Osilodrostat

Indications

Osilodrostat is used for: Cushing Disease

Adult Dose

Cushing Disease Indicated for Cushing disease in adults for whom pituitary surgery is not an option or has not been curative Initial: 2 mg PO BID Titration Initially, titrate by 1-2 mg BID, no more frequently than q2weeks based on rate of cortisol changes, individual tolerability, and improvement in Cushing disease signs and symptoms If patient tolerates 10 mg PO BID and continues to have elevated 24-hr urine free cortisol (UFC) levels >ULN, titrate dosage further by 5 mg BID q2week Monitor cortisol levels from at least two 24-hour UFC collections q1-2weeks until adequate clinical response maintained Maintenance Individualize maintenance dose according to cortisol levels and signs/symptoms Maintenance dosage varied from 2-7 mg BID in clinical trials Maximum recommended maintenance dose: 30 mg BID Once the maintenance dose achieved, monitor cortisol levels at least every 1-2 months or as indicated Hepatic impairment Mild (Child-Pugh A): No dose adjustment required Moderate (Child-Pugh B): Reduce recommended initial dose to 1 mg BID Severe (Child-Pugh C): Reduce recommended initial dose to 1 mg qHS More frequent adrenal function monitoring may be required during dose titration in all patients with hepatic impairment

Child Dose

Renal Dose

Renal impairment No dose adjustment required Caution in interpreting UFC levels with moderate-to-severe renal impairment, owing to reduced UFC excretion

Administration

May take with or without food

Contra Indications

Precautions

Hypocortisolism Osilodrostat lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, dizziness; significant lowering may result in hypotension, abnormal electrolyte levels, and hypoglycemia Can occur at any time during treatment; evaluate for precipitating causes of hypocortisolism (eg, infection, physical stress) Monitor 24-hr urine free cortisol (UFC), serum or plasma cortisol, and signs/symptoms QTc prolongation Associated with dose-dependent QT interval prolongation (maximum mean estimated QTcF increase of up to 5.3 ms at 30 mg), which may cause cardiac arrhythmias Obtain baseline ECG with QTc interval measurement before initiating and monitor QTc interval thereafter Correct hypokalemia and/or hypomagnesemia before initiating and monitor periodically during treatment; correct electrolyte abnormalities if indicated Consider temporary discontinuation if QTc interval >480 ms Elevated adrenal hormone precursors and androgens Osilodrostat blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors (11-deoxy cortisol and 11-deoxycorticosterone) and androgens Elevated 11-deoxycorticosterone levels may activate mineralocorticoid receptors and cause hypokalemia, edema, and hypertension Correct hypokalemia before initiating

Pregnancy-Lactation

Pregnancy Data are not available regarding use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes There are risks to the mother and fetus associated with active Cushing syndrome during pregnancy Clinical considerations Active Cushing syndrome during pregnancy associated with increased risk of maternal and fetal morbidity and mortality (including gestational diabetes, gestational hypertension, preeclampsia, maternal death, miscarriage, fetal loss, preterm birth) Animal data No adverse developmental outcomes observed in reproduction studies in pregnant rats and rabbits when exposed during organogenesis at doses that produced maternal exposures of 7 and 0.5 times the 30-mg BID maximum clinical dose, by AUC In rabbits, exposures associated with maternal toxicity at 7 times the maximum clinical dose resulted in decreased fetal viability No adverse developmental outcomes were observed in a prenatal and postnatal development study with administration to pregnant rats from organogenesis through lactation at 8 times the 30-mg BID maximum clinical dose Lactation Data are not available regarding presence in human or animal milk, effects on breastfed infants, or effects on milk production Because of potential for serious adverse effects (eg, adrenal insufficiency), do not breastfeed during treatment and for at least 1 week after discontinuing drug

Interactions

Adverse Effects

Side effects of Osilodrostat : >10% Adrenal insufficiency (43.1%) Fatigue (38.7%) Nausea (37.2%) Headache (30.7%) Edema (21.2%) Nasopharyngitis (19.7%) Vomiting (19%) Arthralgia (17.5%) Back pain (15.3%) Rash (15.3%) Diarrhea (14.6%) Blood corticotrophin increased (13.9%) Dizziness (13.9%) Abdominal pain (13.1%) Hypokalemia (12.4%) Myalgia (12.4%) Decreased appetite (11.7%) Hormone level abnormal (11.7%) Hypotension (11.7%) Urinary tract infection (11.7%) Blood testosterone increased (10.9%) Pyrexia (10.9%) Anemia (10.2%) Cough (10.2%) Hypertension (10.2%) Influenza (10.2%) 1-10% Hirsutism (9.5%) Acne (8.8%) Dyspepsia (8%) Insomnia (8%) Anxiety (7.3%) Depression (7.3%) Gastroenteritis (7.3%) Malaise (6.6%) Tachycardia (6.6%) Alopecia (5.8%) Transaminases increased (4.4%) ECG QT prolongation (3.6%) Syncope (1.5%)

Mechanism of Action

Orally administered steroidogenesis inhibitor of 11-beta-hydroxylase, an enzyme that catalyzes the final step of cortisol synthesis in the adrenal cortex