ISTURISA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ISTURISA (ISTURISA).

How it works

ISTURISA (osilodrostat) is an orally administered inhibitor of 11β-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol synthesis in the adrenal cortex. By blocking this enzyme, it reduces cortisol production. It also inhibits aldosterone synthase (CYP11B2) to a lesser extent.

What the body does with it

Metabolism	Primarily metabolized by CYP3A4 and CYP2D6; also undergoes glucuronidation via UGT1A4 and UGT2B7.
Excretion	Primarily hepatic metabolism via CYP3A4; elimination is mainly fecal (approximately 80%) and renal (about 10% as unchanged drug).
Half-life	Terminal half-life of approximately 5–7 hours; clinical context: supports twice-daily dosing for steady-state attainment.
Protein binding	Approximately 90% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Apparent volume of distribution is about 100–150 L (1.4–2.1 L/kg for a 70 kg adult), indicating extensive tissue distribution.
Bioavailability	Oral bioavailability is approximately 30–40% due to first-pass metabolism; food may increase absorption.
Onset of Action	Oral: clinical effect (cortisol suppression) observed within 2–4 hours after first dose.
Duration of Action	Duration of cortisol suppression is approximately 8–12 hours, consistent with twice-daily dosing; interindividual variability exists.

Classification & Brands

Dosing & administration

1 mg orally twice daily, titrated based on cortisol levels and tolerability; maximum dose 7 mg twice daily.

Dosage form	TABLET
Renal impairment	No dose adjustment required for GFR ≥30 mL/min; insufficient data for GFR <30 mL/min or dialysis.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: not recommended.
Pediatric use	Not established; safety and efficacy not studied in patients <18 years.
Geriatric use	No specific dose adjustment; start at lower end of dosing range due to age-related comorbidities and monitor closely.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ISTURISA (ISTURISA).

Breastfeeding	No data on presence in human milk, effects on breastfed infant, or milk production. Due to potential for serious adverse reactions, breastfeeding is not recommended during therapy. M/P ratio unknown.
Teratogenic Risk	Isturisa (osilodrostat) is an aldosterone synthase inhibitor. In animal studies, embryofetal toxicity including malformations and reduced fetal weight occurred at maternal toxic doses. Human data are absent. First trimester exposure carries highest risk; second and third trimesters may affect fetal adrenal development and electrolyte balance. Use contraindicated in pregnancy.

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to osilodrostat or any excipient.","Concomitant use with strong CYP3A4 inducers.","QTc interval > 480 msec at baseline.","Severe hepatic impairment (Child-Pugh class C)."]

Clinical Precautions

Precautions

["Hypocortisolism: may lead to adrenal insufficiency; monitor cortisol levels and taper glucocorticoid replacement if needed.","QT interval prolongation: dose-dependent; avoid use in patients with congenital long QT syndrome or with other drugs that prolong QTc.","Hypokalemia: monitor potassium levels; may require supplementation.","Elevation of 11-deoxycortisol and androgen precursors: may cause hirsutism, acne, and hypokalemia.","Fetal harm: can cause fetal harm; women of reproductive potential should use effective contraception.","Adrenal crisis: advise patients to carry medical alert identification and have stress doses of glucocorticoids available."]

Clinical Tips & Counseling

Drug interactions

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ISTURISA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for ISTURISA (ISTURISA).

How it works

What the body does with it

Metabolism	Primarily metabolized by CYP3A4 and CYP2D6; also undergoes glucuronidation via UGT1A4 and UGT2B7.
Excretion	Primarily hepatic metabolism via CYP3A4; elimination is mainly fecal (approximately 80%) and renal (about 10% as unchanged drug).
Half-life	Terminal half-life of approximately 5–7 hours; clinical context: supports twice-daily dosing for steady-state attainment.
Protein binding	Approximately 90% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Apparent volume of distribution is about 100–150 L (1.4–2.1 L/kg for a 70 kg adult), indicating extensive tissue distribution.
Bioavailability	Oral bioavailability is approximately 30–40% due to first-pass metabolism; food may increase absorption.
Onset of Action	Oral: clinical effect (cortisol suppression) observed within 2–4 hours after first dose.
Duration of Action	Duration of cortisol suppression is approximately 8–12 hours, consistent with twice-daily dosing; interindividual variability exists.

Classification & Brands

Dosing & administration

1 mg orally twice daily, titrated based on cortisol levels and tolerability; maximum dose 7 mg twice daily.

Dosage form	TABLET
Renal impairment	No dose adjustment required for GFR ≥30 mL/min; insufficient data for GFR <30 mL/min or dialysis.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: not recommended.
Pediatric use	Not established; safety and efficacy not studied in patients <18 years.
Geriatric use	No specific dose adjustment; start at lower end of dosing range due to age-related comorbidities and monitor closely.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for ISTURISA (ISTURISA).

Breastfeeding	No data on presence in human milk, effects on breastfed infant, or milk production. Due to potential for serious adverse reactions, breastfeeding is not recommended during therapy. M/P ratio unknown.
Teratogenic Risk	Isturisa (osilodrostat) is an aldosterone synthase inhibitor. In animal studies, embryofetal toxicity including malformations and reduced fetal weight occurred at maternal toxic doses. Human data are absent. First trimester exposure carries highest risk; second and third trimesters may affect fetal adrenal development and electrolyte balance. Use contraindicated in pregnancy.

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to osilodrostat or any excipient.","Concomitant use with strong CYP3A4 inducers.","QTc interval > 480 msec at baseline.","Severe hepatic impairment (Child-Pugh class C)."]