osilodrostat

General

Pronunciation:
oh-sil-oh-droe-stat

Trade Name(s)

  • Isturisa

Ther. Class.
none assigned

Pharm. Class.
temporary class cortisol synthesis inhibitors

Indications

Cushing's disease in patients in whom pituitary surgery is not an option or has not been curative.

Action

Inhibits 11–beta-hydroxylase, an enzyme responsible for the final step of cortisol synthesis in the adrenal gland.

Therapeutic Effect(s):

Reduction in urine free cortisol levels.

Pharmacokinetics

Absorption: High-fat meals may delay and reduce extent of absorption.

Distribution: Extensively distributed to tissues.

Metabolism and Excretion: Metabolized by CYP3A4, CYP2B6, and CYP2D6 isoenzymes as well as UDP-glucuronosyltransferases. Primarily excreted in urine (91%; 5% as unchanged drug), with minimal excretion in feces.

Half-life: 4 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTEONSETPEAKDURATION
POunknown1 hr12 hr

Contraindication/Precautions

Contraindicated in:

  • Lactation: Lactation.

Use Cautiously in:

  • Congenital long QT syndrome, HF, bradyarrhythmias, hypokalemia, or hypomagnesemia (↑ risk of QT interval prolongation)
  • Concurrent use of QT interval prolonging medications (↑ risk of QT interval prolongation)
  • Moderate or severe hepatic impairment (↓ dose)
  • OB:   Safety not established in pregnancy
  • Pedi:   Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: edema, hypotension, hypertension, QT interval prolongation, tachycardia

Derm: rash, acne (females), alopecia, hirsutism, hypertrichosis

EENT: nasopharyngitis

Endo: HYPOCORTISOLISM, ↑ testosterone levels, hypoglycemia

F and E: hypokalemia

GI: abdominal pain, diarrhea, nausea, vomiting, dyspepsia, ↑ liver enzymes

GU: urinary tract infection

Hemat: anemia

Metabolic: ↓ appetite

MS: arthralgia, myalgia

Neuro: dizziness, headache, anxiety, depression, insomnia, syncope

Resp: cough

Misc: fatigue, fever

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  QT interval prolonging medications  may ↑ risk of QT interval prolongation and torsade de pointes.
  •  Strong CYP3A4 inhibitors, including  clarithromycin  and  itraconazole  may ↑ levels and risk of toxicity; ↓ dose of osilodrostat by 50%.
  •  CYP3A4 inducers  and  CYP2B6 inducers, including  carbamazepine,  phenobarbital, or  rifampin , may ↓ levels and effectiveness; may need to ↑ osilodrostat dose based on urine free cortisol levels.
  • May ↑ levels and risk of toxicity of  CYP1A2 substrates  and  CYP2C19 substrates  with a narrow therapeutic index, including  theophylline  and  tizanidine.

Route/Dosage

PO (Adults): 2 mg twice daily; may ↑ by 1–2 mg twice daily every 2 wk based on urine free cortisol levels, tolerability, and signs/symptoms. If patient continues to have elevated urine free cortisol levels while taking 10 mg twice daily, may ↑ by 5 mg twice daily every 2 wk (max dose = 30 mg twice daily).

Hepatic Impairment 
PO (Adults): Moderate hepatic impairment (Child-Pugh B)– 1 mg twice daily; may ↑ by 1–2 mg twice daily every 2 wk based on urine free cortisol levels, tolerability, and signs/symptoms. If patient continues to have elevated urine free cortisol levels while taking 10 mg twice daily, may ↑ by 5 mg twice daily every 2 wk (max dose = 30 mg twice daily).  Severe hepatic impairment (Child-Pugh B)– 1 mg once daily; may ↑ by 1–2 mg twice daily every 2 wk based on urine free cortisol levels, tolerability, and signs/symptoms. If patient continues to have elevated urine free cortisol levels while taking 10 mg twice daily, may ↑ by 5 mg twice daily every 2 wk (max dose = 30 mg twice daily).

Availability

Tablets: 1 mg, 5 mg, 10 mg

Assessment

  • Obtain baseline ECG. Repeat ECG within 1 wk after starting therapy, and as indicated thereafter. May cause QTc interval prolongation. If QTc interval >480 msec, consider discontinuing osilodrostat temporarily.
  • Monitor for signs and symptoms of hypocortisolism (nausea, vomiting, fatigue, abdominal pain, loss of appetite, dizziness, hypotension, abnormal electrolyte levels, hypoglycemia) during therapy. May occur at any time during therapy. Decrease or temporarily discontinue osilodrostat. May require, glucocorticoid replacement. After discontinuation, cortisol suppression may persist beyond the 4 hr half-life of osilodrostat.

Lab Test Considerations:

Correct hypokalemia and hypomagnesemia before starting therapy. Monitor electrolytes periodically during therapy.

  • Monitor cortisol levels from at least two 24-hour urine free cortisol collections every 1-2 wk until adequate response is maintained, then at least every 1–2 mo. If urine free cortisol levels fall below target range, rapid decrease in cortisol levels occurs, and/or patient reports symptoms of hypocortisolism, decrease or temporarily discontinue osilodrostat. May require glucocorticoid replacement. If therapy is interrupted, restart at a lower dose.

Potential Diagnoses

Implementation

  • PO Administer twice daily without regard to food.

Patient/Family Teaching

  • Instruct patient to take osilodrostat as directed. Omit missed doses; take next dose at regularly scheduled time. Advise patient to read  Patient Information  before starting therapy and with each Rx refill in case of changes.
  • Advise patient to notify health care professional if signs and symptoms of low cortisol levels (nausea, abdominal pain, vomiting, loss of appetite, tiredness, dizziness, low blood pressure) occur.
  • Inform patient of possibility of hyperandrogenism. Advise patient to notify health care professional if signs and symptoms (hirsutism, hypertrichosis, acne in females, swelling of legs and ankles) occur.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Rep:  Advise patient to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during and for 1 wk after final dose.
  • Emphasize importance of regular lab test to monitor for side effects.

Evaluation/Desired Outcomes

Reduction in urine free cortisol levels.

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