Osilodrostat

Osilodrostat is a prescription medication used for the treatment of Cushing’s disease in adults for whom pituitary surgery is not an option or has not been curative.

• Osilodrostat is available under the following different brand names: Isturisa

Common side effects of Osilodrostat include:

• adrenal insufficiency
• fatigue
• nausea
• headache
• fluid retention (edema)
• runny or stuffy nose
• vomiting
• joint pain
• back pain
• rash
• diarrhea
• blood corticotrophin increased
• dizziness
• abdominal pain
• low blood potassium (hypokalemia)
• muscle pain
• decreased appetite
• abnormal hormone levels
• low blood pressure (hypotension)
• urinary tract infection (UTI)
• blood testosterone increased
• fever
• anemia
• cough
• high blood pressure (hypertension)
• influenza

Serious side effects of Osilodrostat include:

• nausea
• stomach (abdominal) pain
• vomiting
• loss of appetite
• tiredness (fatigue)
• dizziness
• low blood pressure

Rare side effects of Osilodrostat include:

• none

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors;
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Tablet

• 1 mg
• 5 mg
• 10 mg

Cushing’s disease

Adult dosage

• Initial: 2 mg orally two times a day
• Titration
  • Initially, titrate by 1–2 mg two times a day, no more frequently than every 2 weeks based on the rate of cortisol changes, individual tolerability, and improvement in Cushing’s disease signs and symptoms
  • If the patient tolerates 10 mg orally two times a day and continues to have elevated 24-hour urine-free cortisol levels more ULN, titrate dosage further by 5 mg two times a day every 2 weeks
  • Monitor cortisol levels from at least two 24-hour UFC collections every 1–2 weeks until an adequate clinical response is maintained
• Maintenance
  • Individualize maintenance dose according to cortisol levels and signs/symptoms
  • Maintenance dosage varied from 2–7 mg two times a day in clinical trials
  • Maximum recommended maintenance dose: 30 mg two times a day
  • Once the maintenance dose is achieved, monitor cortisol levels at least every 1–2 months or as indicated

Dosage Considerations – Should be Given as Follows:

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, healthcare provider, or pharmacist first.

• Osilodrostat has severe interactions with the following drug:
  • lefamulin
• Osilodrostat has serious interactions with the following drugs:
  • abametapir
  • adagrasib
  • amisulpride
  • buprenorphine buccal
  • buprenorphine subdermal implant
  • buprenorphine transdermal
  • buprenorphine, long-acting injection
  • carbamazepine
  • ceritinib
  • dofetilide
  • fexinidazole
  • fosphenytoin
  • grapefruit
  • mobocertinib
  • primidone
  • ribociclib
  • tucatinib
• Osilodrostat has moderate interactions with at least 194 other drugs
• Osilodrostat has minor interactions with the following drugs:
  • acetazolamide
  • anastrozole
  • cyclophosphamide
  • larotrectinib

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• None

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Osilodrostat?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Osilodrostat?”

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, and 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-hour UFC, serum or plasma cortisol, and signs/symptoms
  • Decrease or temporarily discontinue osilodrostat if UFC levels fall below the 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 the target range and patients have symptoms of adrenal insufficiency
  • Reinitiate at a lower dose when urine-free, serum or plasma cortisol levels are within the target range, and/or patient symptoms have resolved
  • After discontinuation, cortisol suppression may persist beyond the 4 hours 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 the QTc interval is above 480 ms
  • Caution with risk factors for QT prolongation, (e.g., congenital long QT syndrome, CHF, bradyarrhythmias, uncorrected electrolyte abnormalities, and 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 women)
• Drug interaction overview
  • Strong CYP3A4 inhibitors
    • Osilodrostat is a substrate of CYP3A4 substrate (major)
    • Reduce the 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
    • Exercise 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

Pregnancy and Lactation

• 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’s syndrome during pregnancy
• Clinical considerations
  • Active Cushing’s syndrome during pregnancy is associated with an increased risk of maternal and fetal morbidity and mortality (including gestational diabetes, gestational hypertension, preeclampsia, maternal death, miscarriage, fetal loss, and preterm birth)
• Lactation
  • Data are not available regarding the presence of human or animal milk, its effects on breastfed infants, or on milk production
  • Because of the potential for serious adverse effects (e.g., adrenal insufficiency), do not breastfeed during treatment and for at least 1 week after discontinuing the drug