ISTURISA

What it is

Isturisa contains osilodrostat phosphate. The medicine is available in three strengths: 1 mg, 5 mg, and 10 mg film-coated tablets. Osilodrostat is a cortisol synthesis inhibitor that works by inhibiting 11β-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.

Approved indications

— Treatment of endogenous Cushing's syndrome in adults.

Dosing overview

The recommended starting dose is 2 mg osilodrostat twice daily. For patients of Asian ancestry, a reduced starting dose of 1 mg twice daily is recommended. The dose can be gradually titrated based on individual response and tolerability, with the aim to achieve normal cortisol levels. The usual maintenance dose in clinical studies varied between 2 and 7 mg twice daily. The maximum recommended dose of Isturisa is 30 mg twice daily. It is recommended that cortisol levels (for example 24-hour urinary free cortisol, serum/plasma cortisol) be monitored every 1–2 weeks until adequate clinical response is maintained. Increases in dose should not occur more frequently than once every 1–2 weeks and should be guided by the results of cortisol assessments and by the individual clinical response.

Key safety warnings

Patients should be monitored closely for hypocortisolism and potentially life-threatening adrenal insufficiency, as inhibition of cortisol synthesis by osilodrostat has led to hypocortisolism-related events such as cortisol withdrawal syndrome and adrenal insufficiency. Patients should be alerted to the signs and symptoms associated with hypocortisolism (for example nausea, vomiting, fatigue, abdominal pain, loss of appetite and dizziness). After osilodrostat discontinuation, cortisol suppression may persist for months or longer, and patients should be closely and regularly monitored after interruption or discontinuation; if necessary, corticosteroid substitution should be initiated. Osilodrostat was associated with a dose-dependent QT interval prolongation (mean maximum estimated QTcF increase by +5.3 ms at the highest recommended dose of 30 mg) which may cause cardiac arrhythmias. An ECG should be performed prior to the start of Isturisa treatment, within one week after treatment initiation, and as clinically indicated thereafter; if the QTc interval exceeds 480 ms prior to or during treatment, cardiology consultation is recommended. Osilodrostat blocks cortisol synthesis and may increase circulating levels of adrenal hormone precursors and testosterone; hypokalaemia should be corrected prior to initiating osilodrostat, and patients should be monitored for hypokalaemia, worsening of hypertension and oedema. Increases in testosterone may lead to hirsutism and acne in females.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in the product information.

PBS listing

Isturisa 5 mg and 1 mg film-coated tablets are listed on the PBS with two items each, both requiring authority approval, with ex-manufacturer prices of A$9660.00 and A$2400.00 respectively.

Regulatory history

The TGA approved Isturisa for the treatment of endogenous Cushing's syndrome in adults, with the decision made on 6 May 2022 and entry onto the ARTG on 12 May 2022. Isturisa is subject to additional monitoring in Australia, which will allow quick identification of new safety information; healthcare professionals are asked to report any suspected adverse events via the TGA reporting system. The PBAC did not recommend Isturisa in March 2023 and March 2024, but recommended it in September 2024 for the treatment of endogenous Cushing's syndrome.