Isturisa

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 
 

Isturisa 1 mg film-coated tablets 

Isturisa 5 mg film-coated tablets 

Isturisa 10 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

Isturisa 1 mg film-coated tablets 

 

Each film-coated tablet contains osilodrostat phosphate corresponding to 1 mg osilodrostat. 

 

Isturisa 5 mg film-coated tablets 

 

Each film-coated tablet contains osilodrostat phosphate corresponding to 5 mg osilodrostat. 

 

Isturisa 10 mg film-coated tablets 

 

Each film-coated tablet contains osilodrostat phosphate corresponding to 10 mg osilodrostat. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Film-coated tablet (tablet). 

 

Isturisa 1 mg film-coated tablets 

 

Pale yellow, round, biconvex bevelled-edge tablets, marked “Y1” on one side and “NVR” on the other 

side. Approximate diameter 6.1 mm. 

 

Isturisa 5 mg film-coated tablets 

 

Yellow, round, biconvex bevelled-edge tablets, marked “Y2” on one side and “NVR” on the other 

side. Approximate diameter 7.1 mm. 

 

Isturisa 10 mg film-coated tablets 

 

Pale orange brown, round, biconvex bevelled-edge tablets, marked “Y3” on one side and “NVR” on 

the other side. Approximate diameter 9.1 mm. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

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

 



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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. 

 

Elderly (65 years or above) 

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. 



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No data are 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. 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. 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 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 



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- 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). 

 

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 – AUC geometric mean ratio of 1.5 for dextromethorphan (CYP2D6 substrate) when 

dosed with osilodrostat compared to when dosed alone. 



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- 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 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). 

 

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 and in women of childbearing potential not using contraception. 

 

Breast-feeding 

 

It is unknown whether osilodrostat or its 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. 

 



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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 may have a 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 

 

The most frequent adverse reactions reported in the pivotal phase III study with osilodrostat were 

adrenal insufficiency (51%), fatigue (44%), oedema (21%), vomiting (22%), nausea (42%) and 

headache (34%). 

 

The most serious adverse reaction associated with the use of osilodrostat is adrenal insufficiency (see 

also sections 4.2 and 4.4). 

 



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Tabulated list of adverse reactions 

 

Adverse drug reactions (Table 1) are listed by MedDRA system organ class. Within each system organ 

class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. 

Within each frequency grouping, adverse drug reactions are presented in order of decreasing 

seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based 

on the following convention (CIOMS III): 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 drug 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 Common Tachycardia 

Vascular disorders Very common Hypotension 

Gastrointestinal disorders  Very common Vomiting, nausea, diarrhoea, abdominal 

pain 

Skin and subcutaneous tissue disorders Very common Rash 

Common Hirsutism**, acne** 

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. 

** Frequency “very common” 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. 

 

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 

listed in Appendix V. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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. 

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group: Anticorticosteroids, ATC code: H02CA02 

 

Mechanism of action 

 

Osilodrostat is a cortisol synthesis inhibitor. It potently inhibits 11β-hydroxylase (CYP11B1), the 

enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland. 

 

CYP11B1 inhibition is associated with the accumulation of precursors such as 11-deoxycortisol and 

acceleration of adrenal biosynthesis including androgens. In Cushing’s disease, the fall in plasma 

cortisol concentration also stimulates ACTH secretion, via the feedback mechanism which accelerates 

steroid biosynthesis (see section 4.8). 

 

Pharmacodynamic effects 

 

In a thorough QT study (n=86 male and female healthy volunteers) with osilodrostat, the maximum 

QTcF interval duration differences to placebo were 1.73 ms (90% CI: 0.15, 3.31) at the 10 mg dose 

and 25.38 ms (90% CI: 23.53, 27.22) at a supratherapeutic dose of 150 mg. Based on an interpolation 

of these results, the mean maximum prolongation at the highest recommended dose of 30 mg is 

estimated to be +5.3 ms. 

 

Clinical efficacy and safety 

 

The efficacy and safety of osilodrostat in patients with Cushing’s disease were evaluated in a 

prospective phase III study (study C2301) that used a randomised withdrawal design. The study 

consisted of a 26-week open-label period of single-arm osilodrostat treatment, followed by an 8-week 

randomised withdrawal period in which patients were randomised in 1:1 ratio to either osilodrostat or 

placebo and a subsequent osilodrostat open-label period. 

 

The eligibility criteria included Cushing’s disease (with confirmation of the pituitary source of excess 

adrenocorticotrophic hormone), and a mean urinary free cortisol (mUFC, derived from three 24-hour 

urine collections) value greater than 1.5 times the upper limit of normal (ULN) at screening. 

 

A total of 137 adult patients were enrolled. The mean age was 41.2 years, and the majority of patients 

were female (77%). Seven patients were aged 65 years or older. Prior therapy included pituitary 

surgery in 88% of patients and prior medical therapy in 75% of patients. The mean and median 

baseline mUFC levels were 1006.0 nmol/24 h and 476.4 nmol/24 h, respectively 

(ULN: 138 nmol/24 h). Co-morbidities at baseline included hypertension (67.9% of patients), obesity 

(29.9%), diabetes mellitus (21.9%) and osteoporosis (27.7%). 

 

Patients received a starting dose of 2 mg osilodrostat twice daily and the dose could be up-titrated 

based on individual response and tolerability during an initial 12-week period. Patients with no further 



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dose increases during the following 12 weeks and with a mUFC ≤ULN at week 24 were randomised in 

a 1:1 ratio at week 26 to receive either osilodrostat or matching placebo for 8 weeks (double-blind 

randomised withdrawal period), followed by open-label osilodrostat for the remainder of the study. At 

week 26, 71 patients were randomised in a 1:1 ratio to continue receiving osilodrostat (n=36) or to 

switch to placebo (n=35). Patients who were not eligible for randomisation at week 24 (n=47) 

continued on open-label osilodrostat treatment. 

 

The primary objective was to compare the proportion of complete responders at week 34 (the end of 

the 8-week randomised withdrawal period) between patients randomised to continued active treatment 

and placebo. For the primary endpoint, a complete response was defined as a mUFC value ≤ULN at 

week 34. Patients whose dose was increased during the randomised withdrawal period or who 

discontinued randomised treatment were considered non-responders. The key secondary endpoint was 

the complete response rate at week 24. Patients with dose increases between weeks 12 and 24 and 

patients with no valid mUFC assessment at week 24 were counted as non-responders for the key 

secondary endpoint. 

 

The study met its primary and key secondary endpoints (Table 2). 

 

Median mUFC levels decreased to 62.5 nmol/24 h (-84.1% change from baseline, n=125) at week 12, 

to 75.5 nmol/24 h (-82.3%, n=125) at week 24 and to 63.3 nmol/24 h (-87.9%, n=108) at week 48. 

 

Table 2 Key results: Phase III study in Cushing’s disease patients (study C2301) 
 

 

Osilodrostat 

n=36 

Placebo 

n=34 

 

Primary endpoint: Proportion of 

responders at the end of the 

randomised withdrawal period 

(week 34) n (%) (95% CI) 

31 (86.1) 

(70.5, 95.3) 

10 (29.4) 

(15.1, 47.5) 

 

Response rate difference (odds 

ratio): osilodrostat vs. placebo 

13.7 (3.7, 53.4) 

2-sided p value <0.001 
 

Secondary endpoints 

All patients 

N=137 

Key secondary endpoint: Proportion with mUFC ≤ULN at week 24 and 

no dose increase after week 12 (95% CI) 

72 (52.6%) 

(43.9, 61.1) 

Complete mUFC response rate (mUFC ≤ULN) at week 48 91 (66.4%) 

(57.9, 74.3) 

Median mUFC value and percentage change at week 48 63.3 nmol/24 h (-87.9%) 

mUFC: mean urinary free cortisol; ULN: upper limit of normal; CI: confidence interval; response: 

mUFC ≤ULN. 

 

Improvements were observed in cardiovascular and metabolic parameters (Table 3) and 85.6% of 

patients with available assessments showed an improvement in at least one physical feature of 

Cushing’s disease at week 48. 

 

Table 3 Cardiovascular and metabolic parameters 
 

 Baseline Week 24 Week 48 

Systolic blood pressure (mmHg) 132.2 124.9 (-4.1%) 121.7 (-6.8%) 

Diastolic blood pressure (mmHg) 85.3 81.0 (-3.8%) 78.9 (-6.6%) 

Body weight (kg) 80.8 77.3 (-3.0%) 75.5 (-4.6%) 

Waist circumference (cm) 103.4 99.1 (-2.6%) 97.4 (-4.2%) 

HbA1c (%) 6.0 5.6 (-4.6%) 5.6 (-5.4%) 

 

Osilodrostat treatment also resulted in an improvement in patient-reported outcomes. Improvements 

from baseline above the established minimal important difference (MID) were observed for Cushing’s 



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QoL (total score, Physical Problems subscale and Psychosocial Issues subscale), EQ-5D Utility index 

and BDI-II (depression) scores. The mean Cushing QoL total score improved from 42.2 at baseline to 

58.3 (+14.1; +52.4% change from baseline) at week 48. 

 

The efficacy of osilodrostat was also assessed in study C1201 in nine adult Japanese patients with 

non-pituitary causes of Cushing’s syndrome. The study enrolled patients with adrenal adenoma (n=5), 

ectopic corticotropin syndrome (n=3) and ACTH-independent macronodular adrenal hyperplasia 

(n=1), and consisted of a 12-week dose titration period (starting dose 2 mg twice daily), a 36-week 

maintenance period and an optional long-term extension. At week 12 (primary endpoint) a complete 

response (mUFC ≤ULN) was observed in 6 patients (66.7%) and a partial response (mUFC decrease 

by at least 50%) in one additional patient (11.1%). The median average dose used in the study was 

2.6 mg/day (range 1.3-7.5 mg/day). The mean duration of treatment in this study was 24 weeks, and 

long-term exposure was limited. 

 

Paediatric population 

 

The European Medicines Agency has deferred the obligation to submit the results of studies with 

Isturisa in one or more subsets of the paediatric population in adrenal cortical hyperfunction (see 

section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 
 

Absorption 

 

Osilodrostat is a highly soluble, highly permeable compound (BCS class 1). It is rapidly absorbed (tmax 

~1 h) and oral absorption in humans is assumed to be nearly complete. Steady state is reached by 

day 2. 

 

Co-administration with food did not affect absorption to a clinically significant extent. In a healthy 

volunteer study (n=20), the administration of a single dose of 30 mg osilodrostat with a high-fat meal 

resulted in a modest reduction of AUC and Cmax by 11% and 21%, respectively, and the median tmax 

was delayed from 1 to 2.5 hours. 

 

No clinically relevant accumulation was observed in clinical studies. An accumulation ratio of 1.3 was 

estimated for the 2 to 30 mg dose range. 

 

Distribution 

 

The median apparent volume of distribution (Vz/F) of osilodrostat is approximately 100 litres. Protein 

binding of osilodrostat and of its major metabolite M34.5 is low (less than 40%) and 

concentration-independent. The osilodrostat blood-to-plasma concentration ratio is 0.85. 

 

Osilodrostat is not a substrate for OATP1B1 or OATP1B3 transporters. 

 

Biotransformation 

 

In a human ADME study in healthy subjects following the administration of a single dose of 50 mg 

[14C]-osilodrostat, metabolism was deemed the most important clearance pathway for osilodrostat 

since ~80% of the dose was excreted as metabolites. The three main metabolites in plasma (M34.5, 

M16.5 and M24.9) represented 51%, 9% and 7% of the dose, respectively. Both M34.5 and M24.9 

have longer half-lives than osilodrostat and some accumulation is expected with twice-daily dosing. 

The decrease in the contribution of osilodrostat to the radioactivity AUC with time post-dose was 

found to coincide closely with a corresponding increase in the contribution of M34.5. 

 

Thirteen metabolites were characterised in the urine, with the three main metabolites being M16.5, 

M22 (an M34.5 glucuronide) and M24.9, with 17, 13 and 11% of the dose, respectively. The 

formation of the major urinary metabolite M16.5 (direct N-glucuronide) was catalysed by UGT1A4, 



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2B7 and 2B10. Less than 1% of the dose was excreted as M34.5 (di-oxygenated osilodrostat) in the 

urine but 13% of the dose was identified as M22 (M34.5-glucuronide). The formation of M34.5 was 

non-CYP-mediated. 

 

Multiple CYP enzymes and UDP glucuronosyltransferases contribute to osilodrostat metabolism and 

no single enzyme contributes more than 25% to the total clearance. The main CYP enzymes involved 

in osilodrostat metabolism are CYP3A4, 2B6 and 2D6. Total CYP contribution is 26%, total UGT 

contribution is 19% and non-CYP non-UGT mediated metabolism was shown to contribute to ~50% 

of total clearance. In addition, osilodrostat showed a high intrinsic permeability, low efflux ratio and 

modest impact of inhibitors on the efflux ratio in vitro. This suggests that 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. 

 

In vitro data indicate that the metabolites do not contribute to the pharmacological effect of 

osilodrostat. 

 

Elimination 

 

The elimination half-life of osilodrostat is approximately 4 hours. 

 

In an ADME study, the majority (91%) of the radioactive dose of osilodrostat was eliminated in the 

urine, with only a minor amount eliminated in the faeces (1.6% of dose). The low percentage of the 

dose eliminated in the urine as unchanged osilodrostat (5.2%) indicates that metabolism is the major 

clearance pathway in humans. 

 

Linearity/non-linearity 

 

Exposure (AUCinf and Cmax) increased more than dose-proportionally over the therapeutic dose range. 

 

Drug-drug interactions (see also section 4.5) 

 

In vitro data indicate that neither osilodrostat nor its major metabolite M34.5 inhibits the following 

enzymes and transporters at clinically relevant concentrations: CYP2A6, CYP2C8, CYP2C9, 

UGT2B7, P-gp, BCRP, BSEP, MRP2, OATP1B3 and MATE2-K. Since the exposure of M34.5 has 

not yet been determined after repeated dosing, the clinical relevance of the in vitro drug-drug 

interaction results for M34.5 is unknown. 

 

Special populations 

 

Hepatic impairment 

In a phase I study in 33 subjects with varying degrees of hepatic function using a single dose of 30 mg 

osilodrostat, AUCinf was 1.4- and 2.7-fold higher in the moderate (Child-Pugh B) and severe 

(Child-Pugh C) hepatic impairment cohorts, respectively. Cmax was 15 and 20% lower in the moderate 

and severe cohorts. The terminal half-life increased to 9.3 hours and 19.5 hours in the moderate and 

severe cohorts. Mild hepatic impairment (Child-Pugh A) did not influence exposure to any significant 

extent. The absorption rate was not affected by the degree of hepatic impairment. 

 

Renal impairment 

In a phase I study in 15 subjects with varying degrees of renal function using a single dose of 30 mg 

osilodrostat, comparable systemic exposure was seen in subjects with severe renal impairment, 

end-stage renal disease and normal renal function. 

 

Race/ethnicity and bodyweight 

The relative bioavailability was approximately 20% higher in Asian patients compared to other 

ethnicities. Body weight was not shown to be a major determinant of this difference. 

 



13 

Age and gender 

Age and gender had no significant impact on osilodrostat exposure in adults. The number of elderly 

patients in clinical studies was limited (see section 4.2). 

 

5.3 Preclinical safety data 
 

Repeat dose toxicity 

 

In repeat dose toxicity studies conducted in mice, rats and dogs, the central nervous system, liver, 

female reproductive organs, and the adrenal gland were the primary target organs. The NOAEL for 

hepatic, reproductive organ and adrenal effects in long-term (26- and 39-week) studies was at least 

four-fold human clinical exposure based on AUC. CNS findings (aggression, hypersensitivity to touch 

and increased or decreased activity) were noted in the rat, mouse and dog. The NOAEL for the CNS 

effects was approximately 2-fold human free Cmax based on the most sensitive species. 

 

Carcinogenicity and mutagenicity 

 

Genotoxicity assays conducted in vitro in bacterial systems and in vitro and in vivo in mammalian 

systems with and without metabolic activation do not indicate a relevant risk in humans. In rat and 

mice carcinogenicity studies, an increased incidence of hepatocellular adenoma/carcinoma (at lower 

doses in males than females), and neoplastic changes of thyroid follicular adenoma/carcinoma (in male 

rats only) were observed. The findings are likely rodent specific and considered not relevant to 

humans. 

 

Fertility and reproductive toxicity 

 

Reproductive studies in rabbits and rats demonstrated embryotoxicity, foetotoxicity (increased 

resorptions and decreased foetal viability, decreased foetal weights, external malformations, and 

visceral and skeletal variations) and teratogenicity at maternally toxic doses. The NOAEL was 10-fold 

human exposure (AUC) in a pre- and postnatal developmental study, and 8- to 73-fold human 

exposure (AUC) in a rat fertility and early embryonic development study. The maternal and foetal 

NOAEL in the rabbit embryofoetal development study was 0.6-fold human exposure (AUC). 

 

Juvenile toxicity 

 

The findings in juvenile rat toxicity studies were largely consistent with those observed in adult rat 

studies. Delayed sexual maturation was noted at high doses with no effects on overall reproductive 

performance or parameters after a 6-week recovery period. There were no effects on long bone growth 

or behavioural performance. 

 

 

6. PHARMACEUTICAL PARTICULARS 
 

6.1 List of excipients 
 

Tablet core 

 

Cellulose, microcrystalline 

Mannitol 

Croscarmellose sodium 

Magnesium stearate 

Silica, colloidal anhydrous 

 



14 

Film coat 

 

Hypromellose 

Titanium dioxide (E171) 

Macrogol 

Talc 

 

1 mg tablet 

Iron oxide yellow (E172) 

Iron oxide red (E172) 

 

5 mg tablet 

Iron oxide yellow (E172) 

 

10 mg tablet 

Iron oxide yellow (E172) 

Iron oxide red (E172) 

Iron oxide black (E172) 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

3 years. 

 

6.4 Special precautions for storage 
 

Do not store above 25°C. Store in the original package in order to protect from moisture. 

 

6.5 Nature and contents of container 
 

Alu/Alu blister of 10 tablets. 

Packs containing 60 tablets (6 blisters of 10 tablets). 

 

6.6 Special precautions for disposal 
 

No special requirements. 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Recordati Rare Diseases 

Immeuble Le Wilson 

70 avenue du Général de Gaulle 

92800 Puteaux 

France 

 

 

 



15 

8. MARKETING AUTHORISATION NUMBER(S) 
 

Isturisa 1 mg film-coated tablets 

 

EU/1/19/1407/001 

 

Isturisa 5 mg film-coated tablets 

 

EU/1/19/1407/002 

 

Isturisa 10 mg film-coated tablets 

 

EU/1/19/1407/003 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

09 January 2020 

 

 

10. DATE OF REVISION OF THE TEXT 
 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

 

  

http://www.ema.europa.eu/


16 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 



17 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturer(s) responsible for batch release 

 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

Recordati Rare Diseases 

Immeuble Le Wilson 

70 avenue du Général de Gaulle 

92800 Puteaux 

France 

 

Recordati Rare Diseases 

Eco River Parc 

30 rue des Peupliers 

92000 Nanterre 

France 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic safety update reports (PSURs) 

 

The requirements for submission of PSURs for this medicinal product are set out in the list of 

Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 

and any subsequent updates published on the European medicines web-portal. 

 

The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 

6 months following authorisation. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk management plan (RMP) 

 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 

activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 

marketing authorisation and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 



18 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



19 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 
  



20 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Isturisa 1 mg film-coated tablets 

osilodrostat 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 1 mg osilodrostat (as phosphate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

60 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25°C. Store in the original package in order to protect from moisture. 

 

 



21 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 

Immeuble Le Wilson 

70 avenue du Général de Gaulle 

92800 Puteaux 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/19/1407/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Isturisa 1 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

  



22 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Isturisa 1 mg tablets 

osilodrostat 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



23 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Isturisa 5 mg film-coated tablets 

osilodrostat 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 5 mg osilodrostat (as phosphate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

60 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25°C. Store in the original package in order to protect from moisture. 

 

 



24 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 

Immeuble Le Wilson 

70 avenue du Général de Gaulle 

92800 Puteaux 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/19/1407/002 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Isturisa 5 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

  



25 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Isturisa 5 mg tablets 

osilodrostat 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



26 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Isturisa 10 mg film-coated tablets 

osilodrostat 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 10 mg osilodrostat (as phosphate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

60 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 25°C. Store in the original package in order to protect from moisture. 

 

 



27 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 

Immeuble Le Wilson 

70 avenue du Général de Gaulle 

92800 Puteaux 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/19/1407/003 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Isturisa 10 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

  



28 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Isturisa 10 mg tablets 

osilodrostat 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Recordati Rare Diseases 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



29 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



30 

Package leaflet: Information for the patient 
 

Isturisa 1 mg film-coated tablets 

Isturisa 5 mg film-coated tablets 

Isturisa 10 mg film-coated tablets 
osilodrostat 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 

- If you have any further questions, ask your doctor or pharmacist. 

- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 
1. What Isturisa is and what it is used for 

2. What you need to know before you take Isturisa 

3. How to take Isturisa 

4. Possible side effects 

5. How to store Isturisa 

6. Contents of the pack and other information 

 

 

1. What Isturisa is and what it is used for 
 

What Isturisa is 
Isturisa is a medicine that contains the active substance osilodrostat. 

 

What Isturisa is used for 
Isturisa is used in adults to treat endogenous Cushing’s syndrome, a condition in which the body 

produces too much of a hormone called cortisol. Too much cortisol may lead to a variety of symptoms 

such as weight gain (particularly around the waist), a moon-shaped face, bruising easily, irregular 

periods, excessive body and facial hair, and generally feeling weak, tired or unwell. 

 

How Isturisa works 
Isturisa blocks the main enzyme that makes cortisol in the adrenal glands. The effect of this is to 

decrease the over-production of cortisol and improve the symptoms of endogenous Cushing’s 

syndrome. 

 

 

2. What you need to know before you take Isturisa 
 

Do not take Isturisa: 
- if you are allergic to osilodrostat or any of the other ingredients of this medicine (listed in 

section 6). 

 

Warnings and precautions 
Talk to your doctor or pharmacist before taking Isturisa. 

 

If any of the following apply to you, tell your doctor before taking Isturisa: 

- if you have a heart disorder or a heart rhythm disorder, such as an irregular heartbeat, including 



31 

a condition called prolonged QT syndrome (QT interval prolongation). 

- if you have a liver disease; your doctor may need to change your dose of Isturisa. 

 

Contact your doctor immediately if you have two or more of these symptoms during your treatment 

with Isturisa. This may indicate that you have adrenal insufficiency (low cortisol levels): 

- weakness 

- light-headedness 

- tiredness 

- lack of appetite 

- nausea (feeling sick) 

- vomiting 

 

Tests before and during treatment 
Your doctor will test your blood and/or urine before you start treatment and regularly during 

treatment. This is to detect any possible abnormalities in your magnesium, calcium and potassium 

levels and also to measure the levels of cortisol. Depending on the results, your doctor may change 

your dose. 

 

This medicine may have an unwanted effect (called QT prolongation) on the function of the heart. 

Your doctor will therefore also check for this effect by performing an electrocardiogram (ECG) before 

you start treatment and during treatment. 

 

If your Cushing’s syndrome is caused by a benign tumour (called adenoma) in the pituitary gland, 

your doctor may consider stopping your treatment if a pituitary scan shows that the adenoma has 

expanded into neighbouring regions. 

 

Children and adolescents 
This medicine is not recommended for patients aged under 18 years. This is because there is a lack of 

data in these patients. 

 

Other medicines and Isturisa 
Tell your doctor if you are taking, have recently taken or might take any other medicines. It is 

particularly important that you mention any of the following medicines: 

- medicines that may have an unwanted effect (called QT prolongation) on the function of the 

heart. These include medicines used for abnormal heart rhythm such as quinidine, sotalol and 

amiodarone; medicines used for allergies (antihistamines); antidepressants such as amitriptyline 

and drugs for mental health disorders (antipsychotics); antibiotics, including the following 

types: macrolides, fluoroquinolones or imidazole; and other medicines for Cushing’s disease 

(pasireotide, ketoconazole) 

- theophylline (used to treat breathing problems) or tizanidine (used to treat muscle pain and 

muscle cramps) 

 

Pregnancy and breast-feeding 
This medicine should not be used during pregnancy or breast-feeding, unless your doctor has advised 

you to do so. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have 

a baby, ask your doctor for advice before taking this medicine. 

 

Contraception 

Women who could become pregnant should use an effective method of contraception during treatment 

and for at least one week after the last dose. Ask your doctor about the need for contraception before 

you start taking Isturisa. 

 

Driving and using machines 
Dizziness and tiredness may occur during treatment with Isturisa. Do not drive or operate machines if 

you get these symptoms. 

 

 



32 

3. How to take Isturisa 
 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 

if you are not sure. 

 

The usual starting dose is two 1 mg tablets twice a day (about every 12 hours). Patients of Asian 

ancestry and patients with liver disease may need a lower starting dose (one 1 mg tablet twice a day). 

 

After you have started treatment, your doctor may change your dose. This will depend on how you 

respond to the treatment. The highest recommended dose is 30 mg twice a day. 

 

Isturisa tablets are taken by mouth and can be taken with or without food. 

 

If you take more Isturisa than you should 
If you have taken more Isturisa than you should and you feel unwell (for example if you feel weak, 

light-headed, tired or sick, or if you have to vomit), or if someone else accidentally takes your 

medicine, contact a doctor or hospital for advice immediately. Medical treatment may be needed. 

 

If you forget to take Isturisa 
Do not take a double dose to make up for a forgotten dose. Instead, just wait until it is time for your 

next dose and take that at the scheduled time. 

 

If you stop taking Isturisa 
Do not stop taking Isturisa unless your doctor tells you to. If you stop your treatment with Isturisa, 

your symptoms may come back. 

 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Some side effects may be serious. Please take particular note of the following: 

- Tell your doctor immediately if you experience a heart disorder or heart rhythm disorder, such 

as a fast and irregular heartbeat, even when you are at rest, heart palpitations, blackouts or 

fainting (this could be a sign of a condition called QT prolongation, a side effect that may affect 

up to 1 in 10 people). 

- Tell your doctor immediately if you have two or more of these symptoms: weakness, 

light-headedness, tiredness (fatigue), lack of appetite, nausea (feeling sick), vomiting. This may 

indicate that you have adrenal insufficiency (low cortisol levels), a side effect that may affect 

more than 1 in 10 people. Adrenal insufficiency occurs when Isturisa lowers the amount of 

cortisol too much. It is more likely to occur during periods of increased stress. Your doctor will 

correct this by using a hormone medicine or by adjusting the dose of Isturisa. 

 

Very common side effects (may affect more than 1 in 10 people): 

- vomiting 

- nausea (feeling sick) 

- diarrhoea 

- abdominal pain 

- tiredness (fatigue) 

- build-up of fluid leading to swelling (oedema), particularly of your ankles 

- abnormal blood tests (increased levels of testosterone, increased levels of adrenocorticotrophic 

hormone, also known as ACTH, low levels of potassium) 

- decreased appetite 

- dizziness 

- headache 

- rash 

- low blood pressure (hypotension) 



33 

 

Common side effects (may affect up to 1 in 10 people): 

- fast heartbeat (tachycardia) 

- general feeling of being unwell (malaise) 

- abnormal results of liver function tests 

- fainting (syncope) 

- excessive facial or body hair growth (hirsutism) 

- acne 

 

Reporting of side effects 
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this 

leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 

By reporting side effects you can help provide more information on the safety of this medicine. 

 

 

5. How to store Isturisa 
 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the carton and on the blister after 

EXP. The expiry date refers to the last day of that month. 

 

Do not store above 25°C. 

 

Store in the original package in order to protect from moisture. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 
 

What Isturisa contains 
- The active substance is osilodrostat. Each film-coated tablet contains 1 mg osilodrostat, 5 mg 

osilodrostat or 10 mg osilodrostat. 

- The other ingredients are: 

- In the tablet core: microcrystalline cellulose, mannitol, croscarmellose sodium, 

magnesium stearate, colloidal anhydrous silica. 

- In the film coating: hypromellose, titanium dioxide (E171), iron oxides (E172, see 

below), macrogol and talc. 

- Isturisa 1 mg film-coated tablets contain iron oxide yellow and iron oxide red. 

- Isturisa 5 mg film-coated tablets contain iron oxide yellow. 

- Isturisa 10 mg film-coated tablets contain iron oxide yellow, iron oxide red and 

iron oxide black. 

 

What Isturisa looks like and contents of the pack 
Isturisa is available in packs containing 60 film-coated tablets. 

 

The 1 mg tablets are pale yellow, round and marked “Y1” on one side and “NVR” on the other side. 

The approximate diameter is 6.1 mm. 

 

The 5 mg tablets are yellow, round and marked “Y2” on one side and “NVR” on the other side. The 

approximate diameter is 7.1 mm. 

 

The 10 mg tablets are pale orange brown, round and marked “Y3” on one side and “NVR” on the 

other side. The approximate diameter is 9.1 mm. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


34 

Marketing Authorisation Holder 
Recordati Rare Diseases 

Immeuble Le Wilson 

70 avenue du Général de Gaulle 

92800 Puteaux 

France 

 

Manufacturer 
Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

Recordati Rare Diseases 

Immeuble Le Wilson 

70 avenue du Général de Gaulle 

92800 Puteaux 

France 

 

Recordati Rare Diseases 

Eco River Parc 

30 rue des Peupliers 

92000 Nanterre 

France 

 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Recordati 

Tél/Tel: +32 2 46101 36 

 

Lietuva 

Recordati AB. 

Tel: + 46 8 545 80 230 

Švedija 

 

България 

Recordati Rare Diseases 

Teл.: +33 (0)1 47 73 64 58 

Франция 

 

Luxembourg/Luxemburg 

Recordati 

Tél/Tel: +32 2 46101 36 

Belgique/Belgien 

Česká republika 

Recordati Rare Diseases 

Tel: +33 (0)1 47 73 64 58 

Francie 

 

Magyarország 

Recordati Rare Diseases 

Tel: +33 (0)1 47 73 64 58 

Franciaország 

Danmark 

Recordati AB. 

Tlf: + 46 8 545 80 230 

Sverige 

 

Malta 

Recordati Rare Diseases 

Tel: +33 1 47 73 64 58 

Franza 

Deutschland 

Recordati Rare Diseases Germany GmbH 

Tel: +49 731 140 554 0 

 

Nederland 

Recordati 

Tel: +32 2 46101 36 

België 

 



35 

Eesti 

Recordati AB. 

Tel: + 46 8 545 80 230 

Rootsi 

 

Norge 

Recordati AB. 

Tlf: + 46 8 545 80 230 

Sverige 

Ελλάδα 

Recordati Hellas 

Τηλ: +30 210 6773822 

 

Österreich 

Recordati Rare Diseases Germany GmbH 

Tel: +49 731 140 554 0 

Deutschland 

 

España 

Recordati Rare Diseases Spain S.L.U. 

Tel: + 34 91 659 28 90 

 

Polska 

Recordati Rare Diseases 

Tel: +33 (0)1 47 73 64 58 

Francja 

 

France 

Recordati Rare Diseases 

Tél: +33 (0)1 47 73 64 58 

 

Portugal 

Jaba Recordati S.A. 

Tel: +351 21 432 95 00 

Hrvatska 

Recordati Rare Diseases 

Tél: +33 (0)1 47 73 64 58 

Francuska 

 

România 

Recordati Rare Diseases 

Tel: +33 (0)1 47 73 64 58 

Franţa 

Ireland 

Recordati Rare Diseases 

Tél: +33 (0)1 47 73 64 58 

France 

 

Slovenija 

Recordati Rare Diseases 

Tel: +33 (0)1 47 73 64 58 

Francija 

Ísland 

Recordati AB. 

Simi: + 46 8 545 80 230 

Svíþjóð 

 

Slovenská republika 

Recordati Rare Diseases 

Tel: +33 (0)1 47 73 64 58 

Francúzsko 

Italia 

Recordati Rare Diseases Italy Srl 

Tel: +39 02 487 87 173 

 

Suomi/Finland 

Recordati AB. 

Puh/Tel : +46 8 545 80 230 

Sverige 

 

Κύπρος 

Recordati Rare Diseases 

Τηλ : +33 1 47 73 64 58 

Γαλλία 

 

Sverige 

Recordati AB. 

Tel : +46 8 545 80 230 

Latvija 

Recordati AB. 

Tel: + 46 8 545 80 230 

Zviedrija 

United Kingdom 

Recordati Rare Diseases UK Ltd. 

Tel: +44 (0)1491 414333 

 

This leaflet was last revised in 
 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 

 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
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	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
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