ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Osilodrostat: Drug information

Osilodrostat: Drug information
(For additional information see "Osilodrostat: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Isturisa
Pharmacologic Category
  • Cortisol Synthesis Inhibitor
Dosing: Adult

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

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).

Dosing: Kidney Impairment: Adult

No dosage adjustment necessary. In patients with moderate to severe renal impairment, consider using methods other than urinary free cortisol levels to adjust dosage (Ref).

Dosing: Hepatic Impairment: Adult

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.

Dosing: Adjustment for Toxicity: Adult

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.

Dosing: Older Adult

Refer to adult dosing.

Adverse Reactions (Significant): Considerations
Adrenocortical insufficiency/hypocortisolism

Osilodrostat may cause adrenocortical insufficiency (Ref), resulting in symptoms of decreased cortisol (eg, abdominal pain, decreased appetite, dizziness, fatigue, nausea, vomiting, hypotension, hypoglycemia). Episodes may resolve with dose reduction, interruption of therapy, and/or corticosteroid treatment when clinically indicated (Ref).

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; most events have been reported during the dose titration period (ie, the first 12 weeks of therapy) (Ref); however, may occur at any time during treatment, and cortisol suppression may persist beyond the 4-hour half-life of osilodrostat.

Risk factors:

• Precipitating causes of decreased cortisol (eg, infection, physical stress)

Androgenic effects

Osilodrostat may cause altered hormone levels; specific alterations may include increased circulating androgen levels and increased testosterone levels, which may lead to acne vulgaris (in females), hirsutism, and hypertrichosis (Ref).

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.

Mineralocorticoid effects

Osilodrostat may cause increased circulating aldosterone precursor levels, resulting in hypokalemia, hypertension, and edema (Ref). Episodes of hypokalemia may require dose reduction, interruption of therapy, and/or treatment (eg, potassium supplements, spironolactone) (Ref).

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:

• Increasing osilodrostat Cmax (Ref)

• Preexisting hypokalemia

QT prolongation

Osilodrostat may cause dose-dependent prolonged QT interval on ECG, resulting in cardiac arrhythmias (Ref); maximum mean estimated QTcF increase of up to 5.3 msec with osilodrostat 30 mg.

Onset: Varied; QT prolongation was reported progressively over 12 weeks of therapy in one study (Ref).

Risk factors:

Drug-induced QT prolongation/torsades de pointes (TdP) (in general):

• Females (Ref)

• Age >65 years (Ref)

• Structural heart disease (eg, history of myocardial infarction or heart failure with reduced ejection fraction) (Ref)

• Genetic defects of cardiac ion channels (Ref)

• History of drug-induced TdP (Ref)

• Congenital long QT syndrome (Ref)

• Baseline QTc interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 msec (Ref); Note: Prescribing information for osilodrostat indicates >480 msec as a potential risk factor.

• Electrolyte disturbances (eg, hypocalcemia, hypokalemia, hypomagnesemia) (Ref)

• Bradycardia (Ref)

• Hepatic impairment (Ref)

• Kidney impairment (Ref)

• Loop diuretic use (Ref)

• Sepsis (Ref)

• Concurrent administration of multiple medications (≥2) that prolong the QT interval or drug interactions that increase serum drug concentrations of QT-prolonging medications (Ref)

Adverse Reactions

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%)

Postmarketing:

Dermatologic: Hypertrichosis (Pivonello 2020)

Nervous system: Asthenia (Detomas 2022)

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Isturisa: 1 mg, 5 mg, 10 mg [DSC]

Generic Equivalent Available: US

No

Pricing: US

Tablets (Isturisa Oral)

1 mg (per each): $198.76

5 mg (per each): $993.79

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Administration: Adult

Oral: May be administered with or without food.

Use: Labeled Indications

Cushing disease: Treatment of Cushing disease in adults for whom pituitary surgery is not an option or has not been curative.

Medication Safety Issues
Sound-alike/look-alike issues:

Osilodrostat may be confused with orlistat.

Metabolism/Transport Effects

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)

Drug Interactions

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

Fezolinetant: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Fezolinetant. Risk X: Avoid combination

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

Pregnancy Considerations

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]).

Breastfeeding Considerations

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.

Monitoring Parameters

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.

Mechanism of Action

Osilodrostat decreases cortisol synthesis via inhibition of 11beta-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.

Pharmacokinetics (Adult Data Unless Noted)

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%.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AT) Austria: Isturisa;
  • (AU) Australia: Isturisa;
  • (CH) Switzerland: Isturisa;
  • (CO) Colombia: Isturisa;
  • (CZ) Czech Republic: Isturisa;
  • (DE) Germany: Isturisa;
  • (ES) Spain: Isturisa;
  • (FI) Finland: Isturisa;
  • (FR) France: Isturisa;
  • (GB) United Kingdom: Isturisa;
  • (HU) Hungary: Isturisa;
  • (IE) Ireland: Isturisa;
  • (IT) Italy: Isturisa;
  • (JP) Japan: Isturisa;
  • (LT) Lithuania: Isturisa;
  • (LV) Latvia: Isturisa;
  • (NL) Netherlands: Isturisa;
  • (NO) Norway: Isturisa;
  • (PL) Poland: Isturisa;
  • (PR) Puerto Rico: Isturisa;
  • (RO) Romania: Isturisa;
  • (SE) Sweden: Isturisa
  1. Braun LT, Riester A, Oßwald-Kopp A, et al. Toward a diagnostic score in Cushing's syndrome. Front Endocrinol (Lausanne). 2019;10:766. doi:10.3389/fendo.2019.00766 [PubMed 31787931]
  2. Detomas M, Altieri B, Deutschbein T, Fassnacht M, Dischinger U. Metyrapone versus osilodrostat in the short-term therapy of endogenous Cushing's syndrome: results from a single center cohort study. Front Endocrinol (Lausanne). 2022;13:903545. doi:10.3389/fendo.2022.903545 [PubMed 35769081]
  3. Isturisa (osilodrostat) [prescribing information]. Lebanon, NJ: Recordati Rare Disease Inc; March 2020.
  4. Luger A, Broersen LHA, Biermasz NR, et al. ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy. Eur J Endocrinol. 2021;185(3):G1-G33. doi:10.1530/EJE-21-0462 [PubMed 34425558]
  5. Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;8(9):748-761. doi:10.1016/S2213-8587(20)30240-0 [PubMed 32730798]
  6. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013‐1022. doi:10.1056/NEJMra032426 [PubMed 14999113]
  7. Tabarin A, Haissaguerre M, Lassole H, et al. Efficacy and tolerance of osilodrostat in patients with Cushing's syndrome due to adrenocortical carcinomas. Eur J Endocrinol. 2022;186(2):K1-K4. doi:10.1530/EJE-21-1008 [PubMed 34905500]
  8. Tisdale JE, Chung MK, Campbell KB, et al. Drug-induced arrhythmias: a scientific statement from the American Heart Association. Circulation. 2020;142(15):e214-e233. doi:10.1161/CIR.0000000000000905 [PubMed 32929996]
  9. Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2013;6(4):479‐487. doi:10.1161/CIRCOUTCOMES.113.000152 [PubMed 23716032]
  10. Tisdale JE, Jaynes HA, Kingery JR, et al. Effectiveness of a clinical decision support system for reducing the risk of QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2014;7(3):381‐390. doi:10.1161/CIRCOUTCOMES.113.000651 [PubMed 24803473]
Topic 127397 Version 65.0

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟