osilodrostat (Rx)

Brand and Other Names:Isturisa
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 1mg
  • 5mg
  • 10mg

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 maintenance dose achieved, monitor cortisol levels at least every 1-2 months or as indicated

Dosage Modifications

Interruptions or modifications

  • Decrease or temporarily discontinue if UFC levels fall below target range, there is a rapid decrease in cortisol levels, and/or symptoms of hypocortisolism occur; if necessary, initiate glucocorticoid
  • Stop osilodrostat and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency
  • If treatment is interrupted, reinitiate at lower dose when cortisol levels are within target ranges and symptoms have resolved

Renal impairment

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

Hepatic impairment

  • Mild (Child-Pugh A): No dose adjustment required
  • Moderate (Child-Pugh B): Reduce initial dose to 1 mg BID
  • Severe (Child-Pugh C): Reduce initial dose to 1 mg qHS
  • May require more frequent adrenal function monitoring during dose titration in all patients with hepatic impairment

Dosing Considerations

Correct hypokalemia and hypomagnesemia before initiating

Obtain baseline ECG; repeat ECG within 1 week after treatment initiation, and as clinically indicated thereafter

Safety and efficacy not established

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Interactions

Interaction Checker

and osilodrostat

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            Adverse Effects

            >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%)

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            Warnings

            Contraindications

            None

            Cautions

            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
            • Decrease or temporarily discontinue osilodrostat if UFC levels fall below target range, there is a rapid decrease in cortisol levels, and/or symptoms of hypocortisolism occur
            • Stop osilodrostat and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency
            • Reinitiate at lower dose when urine free, serum, or plasma cortisol levels are within target range, and/or patient symptoms have resolved
            • After discontinuation, cortisol suppression may persist beyond the 4 hr drug half-life

            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
            • Caution with risk factors for QT prolongation, (eg, congenital long QT syndrome, CHF, bradyarrhythmias, uncorrected electrolyte abnormalities, other drugs known to prolong QT) and consider more frequent ECG monitoring

            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
            • Monitor for hypokalemia, worsening hypertension, and edema
            • Treat osilodrostat-induced hypokalemia with IV or oral potassium supplementation based on event severity; if hypokalemia persists despite potassium supplementation, consider adding mineralocorticoid antagonists; osilodrostat dose reduction or discontinuation may be necessary
            • Accumulation of androgens may lead to hirsutism, hypertrichosis, and acne (in females)

            Drug interaction overview

            • Strong CYP3A4 inhibitors
              • Osilodrostat is a substrate of CYP3A4 substrate (major)
              • Reduce osilodrostat dose by 50% if coadministered with strong CYP3A4 inhibitors
            • Strong CYP3A4 and/or CYP2B6 inducers
              • Osilodrostat is a substrate of CYP3A4 (major) and CYP2B6 (moderate)
              • Coadministration with strong CYP3A4 and/or CYP2B6 inducers may decrease osilodrostat concentration and reduce efficacy
              • Discontinuation of strong CYP3A4 and/or CYP2B6 inducers while using osilodrostat may increase osilodrostat concentration and the related adverse effects
            • CYP1A2 and CYP2C19 substrates
              • Osilodrostat showed inhibition potential on CYP1A2 and CYP2C19 in clinical studies
              • Caution if coadministered with CYP1A2 or CYP2C19 substrates with a narrow therapeutic index
            • QTc prolonging drugs
              • Osilodrostat is associated with dose-dependent QT interval prolongation
              • Caution if coadministered with other drugs known to prolong QT interval
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            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

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            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

            Absorption

            Peak plasma time: 1 hr

            Distribution

            Protein bound: 36.4%

            Vd: 100 L

            Metabolism

            Multiple CYP enzymes (ie, CYP3A4, CYP2B6, CYP2D6) and UDP-glucuronosyltransferases contribute to metabolism

            No single enzyme contributes >25% to total clearance

            Metabolites are not expected to contribute to the pharmacological effect

            Elimination

            Half-life: 4 hr

            Excretion: 90.6% urine (5.2% as unchanged); 1.58% feces

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            Administration

            Oral Administration

            May take with or without food

            Missed dose: Take next dose at the regularly scheduled time

            Storage

            Store at room temperature of 68-77ºF (20-25ºC); excursions permitted to 15-30ºC (59-86ºF)

            Protect from moisture

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.