Drug Interaction:
DRUG INTERACTIONS
CYP3A inducers: Avoid coadministration of strong CYP3A inducers with Zydelig.
CYP3A substrates: Avoid coadministration of CYP3A substrates with Zydelig.
Indication:
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ZYDELIG safely and effectively. See full prescribing information for ZYDELIG. ZYDELIG® (idelalisib) tablets, for oral use
Initial U.S. Approval: 2014
WARNING:
FATAL AND SERIOUS TOXICITIES: HEPATIC,
SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, and
INTESTINAL PERFORATION
See full prescribing information for complete boxed warning.
Fatal and/or serious hepatotoxicity occurred in 11% to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig.
Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 19% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig.
Fatal and/or serious pneumonitis occurred in 4% of Zydeligtreated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig.
Fatal and/or serious infections occurred in 21% to 36% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.
Fatal and serious intestinal perforation can occur in Zydeligtreated patients across clinical trials. Discontinue Zydelig if intestinal perforation is suspected.
INDICATIONS AND USAGE
Zydelig is a kinase inhibitor indicated for the treatment of patients with:
Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.
Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies.
Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.
Limitation of use:
Zydelig is not indicated and is not recommended for first-line treatment
of any patient.
Accelerated approval was granted for FL and SLL based on overall response rate. Improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.
Proprietary Name- ZYDELIG TABLETS*
Established Name- Idelaisib
Applicant- GILEADSCIENCES INC.
Indication- For the treatment of patients with relapsed chronic Lymphocytic
Leukemia (CLL), in combination with Rituximab, for whom
Rituximab alone would be considered appropiate therapy
due to other co-morbidates
Approval Date- 23/7/2014
Approved by U.S.FDA (Ref- FDA approved List- 2014)
Adverse Reaction:
ADVERSE REACTIONS-
The most common adverse reactions (incidence =20%) in patients treated with Zydelig in the monotherapy trial are diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash.
The most common adverse reactions (incidence =30%) in patients treated with Zydelig in combination trials are diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea.
Common laboratory abnormalities include neutropenia, ALT elevations and AST elevations.
Contra-Indications:
CONTRAINDICATIONS
History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.
WARNINGS AND PRECAUTIONS
Severe cutaneous reactions: Monitor patients for the development of severe cutaneous reactions and discontinue Zydelig.
Anaphylaxis: Monitor patients for anaphylaxis and discontinue Zydelig.
Neutropenia: Monitor blood counts.
Embryo-fetal toxicity: may cause fetal harm.
Advise women of potential risk to a fetus and to avoid pregnancy while taking Zydelig.
Dosages/ Overdosage Etc:
Indication- For the treatment of patients with relapsed chronic Lymphocytic
Leukemia (CLL), in combination with Rituximab, for whom
Rituximab alone would be considered appropiate therapy
due to other co-morbidates
INDICATIONS AND USAGE
Zydelig is a kinase inhibitor indicated for the treatment of patients with:
Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.
Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies.
Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.
Limitation of use:
Zydelig is not indicated and is not recommended for first-line treatment
of any patient.
Accelerated approval was granted for FL and SLL based on overall response rate. Improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.
------------------------DOSAGE AND ADMINISTRATION----------------------Recommended starting dose: 150 mg orally, twice daily. (2.1) ----------------------
DOSAGE FORMS AND STRENGTHS--------------------Tablets: 150 mg, 100 mg. (3) --------
-----------------------CONTRAINDICATIONS------------------------------History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis. (4) ------------------------WARNINGS AND PRECAUTIONS----------------------? Severe cutaneous reactions: Monitor patients for the development of severe cutaneous reactions and discontinue Zydelig. (5.6) ? Anaphylaxis: Monitor patients for anaphylaxis and discontinue Zydelig. (5.7) ? Neutropenia: monitor blood counts. (5.8) ? Embryo-fetal toxicity: may cause fetal harm. Advise women of potential risk to a fetus and to avoid pregnancy while taking Zydelig. (5.9) --------------------------------ADVERSE REACTIONS----------------------------The most common adverse reactions (incidence =20%) in patients treated with Zydelig in the monotherapy trial are diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash. (6.1) The most common adverse reactions (incidence =30%) in patients treated with Zydelig in combination trials are diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea. (6.1) Common laboratory abnormalities include neutropenia, ALT elevations and AST elevations. (6.1)
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Physicians and health care professionals are advised to discuss the following with patients prior to treatment with Zydelig:
Hepatotoxicity- Advise patients that Zydelig can cause significant elevations in liver enzymes, and that serial testing of serum liver tests (ALT, AST, and bilirubin) are recommended while taking Zydelig
Advise patients to report symptoms of liver dysfunction including jaundice, bruising, abdominal pain, or bleeding.
Severe Diarrhea or Colitis- Advise patients that Zydelig may cause severe diarrhea or colitis and to notify their healthcare provider immediately if the number of bowel movements in a day increases by six or more
Pneumonitis- Advise patients of the possibility of pneumonitis, and to report any new or worsening respiratory symptoms including cough or dyspnea
Infections - Advise patients that Zydelig can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection (e.g. pyrexia)
Intestinal Perforation- Advise patients of the possibility for intestinal perforation and to notify their healthcare provider immediately if they experience severe abdominal pain
Severe Cutaneous Reactions - Advise patients that Zydelig may cause severe cutaneous reactions and to notify their healthcare provider immediately if they develop a severe skin reaction
Anaphylaxis - Advise patients that anaphylaxis can occur during treatment with Zydelig and to notify their healthcare provider immediately if they experience symptoms of anaphylaxis
Neutropenia- Advise patients of the need for periodic monitoring of blood counts. Advise patients to notify their healthcare provider immediately if they develop a fever or any signs of infection
Pregnancy and Nursing - Advise women of the potential hazard to the fetus and to avoid pregnancy during treatment with Zydelig. If contraceptive methods are being considered, advise to use adequate contraception during therapy and for at least one month after completing therapy. Also advise patients not to breastfeed while taking Zydelig
Instructions for Taking Zydelig- Advise patients to take Zydelig exactly as prescribed and not to change their dose or to stop taking Zydelig unless they are told to do so by their healthcare provider.
Zydelig may be taken with or without food. Zydelig tablets should be swallowed whole.
Advise patients that if a dose of Zydelig is missed by less than 6 hours, to take the missed dose right away and take the next dose as usual.
If a dose of Zydelig is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time.
Manufactured and distributed by:
Gilead Sciences, Inc.
Foster City, CA 94404 GSI and Zydelig are trademarks or registered trademarks of Gilead Sciences, Inc., or its related companies.
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1.Mechanism of Action -
Idelalisib is an inhibitor of PI3Kd kinase, which is expressed in normal and malignant Bcells. 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.
2. Pharmacodynamics
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).
3.Pharmacokinetics
Absorption
Following oral administration of a single dose of Zydelig 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 Zydelig with a highfat meal increased idelalisib AUC 1.4-fold. Zydelig 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 PI3Kd 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.
Specific Populations
Age, Gender, Race, and Weight
Population pharmacokinetic analyses indicated that age, gender, race, and weight had no effect on idelalisib exposure. Pediatric Patients
The pharmacokinetics of idelalisib has not been studied in pediatric patients.
Patients with Renal Impairment
A pharmacokinetic study following a single dose of 150 mg of Zydelig was performed in healthy subjects and subjects with severe renal impairment (CrCl 15 to 29 mL/min). Creatinine clearance had no effect on idelalisib exposure.
No dose adjustment is needed for patients with CrCl =15 mL/min.
Patients with Hepatic Impairment
A pharmacokinetic study of Zydelig was performed in healthy subjects and subjects with hepatic impairment.
The geometric mean AUC increased up to 1.7-fold in subjects with ALT or AST or bilirubin values greater than the upper limit of normal (ULN) compared to subjects with normal AST or ALT or bilirubin values.
Patients with baseline hepatic impairment-
should be monitored for signs of Zydelig toxicity
Follow dose modifications for adverse reactions
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1.Pregnancy Pregnancy Category
Risk Summary
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.
2. 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 Zydelig, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
3. Pediatric Use
Safety and effectiveness of Zydelig in children less than 18 years of age have not been established.
4.Geriatric Use
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%).
5.Females of Reproductive Potential -
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
6. Renal Impairment
No dose adjustment of Zydelig is necessary for patients with creatinine clearance (CrCl) = 15 mL/min
7.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
Patients with baseline hepatic impairment
should be monitored for signs of Zydelig toxicity
(ollow dose modifications for adverse reactions
8.7 Renal Impairment
No dose adjustment of Zydelig is necessary for patients with creatinine clearance (CrCl) = 15 mL/min [see Clinical Pharmacology (12.3)].
8.8 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 [see Clinical Pharmacology (12.3)]. Safety and efficacy data are not available in patients with baseline ALT or AST values greater than 2.5 x ULN or bilirubin values greater than 1.5 x ULN, as these patients were excluded from Studies 1 and 2. Patients with baseline hepatic impairment should be monitored for signs of Zydelig toxicity [see Warnings and Precautions (5)]. Follow dose modifications for adverse reactions [see Dosage and Administration (2.2)].
11 DESCRIPTION
Idelalisib is an inhibitor of phosphatidylinositol 3-kinase, PI3Kd. The chemical name for idelalisib is 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6ylamino)propyl]quinazolin-4(3H)-one. It has a molecular formula of C22H18FN7O and a molecular weight of 415.42 g/mol. Idelalisib has the following structural formula:
Idelalisib is a white to
