Olutasidenib

Olutasidenib – Description

• Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation as detected by an FDA-approved test.
• Olutasidenib has a black box warning for differentiation syndrome; this syndrome can be fatal if untreated.
• Corticosteroid therapy and hemodynamic monitoring are indicated if differentiation syndrome is suspected.
• Hepatotoxicity has also occurred in patients treated with olutasidenib; monitor liver function tests during therapy.⁶⁸²⁴²

Indications & Dosage

•  Acute myelogenous leukemia (AML)

For the treatment of acute myelogenous leukemia (AML)

NOTE: The FDA has designated olutasidenib as an orphan drug for the treatment of AML.

for the treatment of relapsed or refractory AML with an isocitrate dehydrogenase-1 (IDH1) mutation

NOTE: Evaluate patients for the presence of the IDH1 mutation in the blood or bone marrow using an FDA-approved detection test www.fda.gov/CompanionDiagnostics.

Oral dosage

Adults:

• 150 mg orally twice daily until disease progression. Treat patients without disease progression for a minimum of 6 months to allow time for clinical response. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop toxicity.
• Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.⁶⁸²⁴² 
• At a median follow-up of 10.2 (range, 0.2 to 38.1) months, treatment with olutasidenib resulted in a complete remission (CR) or a CR with partial hematologic recovery (CRh) rate of 35% in 147 patients with relapsed or refractory IDH1-mutated acute myeloid leukemia in a multicenter, multi-cohort, 1/2 (Study 2102-HEM-101) trial. In patients who achieved a CR/CRh, the median time to first response and duration of response were 1.9 months (range, 0.9 to 5.6 months) and 25.9 months, respectively.
• The median overall survival time was 11.6 months. Of the 86 patients who were dependent on red blood cell or platelet transfusions at baseline, 34% of patients became transfusion independent during any 56-day post baseline period.
• Before enrolling in this trial, patients (median age, 71 years; range, 32 to 87 years) had received a median of 2 (range, 1 to 7) prior therapies; 12% of patients had undergone prior allogeneic hemopoietic stem-cell transplantation.^70600 68242

Therapeutic Drug Monitoring:

Recommended Monitoring

• Complete blood cell counts (CBC): Monitor CBC at baseline, at least once weekly for the first 2 months, once every other week for the third month, once in the fourth month, and once every other month thereafter during therapy.
• Chemistries: Monitor blood chemistries at baseline, at least once weekly for the first 2 months, once every other week for the third month, once in the fourth month, and once every other month thereafter during therapy.
• Hepatic function: Monitor patients for signs of hepatic disease/impairment (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice); evaluate liver function tests (LFTs) at baseline, at least once weekly for the first 2 months, once every other week for the third month, once in the fourth month, and once every other month thereafter during therapy.
• Differentiation syndrome: Monitor patients for signs and symptoms of differentiation syndrome such as dyspnea, pulmonary infiltrates, pleural or pericardial effusion, kidney injury, fever, edema, and weight gain.⁶⁸²⁴²

Management of Treatment-Related Toxicities

Differentiation Syndrome

• First occurrence: Hold olutasidenib therapy until signs and symptoms improve if differentiation syndrome is suspected. Administer corticosteroid therapy (e.g., dexamethasone 10 mg IV every 12 hours) and closely monitor hemodynamic parameters until symptom resolution and for a minimum of 3 days. Resume olutasidenib therapy at 150 mg twice daily after resolution of differentiation syndrome.
• Suspected recurrence: Hold olutasidenib therapy and institute measures (e.g., corticosteroids and hemodynamic parameters) as for first occurrence guidance above. Resume olutasidenib therapy at a reduced dose of 150 mg once daily after symptoms resolve.

Noninfectious Leukocytosis

• Start hydroxyurea per standard cinical practice. Taper hydroxyurea after leukocytosis improves or resolves.

Other Toxicity

• Grade 3 or higher toxicity: Hold olutasidenib therapy until toxicity resolves to grade 2 or less. Resume olutasidenib therapy at 150 mg PO once daily; discontinue therapy if grade 3 or higher toxicity recurs at this dosage. If the toxicity resolves to grade 1 or less for at least 1 week at the 150 mg PO once daily dosage, may increase the olutasidenib dosage to 150 mg PO twice daily.⁶⁸²⁴²

Maximum Dosage Limits:

•Adults

300 mg/day PO.

•Geriatric

300 mg/day PO.

•Adolescents

Safety and efficacy have not been established.

•Children

Safety and efficacy have not been established.

•Infants

Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing

Baseline Hepatic Impairment

Mild (total bilirubin level up to 1 time the ULN and any AST level more than ULN OR total bilirubin level more than 1 to 1.5 times the ULN and any AST level) or moderate (total bilirubin level more than 1.5 to 3 times the ULN and any AST level) hepatic impairment: No initial dosage adjustment is recommended; closely monitor for increased probability of differentiation syndrome.
Severe hepatic impairment (total bilirubin level more than 3 times the ULN with any AST level): Recommended dosage has not been established; specific guidelines for dosage adjustments are not available.

Treatment-Related Hepatotoxicity

Grade 3 toxicity: Hold olutasidenib therapy and monitor liver function tests (LFTs) twice weekly until toxicity resolves to baseline or grade 1 or less. Resume olutasidenib therapy at 150 mg PO once daily; discontinue therapy if grade 3 toxicity recurs at this dosage. If the toxicity resolves to baseline for at least 28 days at the 150 mg PO once daily dosage, may increase the olutasidenib dosage to 150 mg PO twice daily.
Grade 4 toxicity OR AST or ALT level more than 3 times the ULN, total bilirubin level more than 2 times the ULN, and alkaline phosphatase level less than 2 times the ULN in the absence of a clear alternative etiology: Discontinue olutasidenib therapy.⁶⁸²⁴²

Patients with Renal Impairment Dosing

Mild to moderate renal impairment (creatinine clearance (CrCl) as estimated by Cockcroft-Gault, 30 to less than 90 mL/min): No initial dosage adjustment is recommended.
Severe renal impairment (CrCl, 15 to 29 mL/min), renal failure (CrCl less than 15 mL/min), or dialysis: Recommended dosage has not been established; specific guidelines for dosage adjustments are not available.⁶⁸²⁴²

Precautions

•  Breast-feeding
•  Child-Pugh class A
•  Child-Pugh class B
•  Child-Pugh class C
•  Contraception requirements
•  Differentiation syndrome
•  Hepatic failure
•  Pregnancy
•  Reproductive risk

Pregnancy

Olutasidenib may cause fetal harm when administered during pregnancy, based on animal studies. Discuss the potential hazard to the fetus if olutasidenib is used during pregnancy or if a patient becomes pregnant while taking this drug. Reduced maternal weight gain and embryo-fetal toxicities including an increase in fetal supernumerary rib and increased post-implantation loss were observed when olutasidenib was administered to pregnant rabbits during organogenesis at doses resulting in exposures of approximately 0.7 time the exposure in humans (at the recommended dose). Additionally, an increase in fetal supernumerary rib and an increase in post-implantation loss occurred in pregnant rats who received olutasidenib doses resulting in exposures up to 10 times the exposure in humans.⁶⁸²⁴²

Lactation

It is not known if olutasidenib is secreted in human milk or if it has effects on the breast-fed child or on milk production. Because there is a potential for adverse reactions in a nursing child from olutasidenib, patients should avoid breast-feeding during olutasidenib therapy and for 2 weeks after the last dose.⁶⁸²⁴²

Interactions

•  Acetaminophen; Codeine
•  Acetaminophen; Hydrocodone
•  Acetaminophen; Oxycodone
•  Alfentanil
•  Amobarbital
•  Apalutamide
•  Aspirin, ASA; Butalbital; Caffeine
•  Aspirin, ASA; Carisoprodol; Codeine
•  Aspirin, ASA; Oxycodone
•  Atogepant
•  Avanafil
•  Barbiturates
•  Benzhydrocodone; Acetaminophen
•  Bexarotene
•  Bosentan
•  Buprenorphine
•  Buprenorphine; Naloxone
•  Butalbital; Acetaminophen
•  Butalbital; Acetaminophen; Caffeine
•  Butalbital; Acetaminophen; Caffeine; Codeine
•  Butalbital; Aspirin; Caffeine; Codeine
•  Carbamazepine
•  Cariprazine
•  Celecoxib; Tramadol
•  Cenobamate
•  Chlorpheniramine; Codeine
•  Chlorpheniramine; Hydrocodone
•  Clozapine
•  Codeine
•  Codeine; Guaifenesin
•  Codeine; Guaifenesin; Pseudoephedrine
•  Codeine; Phenylephrine; Promethazine
•  Codeine; Promethazine
•  Cyclosporine
•  Dabrafenib
•  Diazepam
•  Doravirine
•  Doravirine; Lamivudine; Tenofovir disoproxil fumarate
•  Efavirenz
•  Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate
•  Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate
•  Elagolix
•  Elagolix; Estradiol; Norethindrone acetate
•  Encorafenib
•  Enzalutamide
•  Eslicarbazepine
•  Etravirine
•  Fentanyl
•  Fexinidazole
•  Fosphenytoin
•  Homatropine; Hydrocodone
•  Hydrocodone
•  Hydrocodone; Ibuprofen
•  Isradipine
•  Lopinavir; Ritonavir
•  Lorlatinib
•  Lumacaftor; Ivacaftor
•  Lumacaftor; Ivacaftor
•  Lumateperone
•  Mefloquine
•  Meperidine
•  Methadone
•  Methohexital
•  Mitotane
•  Nafcillin
•  Nanoparticle Albumin-Bound Paclitaxel
•  Nanoparticle Albumin-Bound Sirolimus
•  Nimodipine
•  Nirmatrelvir; Ritonavir
•  Nisoldipine
•  Omeprazole; Amoxicillin; Rifabutin
•  Oxycodone
•  Paclitaxel
•  Pacritinib
•  Pentobarbital
•  Pexidartinib
•  Phenobarbital
•  Phenobarbital; Hyoscyamine; Atropine; Scopolamine
•  Phenytoin
•  Primidone
•  Repotrectinib
•  Rifabutin
•  Rifampin
•  Rifapentine
•  Ritonavir
•  Secobarbital
•  Sildenafil
•  Sirolimus
•  Sotorasib
•  St. John’s Wort, Hypericum perforatum
•  Sufentanil
•  Tacrolimus
•  Tramadol
•  Tramadol; Acetaminophen
•  Ubrogepant
•  Ulipristal
•  Warfarin

Adverse Reactions

•  abdominal pain
• acute respiratory distress syndrome (ARDS)
•  anorexia
• arthralgia
• back pain
•  bone pain
•  cholangitis
•  cholestasis
•  colitis
•  constipation
•  cough
• diarrhea
• differentiation syndrome
• dyspnea
•  edema
•  elevated hepatic enzymes
•  fatigue
•  fever
•  gingivitis
•  headache
•  hepatic failure
•  hepatitis
•  hepatotoxicity
•  hyperbilirubinemia
•  hypertension
•  hyperuricemia
•  hypokalemia
•  hyponatremia
•  hypoxia
•  ischemic colitis
•  jaundice
•  leukocytosis
•  lymphocytosis
•  malaise
•  nausea
•  nephrotoxicity
•  oral ulceration
•  pericardial effusion
•  pharyngitis
•  pleural effusion
•  QT prolongation
•  rash
•  respiratory failure
•  stomatitis
•  vomiting
•  weight gain

Monitoring Parameters

Monitoring Parameters

•  CBC with differential
•  LFTs
•  serum creatinine/BUN
•  serum electrolytes

Classifications

• Antineoplastic and Immunomodulating Agents
  • Antineoplastics
    • Small Molecule Antineoplastic Isocitrate Dehydrogenase (IDH) Inhibitors
      •  Small Molecule Antineoplastic Isocitrate Dehydrogenase-1 (IDH-1) Inhibitors

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