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enasidenib
enasidenib
COMMON TRADE NAME(S): Idhifa®
Enasidenib has been withdrawn from the Canadian market as of June 30th, 2023.
Enasidenib failed to demonstrate improved overall survival when compared to conventional care regimens in a Phase 3 confirmatory study. The safety profile remains unchanged.
Healthcare professionals are advised to:
- NOT initiate enasidenib in new patients;
- discuss with their patients whether to continue treatment with enasidenib;
- apply to Health Canada’s Special Access Program (SAP) to request enasidenib for patients who require continued treatment.
Refer to the Health Canada communication for details.
Enasidenib inhibits the mutant isocitrate dehydrogenase 2 (IDH2) enzyme. Mutant IDH2 enzyme catalyzes the production of the oncogenic metabolite 2-hydroxyglutarate (2-HG), which blocks cell differentiation. Inhibition of IDH2 enzyme leads to reduced 2-HG levels, induced myeloid differentiation, decreased myeloblasts counts and increased percentage of mature myeloid cells.
| Bioavailability |
57% |
| Effects with food |
Consumption of a high fat, high calorie meal increased AUC by 50% and Cmax by 63%. Food does not appear to have any clinically important effects. |
| Peak plasma levels |
4 h (single dose); 2.15 h (steady-state) |
| Time to reach steady state |
29 days |
| PPB |
98.5% (parent) and 96.6% (active metabolite) to human plasma protein |
Metabolized by multiple CYP enzymes and multiple UGTs.
| Active metabolites |
Yes |
Enasidenib is primarily excreted in feces.
| Feces |
89% (34% unchanged) |
| Urine |
11% (0.4% unchanged) |
| Half-life |
terminal: 7.9 days |
Enasidenib has been withdrawn from the Canadian market as of June 30th, 2023.
Previous Indication:
For the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation
Emetogenic Potential:
The following adverse effects include those reported in ≥ 10% of patients with relapsed or refractory AML in a Phase I/II study. Severe or life-threatening adverse events may also be included.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Heart failure (<10%) | D | |||
| Gastrointestinal | Anorexia (19%) | E D | |||
| Diarrhea (15%) | E | ||||
| Nausea, vomiting (28%) | E | ||||
| General | Fatigue (15%) | E D | |||
| Other (13%) (differentiation syndrome, 7% severe) | E D | ||||
| Hematological | Disseminated intravascular coagulation (<10%) | E | |||
| Leukocytosis (8%) (2% severe) | E D | ||||
| Myelosuppression ± infection, bleeding (7%) (6% severe anemia) | E D | ||||
| Hepatobiliary | ↑ ALT (7%) (2% severe) | E | |||
| ↑ Bilirubin (27%) (5% severe) | E | ||||
| Pancreatitis (1%) | E | ||||
| Metabolic / Endocrine | Abnormal electrolyte(s) (76%) (↓ Ca, K, or PO4; 16% severe) | E D | |||
| Tumor lysis syndrome (2%) | E | ||||
| Nervous System | Dysgeusia (10%) | E | |||
| Renal | Renal failure (<10%) | E | |||
| Respiratory | Dyspnea (9%) | E | |||
| Pneumonitis (<10%) | E | ||||
| Pulmonary edema , hypoxia (2%) | E | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for enasidenib include nausea, vomiting, ↑ bilirubin, anorexia, severe ↓ Ca, K, or PO4, diarrhea, and fatigue.
Differentiation syndrome, which may be serious or fatal if not treated, has been reported. Symptoms may include the following: unexplained fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multi-organ dysfunction. Time of onset has been reported as early 1 day and up to 5 months after initiation of treatment.
Serious cases of noninfectious leukocytosis have occurred. The majority of cases had an onset during the first 3 months of treatment.
Hyperuricemia associated with abnormal electrolyte changes, consistent with signs and symptoms of tumor lysis syndrome (TLS), has been reported. Time of onset was usually within the first 3 months of treatment.
Enasidenib may interfere with bilirubin metabolism through UGT 1A1 inhibition. It has caused dose-dependent hyperbilirubinemia, starting from the onset of treatment and stabilizing by the end of the first month. Patients with congenital UGT1A1 deficiency (Gilbert Syndrome) experienced a more rapid increase in bilirubin and more frequently experienced an increase > 3 x ULN.
Gastrointestinal adverse events were generally mild to moderate. Symptoms usually occurred during the first month of treatment and often resolved with continued treatment.
Refer to protocol by which patient is being treated.
Treatment should be initiated following confirmation of IDH2 mutation through a validated test.
| Dose Level | Enasidenib Dose (mg/day) |
| 0 | 100 |
| -1 | 50 |
| -2 | Discontinue |
| Toxicity | Action |
| Differentiation syndrome |
If suspected, initiate systemic corticosteroids and hemodynamic monitoring. Hold enasidenib for severe pulmonary symptoms (requiring intubation or ventilator support) and/or renal dysfunction > 48 hours after initiation of corticosteroids. Resume when toxicity ≤ Grade 2. |
| Noninfectious leukocytosis (WBC > 30 x 109/L) |
Initiate hydroxyurea (per standard institutional practices). Hold enasidenib if leukocytosis does not improve with hydroxyurea. Resume when WBC < 30 x 109/L, at current dose. |
| Bilirubin > 3 x ULN for ≥ 2 weeks (without elevated transaminases or other hepatic disorders) |
Decrease to 50 mg daily. Increase to 100 mg daily when bilirubin < 2 x ULN. |
| Other ≥ Grade 3 toxicity, including tumour lysis syndrome |
Hold. Resume when toxicity ≤ Grade 2, at 50 mg daily; May increase to 100 mg daily when toxicity ≤ Grade 1. If ≥ Grade 3 toxicity recurs, discontinue. |
Patients with hepatic impairment have not been studied; there are no specific dose adjustments recommended. Mild hepatic impairment does not have a clinically meaningful effect based on the covariate population pharmacokinetic (PK) analysis.
Starting dose adjustment is not recommended in patients with congenital UGT1A1 deficiency. Dose can be reduced for higher bilirubin levels.
Population PK analyses in patients with advanced hematologic malignancies, which included patients with mild or moderate renal impairment, identified no apparent relationship between renal function or serum creatinine levels and enasidenib exposure.
| Creatinine Clearance (mL/min) | Enasidenib Dose |
| ≥ 30 | No dose adjustment required. |
| < 30 | No data available. |
No dose adjustment is required in patients ≥ 65 years of age. In clinical studies, use in patients ≥ 65 years of age was not associated with differences in safety or efficacy.
The effects of gender on pharmacokinetics have not been formally studied; no clinically meaningful effects on pharmacokinetics based on gender were observed in population PK analysis.
The effects of race on pharmacokinetics have not been formally studied; no clinically meaningful effects on pharmacokinetics based on race (White, Black or Asian) were observed in population PK analysis.
Safety and efficacy in children have not been established.
- Enasidenib may be administered with or without food.
- Tablets should be swallowed whole with water and not chewed, crushed or split.
- If a dose is missed, patient may take the dose as soon as possible if within the same day, otherwise the dose should be skipped and the next dose should be taken as scheduled. Patients should not take 2 doses at the same time to make up for a missed dose.
- Store at room temperature (15 – 25°C) in the original bottle. Protect from moisture.
- Patients who are hypersensitive to this drug or to any ingredient in the formulation, or component of the container
- Patients with congenital UGT1A1 deficiency (Gilbert Syndrome) should be monitored closely.
- Patients with severe renal impairment (CrCl < 30 mL/min) were excluded from clinical trials.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Genotoxicity:
No
-
Mutagenicity:
No
-
Embryotoxicity:
Documented in animals
-
Fetotoxicity:
Documented in animals
- Enasidenib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 8 weeks after the last dose. Enasidenib may affect the effectiveness of combined hormonal contraceptives.
- Enasidenib and its metabolite can transfer through the blood placental barrier in animals.
-
Excretion into breast milk:
Unknown
- Breastfeeding is not recommended during treatment, and for at least 8 weeks after the last dose.
-
Fertility effects:
Probable
- Histiopathologic changes in testes, epididymides and/or ovary have been observed in animal studies.
Enasidenib is metabolized by multiple CYP enzymes (e.g., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and multiple UGTs (e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15). The active metabolite, AGI-16903, is metabolized by multiple enzymes (e.g., CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9).
In vitro, enasidenib and its active metabolite inhibit several enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and UGT1A1) and drug transporters (P-gp, BCRP, OAT1, OATP1B1, OATP1B3, and OCT2) and also induce CYP2B6 and CYP3A4.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| OATP1B1, OATP1B3 and BCRP substrates (i.e. rosuvastatin) | ↑ substrate concentration and/or toxicity (increased rosuvastatin AUC by 3.5-fold) | Enasidenib is a OATP1B1, OATP1B3, and BCRP inhibitor | Monitor for clinical signs of toxicity. Adjust dose of substrates as clinically indicated. |
| P-glycoprotein substrates (i.e. digoxin) | ↑ substrate concentration and/or toxicity (increased digoxin AUC by 1.2- fold) | Enasidenib is a P-gp inhibitor | Monitor for clinical signs of toxicity. Adjust dose of substrates with narrow therapeutic indices as clinically indicated. |
| Combined hormonal contraceptives | ↑ or ↓ substrate concentration and/or toxicity (theoretical) | Clinical significance is unknown. |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
CBC, including differential distribution |
Baseline, every 2 weeks for at least 3 months, and as clinically indicated |
Liver function tests |
Baseline and as clinically indicated |
Renal function tests |
Baseline and as clinically indicated |
Serum uric acid and electrolytes (including Ca, K, PO4) |
Baseline, every 2 weeks for at least 3 months, and as clinically indicated |
Clinical toxicity assessment for respiratory effects (including differentiation syndrome), infection, bleeding, and GI effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Dittakavi S, Hallur G, Purra BR, Kiran V, Zakkula A, Mullangi R. Validated LC-MS/MS Method for Simultaneous Quantitation of Enasidenib and its Active Metabolite, AGI-16903 in Small Volume Mice Plasma: Application to a Pharmacokinetic Study. Drug Res (Stuttg). 2020 Jan;70(1):41-48.
Enasidenib. Lexicomp Inc. Accessed Feb 11, 2020.
Health Canada health professional risk communication: IDHIFA (enasidenib mesylate) – Market withdrawal and continued access. June 8, 2023.
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Antiemesis: Version 1.2019, 2019.
Prescribing Information: Idhifa (enasidenib). Celgene Corporation, NJ. Nov 2020.
Product Monograph: Idhifa (enasidenib). Celgene Inc. Nov 30, 2020.
July 2023 Updated section A on enasidenib withdrawal from market
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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