Special Warning : אזהרת שימוש

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

-      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).

Effects on Driving

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.