temporary classcortisol synthesis inhibitors
Cushing's disease in patients in whom pituitary surgery is not an option or has not been curative.
Inhibits 11–beta-hydroxylase, an enzyme responsible for the final step of cortisol synthesis in the adrenal gland.
Reduction in urine free cortisol levels.
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)
|PO||unknown||1 hr||12 hr|
- 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
Endo: HYPOCORTISOLISM, ↑ testosterone levels, hypoglycemia
F and E: hypokalemia
GI: abdominal pain, diarrhea, nausea, vomiting, dyspepsia, ↑ liver enzymes
GU: urinary tract infection
Metabolic: ↓ appetite
MS: arthralgia, myalgia
Neuro: dizziness, headache, anxiety, depression, insomnia, syncope
Misc: fatigue, fever
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- 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.
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).
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).
Tablets: 1 mg, 5 mg, 10 mg
- 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.
- Deficient knowledge, related to medication regimen (Patient/Family/Teaching)
- PO Administer twice daily without regard to food.
- 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.
Reduction in urine free cortisol levels.