Note: Correct hypokalemia and hypomagnesemia prior to initiating therapy. Obtain baseline ECG; repeat ECG within 1 week after treatment initiation, and as clinically indicated thereafter.
Cushing disease: Oral: Initial: 2 mg twice daily. Titrate by 1 to 2 mg twice daily no more frequently than every 2 weeks according to rate of cortisol changes, tolerability, and clinical response. If patient tolerates a dosage of 10 mg twice daily but cortisol target is not achieved, dosage may be increased by 5 mg twice daily every 2 weeks; typical maintenance dosage: 2 to 7 mg twice daily (maximum: 30 mg twice daily).
No dosage adjustment necessary. In patients with moderate to severe renal impairment, consider using methods other than urinary free cortisol levels to adjust dosage (Braun 2019).
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh class B): Initial: 1 mg twice daily.
Severe impairment (Child-Pugh class C): Initial: 1 mg once daily in the evening.
Refer to adult dosing.
Adrenal insufficiency: Decrease dose or temporarily interrupt therapy if cortisol drops below target or is rapidly decreasing, or if symptoms of hypocortisolism/adrenal insufficiency occur. May restart at lower dose following normalization of cortisol and resolution of symptoms.
Hypokalemia: If hypokalemia persists during therapy despite potassium supplementation, dose reduction or discontinuation of osilodrostat may be necessary.
QTc prolongation: Consider temporary discontinuation for QTc interval >480 msec during therapy.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Isturisa: 1 mg, 5 mg, 10 mg
No
Oral: May be administered with or without food.
Cushing disease: Treatment of Cushing disease in adults for whom pituitary surgery is not an option or has not been curative.
Osilodrostat may be confused with orlistat.
May commonly cause adrenocortical insufficiency resulting in symptoms of decreased cortisol (eg, anorexia, fatigue, hypoglycemia, hyponatremia, hypotension, nausea, vomiting, weakness).
Mechanism: Dose related; related to the pharmacologic action. Inhibits cortisol synthesis by inhibition of 11-beta-hydroxylase (CYP11B1), an enzyme needed for the final step of cortisol biosynthesis in the adrenal gland.
Onset: Varied; can occur at any time during treatment. Cortisol suppression may persist beyond the 4-hour half-life of osilodrostat.
Risk factors:
• Precipitating causes of decreased cortisol (eg, infection, physical stress).
May commonly cause altered hormone levels; specific alterations include increased circulating androgen levels and increased testosterone levels, which may lead to hirsutism, hypertrichosis, and acne vulgaris (in females).
Mechanism: Dose-related; related to the pharmacologic action. Inhibits cortisol synthesis by inhibition of 11-beta-hydroxylase (CYP11B1), an enzyme needed for the final step of cortisol biosynthesis. CYP11B1 inhibition is associated with adrenal steroid precursor accumulation and may increase circulating androgen and testosterone levels.
May commonly cause increased circulating aldosterone precursor levels, resulting in hypokalemia, hypertension, and edema.
Mechanism: Dose-related; related to the pharmacologic action. Inhibits cortisol synthesis and may increase circulating levels of aldosterone precursors (11-deoxycortisol and 11-deoxycorticosterone). Elevated 11-deoxycorticosterone levels may activate mineralocorticoid receptors.
Risk factors:
• Preexisting hypokalemia
May cause dose-dependent prolonged QT interval on ECG, resulting in cardiac arrhythmias; maximum mean estimated QTcF increase of up to 5.3 msec with osilodrostat 30 mg.
Mechanism: Dose-related; exact mechanism is unknown.
Onset: Varied; effect is concentration-dependent; therefore, timing may be impacted by high doses or accumulation.
Risk factors:
In general, risk factors for drug-induced QT prolongation include (Ref):
• Females
• Age >65 years
• Structural heart disease (eg, history of myocardial infarction or heart failure with reduced ejection fraction)
• Genetic defects of cardiac ion channels
• History of drug-induced torsades de pointes
• Congenital long QT syndrome
• Baseline QTc interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 msec
• Electrolyte disturbances (eg, hypocalcemia, hypokalemia, hypomagnesemia)
• Bradycardia
• Hepatic impairment
• Kidney impairment
• Loop diuretic use
• Sepsis
• Concurrent administration of multiple medications (≥2) that prolong the QT interval or drug interactions that increase serum drug concentrations of QT-prolonging medications
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Edema (7% to 21%), hypertension (10% to 14%), hypotension (12%)
Dermatologic: Acne vulgaris (9% to 11%), skin rash (15%)
Endocrine & metabolic: Adrenocortical insufficiency (43%), altered hormone level (12%; corticotrophin increased: 14%), decreased cortisol (18% to 31%), hirsutism (10% to 12%), hypokalemia (12% to 17%), increased testosterone level (11%)
Gastrointestinal: Abdominal pain (13%), decreased appetite (12%), diarrhea (15%), nausea (37%), vomiting (19%)
Genitourinary: Urinary tract infection (12%)
Hematologic & oncologic: Benign neoplasm (decrease in pituitary corticotroph tumor volume >20%: 18%), tumor growth (increase in pituitary corticotroph tumor volume >20%: 15%; no correlation between tumor volume and increase in adrenocorticotrophic hormone)
Nervous system: Dizziness (14%), fatigue (39%), headache (31%)
Neuromuscular & skeletal: Arthralgia (18%), back pain (15%), myalgia (12%)
Respiratory: Nasopharyngitis (20%)
Miscellaneous: Fever (11%)
1% to 10%:
Cardiovascular: Prolonged QT interval on ECG (4%), syncope (2%), tachycardia (7%)
Dermatologic: Alopecia (6%)
Gastrointestinal: Dyspepsia (8%), gastroenteritis (7%)
Hematologic & oncologic: Anemia (10%), neutropenia (1%)
Hepatic: Increased serum transaminases (4%)
Infection: Influenza (10%)
Nervous system: Anxiety (7%), depression (7%), insomnia (8%), malaise (7%)
Respiratory: Cough (10%)
There are no contraindications listed in the manufacturer's labeling.
Substrate of CYP2B6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP2C19 (weak), CYP2D6 (weak), CYP3A4 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
ALPRAZolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ALPRAZolam. Risk C: Monitor therapy
CarBAMazepine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy
CloBAZam: CYP2C19 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Weak) may increase the serum concentration of CloBAZam. Risk C: Monitor therapy
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
CycloSPORINE (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Osilodrostat. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Osilodrostat. Management: Reduce osilodrostat dose by 50% during coadministration with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification
Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Finerenone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Finerenone. Risk C: Monitor therapy
Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Risk C: Monitor therapy
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Ixabepilone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ixabepilone. Risk C: Monitor therapy
Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Risk D: Consider therapy modification
Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Risk D: Consider therapy modification
Lonafarnib: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lonafarnib. Management: Avoid concurrent use of lonafarnib with weak CYP3A4 inhibitors. If concurrent use is unavoidable, reduce the lonafarnib dose to or continue at a dose of 115 mg/square meter. Monitor for evidence of arrhythmia, syncope, palpitations, or similar effects. Risk D: Consider therapy modification
Mavacamten: CYP2C19 Inhibitors (Weak) may increase the serum concentration of Mavacamten. Management: Start mavacamten at 5 mg/day if stable on a weak CYP2C19 inhibitor. For those stable on mavacamten who are initiating a weak CYP2C19 inhibitor, reduce mavacamten dose by one dose level. Risk D: Consider therapy modification
Midazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Midazolam. Risk C: Monitor therapy
NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Risk C: Monitor therapy
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Simvastatin: CYP3A4 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Weak) may increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m2 when used concomitantly with a weak CYP3A4 inhibitor. Risk D: Consider therapy modification
Tacrolimus (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Thioridazine: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication. Risk D: Consider therapy modification
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification
Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Risk D: Consider therapy modification
Adverse events were not observed in animal reproduction studies.
Information related to the use of osilodrostat is insufficient to recommend its use for the treatment of Cushing syndrome during pregnancy (ESE [Luger 2021]).
It is not known if osilodrostat is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy or for 1 week after the last osilodrostat dose.
Cortisol levels (initially from at least two 24-hour urine free cortisol collections every 1 to 2 weeks until adequate clinical response is maintained, then at least every 1 to 2 months or as indicated); use caution in interpreting urine free cortisol levels in patients with moderate to severe renal impairment due to reduced urine free cortisol excretion; consider using methods other than urinary free cortisol levels for cortisol monitoring (Braun 2019).
Serum potassium and magnesium (prior to initiation and periodically thereafter); ECG (baseline, after 1 week, and as clinically indicated thereafter); QTc interval (prior to initiation and as clinically indicated thereafter, especially in patients with risk factors for QT prolongation); BP; signs of edema. Signs and symptoms of adrenal insufficiency (eg, anorexia, fatigue, hypoglycemia, hyponatremia, hypotension, nausea, vomiting, weakness); monitor more frequently in patients with hepatic impairment.
Osilodrostat decreases cortisol synthesis via inhibition of 11beta-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.
Distribution: Vd: ~100 L.
Protein binding: 36.4%.
Metabolism: Hepatically metabolized by multiple CYP enzymes (eg, CYP3A4, CYP2B6, CYP2D6) and UDP-glucuronosyltransferases to inactive metabolites; no single enzyme contributes >25% to the total clearance.
Half-life elimination: ~4 hours.
Time to peak: ~1 hour.
Excretion: Urine: 90.6% (5.2% as unchanged drug); feces: 1.58%.
Tablets (Isturisa Oral)
1 mg (per each): $173.70
5 mg (per each): $585.49
10 mg (per each): $695.27
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