4.1. Therapeutic indications

Isturisa is indicated for the treatment of endogenous Cushing's syndrome in adults.

4.2. Posology and method of administration

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.

Posology

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 (see section 5.2).

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. It is recommended that cortisol levels (e.g. 24-hour urinary free cortisol, serum/plasma cortisol) be monitored every 1-2 weeks until adequate clinical response is maintained. Thereafter, less frequent monitoring may be considered as clinically indicated, unless there are reasons for additional monitoring (see sections 4.4 and 4.5). 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.

The dose of osilodrostat should be decreased or treatment temporarily interrupted if cortisol levels are below the lower limit of normal, or if there is a rapid decrease in cortisol levels to the lower part of the normal range, or if the patient has signs or symptoms suggestive of hypocortisolism (see section 4.4). 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.

Renal impairment

No dose adjustment is required for patients with renal impairment (see section 5.2). 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. For patients with severe hepatic impairment (Child-Pugh C), the recommended starting dose is 1 mg once daily in the evening, with initial up-titration to 1 mg twice daily (see section 5.2).

Data on use in patients with hepatic impairment is limited. More frequent monitoring of adrenal function may be required in patients with hepatic impairment during dose titration.

Paediatric population

The safety and efficacy of Isturisa in patients less than 18 years of age have not yet been established. No data is available.

Method of administration

Oral use.

Isturisa can be taken with or without food.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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).

Cortisol levels should be monitored at regular intervals (see section 4.2), since hypocortisolism-related events can occur at any time during treatment and after treatment discontinuation. Additional monitoring is recommended especially during conditions of increased cortisol demand, such as physical or psychological stress, or during changes in concomitant medications that may affect osilodrostat exposure (see section 4.5). 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.

Patients should be alerted to the signs and symptoms associated with hypocortisolism (e.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.

QTc prolongation

In a thorough QT study, 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 (see section 5.1). 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.

Isturisa should be used with caution and the benefit-risk carefully weighed in patients with risk factors for QT prolongation such as:

- congenital long QT syndrome,

- significant cardiovascular disease (including congestive heart failure, recent myocardial infarction, unstable angina, sustained ventricular tachycardia, advanced heart block and clinically significant bradyarrhythmias), and

- concomitant medicinal products known to prolong the QT interval (see section 4.5).

If Isturisa is used in patients with these risk factors, more frequent -ECG- monitoring is recommended.

Corticotroph tumour growth

Discontinuation of osilodrostat treatment should be considered in patients who develop MRI-verified corticotroph tumour invasiveness during treatment.

Concomitant use with strong enzyme inhibitors and inducers

Caution and closer monitoring are advised when co-administered medicinal products that strongly inhibit or induce multiple enzymes are introduced or discontinued during osilodrostat treatment (see section 4.5), as they may affect osilodrostat exposure and may result in a risk of adverse events (due to a potential increase in exposure) or of decreased efficacy (due to a potential decrease in exposure).

Women of childbearing potential

Isturisa may cause foetal harm. Pregnancy status should be verified in women of childbearing potential prior to the initiation of Isturisa, and these patients should be advised of a potential risk to the foetus and of the need to use effective contraception during treatment and for at least one week after stopping treatment (see section 4.6).

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Potential pharmacodynamic interactions

Co-administration of osilodrostat with other therapies known to affect the QT interval can lead to QT prolongation in patients with known cardiac rhythm disorders (see sections 4.4 and 5.1). A washout period should be considered when switching from other products known to affect the QT interval such as pasireotide or ketoconazole.

Effects of other medicinal products on the pharmacokinetics of osilodrostat

The potential for clinical drug-drug interactions (DDI) with concomitantly administered medicinal products that inhibit transporters or a single CYP or UGT enzyme is low (see section 5.2).

Strong enzyme inhibitors

Caution is advised when co-administered medicinal products that strongly inhibit multiple enzymes are introduced or discontinued during osilodrostat treatment (see section 4.4).

Strong enzyme inducers

Caution is advised when co-administered medicinal products that strongly induce multiple enzymes (e.g. rifampin) are introduced or discontinued during osilodrostat treatment (see section 4.4).

Effects of osilodrostat on the pharmacokinetics of other medicinal products

Because osilodrostat and its major metabolite M34.5 may inhibit and/or induce multiple enzymes and transporters, general caution is advised when osilodrostat is co-administered with sensitive enzyme or transporter substrates with a narrow therapeutic index. Available interaction data is summarised below (see also section 5.2).

Clinical studies

In a healthy volunteer study (n=20) using a single dose of 50 mg osilodrostat and a probe drug cocktail, osilodrostat was found to be a mild inhibitor of CYP2D6 and CYP3A4/5, a mild to moderate inhibitor of CYP2C19, and a moderate inhibitor of CYP1A2.

- CYP2D6 – area under the curve (AUC) geometric mean ratio of 1.5 for dextromethorphan (CYP2D6 substrate) when dosed with osilodrostat compared to when dosed alone.

- CYP3A4 – AUC geometric mean ratio of 1.5 for midazolam (CYP3A4 substrate) when dosed with osilodrostat compared to when dosed alone.

- CYP2C19 –AUC geometric mean ratio of 1.9 for omeprazole (CYP2C19 substrate) when dosed with osilodrostat compared to when dosed alone. However, an in vitro signal of time-dependent inhibition has been observed, thus the consequence following repeated dosing is unclear. Osilodrostat should be used with caution when co-administered with sensitive CYP2C19 substrates with a narrow therapeutic index.

- CYP1A2 –AUC geometric mean ratio of 2.5 for caffeine (CYP1A2 substrate) when dosed with osilodrostat compared to when dosed alone. However, an in vitro signal of CYP1A2 induction has been observed, thus the consequence following repeated dosing is unclear. Osilodrostat should be used with caution when co-administered with sensitive CYP1A2 substrates with a narrow therapeutic index such as theophylline and tizanidine.

In a healthy volunteer study (n=24), osilodrostat (30 mg twice daily for 7 days before concomitant administration with a combined oral contraceptive containing 0.03 mg ethinyl oestradiol and 0.15 mg levonorgestrel and continued for another 5 days) did not have a clinically meaningful effect on the AUC and maximum serum concentration Cmax of ethinyl estradiol (geometric mean ratio: 1.03 and 0.88, respectively) and AUC of levonorgestrel (geometric mean ratio: 1.02). The Cmax of levonorgestrel fell slightly outside the bioequivalence acceptance range (geometric mean ratio: 0.86; 90% confidence interval : 0.737-1.00). The effects of a longer induction period and an interaction with other hormonal contraceptives have not been studied (see also sections 4.4 and 4.6).

In vitro data

In vitro data for osilodrostat and its major metabolite M34.5 suggest a potential for both inhibition and induction for CYP1A2, CYP2B6 and CYP3A4/5, a potential for time-dependent inhibition of CYP2C19, and an inhibitory potential for CYP2E1 and UGT1A1. It cannot be excluded that osilodrostat may affect the exposure of sensitive substrates for these enzymes.

In vitro data for osilodrostat and its major metabolite M34.5 suggest an inhibitory potential for OATP1B1, OCT1, OCT2, OAT1, OAT3 and MATE1. It cannot be excluded that osilodrostat may affect the exposure of sensitive substrates for these transporters.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Based on preclinical data, osilodrostat may cause foetal harm when administered to a pregnant woman. A pregnancy test before initiating treatment is recommended in women of childbearing potential. Women of childbearing potential have to use effective contraception during and for at least one week after treatment. If hormonal contraceptives other than the oral combination of ethinylestradiol and levonorgestrel are used, an additional barrier method of contraception is recommended (see section 4.5). Isturisa should not be used in women of childbearing potential not using contraception.

Pregnancy

There are no or limited amount of data from the use of osilodrostat in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Isturisa should not be used during pregnancy.

Breast-feeding

It is unknown whether osilodrostat / metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Isturisa and for at least one week after treatment.

Fertility

There is no information on the effect of osilodrostat on human fertility. Animal studies have shown effects on the menstrual cycle and reduced female fertility in rats (see section 5.3).

4.7. Effects on ability to drive and use machines

Isturisa has minor influence on the ability to drive and use machines. Patients should be warned about the potential for dizziness and fatigue (see section 4.8) and should be advised not to drive or use machines if these symptoms occur.

4.8. Undesirable effects

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.

The most frequent (incidence ≥10%) adverse reactions reported in the pivotal Phase III studies (C2301 and C2302) with Isturisa were adrenal insufficiency (see section 4.4 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).

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. The term “adrenal insufficiency” includes the terms “glucocorticoid deficiency”, “adrenocortical insufficiency acute”, “steroid withdrawal syndrome”, “urine free cortisol decreased”, “cortisol decreased”.

** Observed in female patients.

Description of selected adverse reactions

CYP11B1 inhibition by osilodrostat is associated with adrenal steroid precursor accumulation and testosterone increases. In a clinical study with osilodrostat, mean testosterone levels in female patients increased from high normal at baseline to above the upper limit of the normal range. The increases reversed when treatment was interrupted. The testosterone increase was associated with mild to moderate cases of hirsutism or acne in a subset of patients.

Adrenocorticotropic Hormone ACTH values above 10-fold upper limit of normal were observed in some Cushing's disease patients treated with osilodrostat in the clinical studies (see section 5.1) and may be associated with cortisol values below the lower limit of normal.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdosage may result in severe hypocortisolism. Signs and symptoms suggestive of hypocortisolism may include nausea, vomiting, fatigue, low blood pressure, abdominal pain, loss of appetite, dizziness and syncope.

In case of suspected overdosage, Isturisa should be interrupted, cortisol levels checked, and if necessary corticosteroid supplementation initiated. Close surveillance may be necessary including monitoring of the QT interval, blood pressure, glucose, fluid and electrolyte balance until the patient's condition is stable.