Isturisa

Treatment should be initiated and supervised by physicians experienced in endocrinology or internal medicine and with access to the appropriate facilities for monitoring of biochemical responses since the dose must be adjusted to meet the patient’s therapeutic needs, based on the normalisation of cortisol levels.

3 Posology The recommended starting dose is 2 mg osilodrostat twice daily. 2). The dose can be gradually titrated (initially by dose increments of 1 or 2 mg) based on individual response and tolerability, with the aim to achieve normal cortisol levels.

g. 24-hour urinary free cortisol, serum/plasma cortisol) be monitored every 1-2 weeks until adequate clinical response is maintained. 5). 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.

4). Isturisa may be resumed after resolution of symptoms at a lower dose, provided that cortisol levels are above the lower limit of normal in the absence of glucocorticoid substitution. Management of other suspected adverse reactions at any time during treatment may also require a temporary dose reduction or temporary interruption of treatment.

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. If a dose is missed, the patient should take the prescribed dose at the next scheduled time; the next dose should not be doubled.

Special populations Elderly There is no evidence to suggest that dose adjustment is required in patients aged 65 years or above. However, data on the use of osilodrostat in this population are limited and Isturisa should therefore be used with caution in this age group.

2). Urinary free cortisol (UFC) levels should be interpreted with caution in patients with moderate to severe renal impairment, due to reduced UFC excretion. Alternative methods for cortisol monitoring should be considered in these patients.

Hepatic impairment No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh A). For patients with moderate hepatic impairment (Child-Pugh B), the recommended starting dose is 1 mg twice daily. 2). Data on use in patients with hepatic impairment is limited.

Summary of the safety profile A total of 210 patients with Cushing´s disease has been treated with osilodrostat in the pivotal Phase III studies. 4 Warnings and precaution), fatigue, oedema, vomiting, nausea, decreased appetite headache, dizziness, hypotension, arthralgia, myalgia, tachycardia and blood testosterone increased.

The safety profile of Isturisa was generally consistent across all types of Cushing’s syndrome studied in clinical trials. Tabulated list of adverse reactions Adverse reactions (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000).

8 Table 1 Adverse reactions System organ class Frequency category Preferred term* Endocrine disorders Very common Adrenal insufficiency Metabolism and nutrition disorders Very common Hypokalaemia, decreased appetite Nervous system disorders Very common Dizziness, headache Common Syncope Cardiac disorders Very common Tachycardia Vascular disorders Very common Hypotension Gastrointestinal disorders Very common Vomiting, nausea, diarrhoea, abdominal pain Skin and subcutaneous tissue disorders Very common Rash , hirsutism**, acne** Musculoskeletal and connective tissue disorders Very common Myalgia, arthralgia General disorders and administration site conditions Very common Fatigue, oedema Common Malaise Investigations Very common Blood testosterone increased**, blood corticotrophin increased Common Electrocardiogram QT prolonged, transaminases increased * Some terms denote grouped term of two or more MedDRA preferred terms that were considered clinically similar.

Hypocortisolism Inhibition of cortisol synthesis by osilodrostat has led to hypocortisolism-related events such as cortisol withdrawal syndrome (symptomatic decrease of cortisol levels, but still above the lower limit of the normal range) and adrenal insufficiency (cortisol levels below the normal range).

2), since hypocortisolism-related events can occur at any time during treatment and after treatment discontinuation. 5). It is recommended to use laboratory methods that do not exhibit significant cross-reactivity with cortisol precursors such as 11-deoxycortisol that may increase during osilodrostat treatment.

g. nausea, vomiting, fatigue, abdominal pain, loss of appetite and dizziness). Symptomatic patients should be monitored for hypotension, hyponatraemia, hyperkalaemia and/or hypoglycaemia. If hypocortisolism is suspected, cortisol levels should be measured and temporary dose reduction or interruption of osilodrostat considered.

After osilodrostat discontinuation, cortisol suppression may persist for months, irrespective of osilodrostat administered dose, and might require additional monitoring. If necessary, corticosteroid substitution should be initiated.

Isturisa may be resumed after resolution of symptoms at a lower dose, provided that cortisol levels are above the lower limit of normal in the absence of glucocorticoid substitution. 1). Adverse reactions of QT prolongation and clinically relevant ECG findings have been reported in clinical studies.

An electrocardiogram (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.

Temporary dose reduction or interruption may be required. Any hypokalaemia, hypocalcaemia or hypomagnesaemia should be corrected prior to Isturisa administration and electrolyte levels should be monitored periodically during therapy.

1.