10 times the ULN, withhold idelalisib; monitor liver function tests at least weekly.1 When ALT, AST, and bilirubin concentrations return to within normal limits, resume therapy at reduced dosage of 100 mg twice daily.1

If ALT and/or AST concentrations increase to >20 times the ULN or bilirubin concentrations increase to >10 times ULN, permanently discontinue idelalisib.1

If moderate diarrhea (4–6 stools per day over baseline) occurs, continue idelalisib at the same dosage and monitor patient at least weekly until diarrhea resolves.1

If severe diarrhea (≥7 stools per day over baseline) or diarrhea requiring hospitalization occurs, withhold idelalisib and monitor patient at least weekly; when diarrhea resolves, resume therapy at reduced dosage of 100 mg twice daily.1

If life-threatening diarrhea occurs, permanently discontinue idelalisib.1

If ANC is 1000 to <1500/mm3 or platelet count is 50,000 to <75,000/mm3, continue idelalisib at the same dosage.1

If ANC is 500 to <1000/mm3 or platelet count is 25,000 to <50,000/mm3, continue idelalisib at the same dosage; monitor ANC and platelet count at least weekly.1

If ANC is <500/mm3 or platelet count is <25,000/mm3, withhold idelalisib; monitor ANC and platelet count at least weekly.1 When ANC is ≥500/mm3 and platelet count is ≥25,000/mm3, resume therapy at reduced dosage of 100 mg twice daily.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time; however, monitor for signs of toxicity and adjust dosage as appropriate.1 (See Hepatotoxicity under Dosage and Administration and also see Hepatic Impairment under Cautions.)

Renal Impairment

Clcr ≥15 mL/minute: No dosage adjustment needed.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Contraindications

• History of serious hypersensitivity reactions, including anaphylaxis and toxic epidermal necrolysis.1

Warnings/Precautions

Warnings

Serious and/or fatal hepatotoxicity reported.1

ALT or AST elevations of >5 times the ULN reported; elevations generally occurred during initial 12 weeks of therapy.1 ALT or AST elevations reversible following temporary interruption of therapy; however, recurrence reported in 26% of patients following resumption of idelalisib therapy at reduced dosage.1

Monitor serum ALT and AST concentrations at baseline, every 2 weeks during the first 3 months of therapy, every 4 weeks during the next 3 months, and then every 1–3 months thereafter.1 If hepatotoxicity occurs, monitor liver function tests more frequently until levels return to within normal limits.1 May need to interrupt therapy, reduce dosage, and/or permanently discontinue idelalisib depending on severity of hepatotoxicity.1 (See Hepatotoxicity under Dosage and Administration.)

Discontinue therapy if hepatotoxicity recurs.1

Avoid concomitant use with drugs that may cause hepatotoxicity.1

Severe (≥grade 3) diarrhea or colitis reported.1

Diarrhea can occur at any time and responds poorly to antimotility agents.1

Diarrhea resolves within a median of 1 week to 1 month following temporary interruption of therapy and, in some instances, use of corticosteroids.1

Monitor for development of severe diarrhea or colitis.1 If moderate or severe diarrhea occurs, monitor patients at least weekly until diarrhea resolves.1 May need to interrupt therapy, reduce dosage, and/or permanently discontinue idelalisib depending on severity of diarrhea.1 (See Diarrhea under Dosage and Administration.) If life-threatening diarrhea occurs, permanently discontinue idelalisib.1

Avoid concomitant use with drugs that may cause diarrhea.1

Severe and fatal intestinal perforation reported.1 At the time of perforation, some patients had moderate to severe diarrhea.1

If intestinal perforation occurs, permanently discontinue idelalisib.1 (See Advice to Patients.)

Serious or fatal pneumonitis reported.1

Evaluate patients for possible pneumonitis if pulmonary manifestations (e.g., cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, >5% decrease in oxygen saturation) occur.1 If pneumonitis is suspected, withhold therapy until etiology of pulmonary symptoms has been determined.1

Treatment for idelalisib-induced pneumonitis has included discontinuance of idelalisib and administration of corticosteroids.1

Sensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, reported.1 If severe hypersensitivity reaction occurs, permanently discontinue idelalisib and institute supportive treatment.1

Other Warnings and Precautions

Severe or life-threatening dermatologic reactions, including exfoliative dermatitis, rash (i.e., erythematous, generalized, macular, maculopapular, papular, pruritic, and exfoliative rash), and toxic skin reactions reported.1

Toxic epidermal necrolysis reported in at least one patient receiving idelalisib in combination with rituximab and bendamustine.1

Monitor patients for development of severe dermatologic reactions.1 If severe dermatologic reactions occur, discontinue idelalisib.1

Severe (grade 3 or 4) neutropenia reported.1

Monitor CBC at least every 2 weeks during the first 3 months of therapy.1 If neutropenia occurs, monitor CBC more frequently.1 May need to interrupt therapy and reduce dosage depending on severity of neutropenia.1 (See Myelosuppression under Dosage and Administration.)

May cause fetal harm.1 Teratogenicity and embryofetal toxicity demonstrated in animals receiving dosages equivalent to 12–30 times human exposure.1 Avoid pregnancy during therapy and for ≥1 month after drug discontinuance.1 (See Advice to Patients.) If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Specific Populations

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Not known whether distributed into milk; discontinue nursing or the drug.1

Safety and efficacy not established in pediatric patients <18 years of age.1

No overall differences in efficacy in geriatric patients (≥65 years of age) compared with younger adults.1

Higher incidences of serious adverse reactions, death, or discontinuance of idelalisib due to adverse reactions observed in patients ≥65 years of age or older with CLL or NHL compared with younger adults.1

Increased systemic exposure in patients with elevated ALT, AST, or bilirubin concentrations.1 (See Special Populations under Pharmacokinetics.) Monitor for adverse effects.1 (See Hepatic Impairment under Dosage and Administration.)

Safety and efficacy not established in patients with baseline ALT or AST concentrations >2.5 times the ULN or bilirubin concentrations >1.5 times the ULN because these patients were excluded from clinical studies.1

Systemic exposure not affected by severe renal impairment (Clcr 15–29 mL/minute).1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Combination therapy with rituximab in patients with relapsed CLL: Pyrexia,1 2 nausea,1 pneumonia,1 diarrhea,1 2 chills,1 2 rash,1 2 vomiting,1 2 decreased appetite,2 night sweats,2 headache,1 sepsis,1 sinusitis,1 pain,1 arthralgia,1 gastroesophageal reflux disease (GERD),1 stomatitis,1 bronchitis,1 nasal congestion,1 urinary tract infection,1 neutropenia,1 2 hypertriglyceridemia,1 hyperglycemia,1 elevated aminotransferase (ALT or AST) and γ-glutamyltransferase ([gamma]-glutamyltranspeptidase, GGT, GGTP) concentrations,1 2 decreased or increased lymphocyte count,1 hyponatremia,1 hypoglycemia.1

Monotherapy in patients with indolent NHL: Diarrhea,1 fatigue,1 nausea,1 cough,1 pyrexia,1 abdominal pain,1 pneumonia,1 rash,1 dyspnea,1 decreased appetite,1 vomiting,1 asthenia,1 upper respiratory tract infection,1 night sweats,1 insomnia,1 headache,1 peripheral edema,1 neutropenia,1 elevated ALT or AST concentrations,1 decreased hemoglobin concentrations,1 thrombocytopenia.1

• If you have an allergy to idelalisib or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are taking any of these drugs: Carbamazepine, phenytoin, rifampin, or St. John's wort.
• If you are taking any drugs that can raise the chance of liver problems. There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.
• If you are taking any drugs that can cause loose stools (diarrhea). There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.
• If you are breast-feeding. Do not breast-feed while you take idelalisib.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take idelalisib with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of dehydration like dry skin, mouth, or eyes; thirst; fast heartbeat; dizziness; fast breathing; or confusion.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Mouth irritation or mouth sores.
• Night sweats.
• Swelling in the arms or legs.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.

• Antineoplastic Agent, Phosphatidylinositol 3-Kinase Inhibitor

Potent small molecule inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ), which is highly expressed in malignant lymphoid B-cells. PI3Kδ inhibition results in apoptosis of malignant tumor cells. In addition, idelalisib inhibits several signaling pathways, including B-cell receptor, CXCR4 and CXCR5 signaling which may play important roles in CLL pathophysiology (Furman, 2014).

Distribution

23 L

Metabolism

Hepatic; primarily via aldehyde oxidase and CYP3A (to major metabolite GS-563117); minor metabolism via UGT1A4

Excretion

Feces (78%; 44% as GS-563117); urine (14%; 49% as GS-563117)

Time to Peak

Median: 1.5 hours

Half-Life Elimination

~8 hours

Protein Binding

>84%

Serious hypersensitivity reactions (including anaphylaxis and toxic epidermal necrolysis) to idelalisib or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Use in first-line chronic lymphocytic leukemia and early-line indolent non-Hodgkin lymphoma outside of a clinical trial

CrCl ≥15 mL/minute: No dosage adjustment necessary (Jin 2015b).

CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

As reported with monotherapy.

>10%:

Central nervous system: Fatigue (30%), insomnia (12%), headache (11%)

Dermatologic: Skin rash (21%), night sweats (12%)

Gastrointestinal: Diarrhea (47%), nausea (29%), abdominal pain (26%), decreased appetite (16%), vomiting (15%)

Hematologic & oncologic: Decreased neutrophils (53%; grade 3: 14%; grade 4: 11%), decreased hemoglobin (28%; grade 3: 2%), decreased platelet count (26%; grade 3: 3%; grade 4: 3%)

Hepatic: Increased serum ALT (50%), increased serum AST (41%), severe hepatotoxicity (18%)

Infection: Severe infection (21%; including sepsis, febrile neutropenia)

Neuromuscular & skeletal: Weakness (12%)

Respiratory: Cough (29%), pneumonia (15% to 25%), dyspnea (17%), upper respiratory tract infection (12%)

Miscellaneous: Fever (28%)

1% to 10%:

Cardiovascular: Peripheral edema (10%)

Respiratory: Pneumonitis (4%)

<1% (Limited to important or life-threatening): Anaphylaxis, cytomegalovirus disease, erythematous rash, exfoliative dermatitis, hypersensitivity reaction, intestinal perforation, macular eruption, maculopapular rash, papular rash, pneumonia due to pneumocystic carinii, pruritic rash, Stevens-Johnson syndrome, toxic epidermal necrolysis

Fatal and/or serious hepatotoxicity occurred in 11% to 18% 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% to 19% of idelalisib-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue idelalisib as recommended.

Fatal and/or serious pneumonitis occurred in 4% of idelalisib-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue idelalisib as recommended.

Fatal and/or serious infection occurred in 21% to 36% of idelalisib-treated patients. Monitor for signs and symptoms of infection. Interrupt idelalisib if infection is suspected.

Fatal and serious intestinal perforation can occur in idelalisib-treated patients across clinical trials. Discontinue idelalisib for intestinal perforation.

Complete blood counts with differential at least every 2 weeks for the first 6 months, and at least weekly in patients with neutropenia (ANC <1,000/mm3 ), or as clinically necessary; liver function tests at baseline and every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter, or as clinically necessary; monitor for infections (including sepsis, pneumonia, PCP, and CMV); monitor for signs/symptoms of diarrhea/colitis, intestinal perforation, pneumonitis, dermatologic toxicity, and hypersensitivity reactions

150 mg orally twice a day
Duration of therapy: Continue treatment until disease progression or unacceptable toxicity

Uses:
-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
-The treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received at least two prior systemic therapies
-The treatment of patients with relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies.

150 mg orally twice a day
Duration of therapy: Continue treatment until disease progression or unacceptable toxicity

Uses:
-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
-The treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received at least two prior systemic therapies
-The treatment of patients with relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies.

Dose Modifications for Adverse Reactions:
Diarrhea:
-If moderate diarrhea develops during treatment (increase of 4 to 6 stools per day over baseline), maintain dose and monitor at least weekly until resolved.
-If severe diarrhea develops during treatment (increase of 7 or more stools per day over baseline), withhold drug and monitor at least weekly until resolved. May resume at 100 mg twice a day.
-If life-threatening diarrhea develops during treatment, discontinue drug permanently.

Neutropenia:
-If neutropenia develops during treatment (ANC 0.5 to less than 1.0 Gi/L), maintain dose and monitor at least weekly.
-If neutropenia develops during treatment (ANC less than 0.5 Gi/L), interrupt drug and monitor at least weekly until ANC is greater than or equal to 0.5 Gi/L. May resume at 100 mg twice a day.

Thrombocytopenia:
-If thrombocytopenia develops during treatment (platelets 25 to less than 50 Gi/L), maintain dose and monitor at least weekly.
-If thrombocytopenia develops during treatment (platelets less than 25 Gi/L), withhold drug and monitor at least weekly. May resume at 100 mg twice a day when platelets are greater than or equal to 25 Gi/L.

Other Severe or Life-Threatening Toxicities:
-Withhold drug until toxicity is resolved.
-May resume at 100 mg twice a day.
-Recurrence of severe or life-threatening toxicity upon rechallenge should result in permanent discontinuation of the drug.