Isturisa^® (Tablets) Instructions for Use

Marketing Authorization Holder

Recordati Rare Diseases (France)

Manufactured By

Penn Pharmaceutical Services, Limited (United Kingdom)

Quality Control Release

RECORDATI RARE DISEASES (France)

ATC Code

H02CA02 (Osilodrostat)

Active Substance

Osilodrostat (Rec.INN registered by WHO)

Dosage Forms

	Isturisa^®	Film-coated tablets, 1 mg: 60 pcs.
		Film-coated tablets, 5 mg: 60 pcs.
		Film-coated tablets, 10 mg: 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light brownish-yellow in color, round, biconvex, with beveled edges, imprinted with “1” on one side; the cross-section shows a white core surrounded by a single layer of coating.

	1 tab.
Osilodrostat (in the form of osilodrostat phosphate)	1 mg

Excipients: microcrystalline cellulose, mannitol, magnesium stearate, colloidal silicon dioxide (anhydrous), croscarmellose sodium; film coating: hypromellose (hydroxypropyl methylcellulose), titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), macrogol 4000 (polyethylene glycol 4000), talc.

10 pcs. – blisters (6) – cardboard packs.

Film-coated tablets brownish-yellow in color, round, biconvex, with beveled edges, imprinted with “5” on one side; the cross-section shows a white core surrounded by a single layer of coating.

	1 tab.
Osilodrostat (in the form of osilodrostat phosphate)	5 mg

10 pcs. – blisters (6) – cardboard packs.

Film-coated tablets light orange-brown in color, round, biconvex, with beveled edges, imprinted with “10” on one side; the cross-section shows a white core surrounded by a single layer of coating.

	1 tab.
Osilodrostat (in the form of osilodrostat phosphate)	10 mg

10 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Adrenal cortex hormone synthesis inhibitor

Pharmacotherapeutic Group

Systemic corticosteroids; drugs suppressing adrenal cortex function; anticorticosteroids

Pharmacological Action

Cortisol synthesis inhibitor. Osilodrostat is a potent inhibitor of 11β-hydroxylase (CYP11B1), an enzyme that catalyzes the final step of endogenous cortisol biosynthesis in the adrenal glands.

Inhibition of CYP11B1 is accompanied by accumulation of cortisol precursors, such as 11-deoxycortisol, and acceleration of the biosynthesis of other steroid hormones in the adrenal glands, including androgens.

In Cushing’s disease, the decrease in plasma cortisol concentration also stimulates ACTH secretion via a feedback mechanism, which in turn stimulates corticosteroid biosynthesis.

Pharmacokinetics

Osilodrostat belongs to substances with high solubility and high permeability (BCS Class I). Osilodrostat is rapidly and almost completely absorbed from the gastrointestinal tract, with C_max reached in approximately 1 hour.

Steady state is reached by day 2 of therapy.

A single 30 mg dose of osilodrostat taken with a high-fat meal resulted in a slight decrease in osilodrostat AUC and C_max by 11% and 21%, respectively, and the median T_max increased from 1 to 2.5 hours.

No clinically significant accumulation was observed. The accumulation ratio in the dose range from 2 to 30 mg was 1.3.

The median V_d of osilodrostat is approximately 100 L.

The binding of osilodrostat and its main metabolite M34.5 to plasma proteins is low (less than 40%) and is concentration-independent.

The ratio of osilodrostat concentrations in whole blood and plasma is 0.85.

It undergoes metabolism to form three main metabolites in plasma (M34.5, M16.5 and M24.9) accounted for 51%, 9% and 7% of the osilodrostat dose, respectively.

Metabolites M34.5 and M24.9 have a longer half-life than Osilodrostat, so accumulation is to be expected with twice-daily administration.

Thirteen metabolites were detected in urine; of which the three main ones – M16.5, M22 (glucuronide of M34.5) and M24.9 – accounted for 17%, 13% and 11% of the administered dose, respectively.

The formation of the main urinary metabolite M16.5 (direct N-glucuronide) occurs under the influence of UGT1A4, CYP2B7 and CYP2B10 enzymes.

Less than 1% of the dose was excreted in urine as metabolite M34.5 (dioxygenated Osilodrostat), but 13% of the dose was determined as M22 (glucuronide of M34.5).

The formation of M34.5 occurs without the involvement of CYP isoenzymes.

Multiple CYPs and UGTs are involved in the metabolism of osilodrostat, and no single enzyme contributes more than 25% to the total clearance.

The main cytochrome P450 isoenzymes involved in the metabolism of osilodrostat are CYP3A4, CYP2B6 and CYP2D6.

The total contribution of the cytochrome P450 system is 26%, the total contribution of UGT is 19%, and metabolism not associated with cytochrome P450 and UGT isoenzymes accounts for about 50% of the total clearance.

Furthermore, in vitro studies have shown that Osilodrostat penetrates well into cells and has a low efflux ratio, which is moderately affected by inhibitors.

This indicates that the likelihood of clinically significant drug interactions with drugs that inhibit transporter proteins or one of the CYPs or UGTs is low.

The metabolites of osilodrostat are pharmacologically inactive.

The T_1/2 of osilodrostat is approximately 4 hours.

In a study with labeled osilodrostat, most (91%) of the radioactive label was excreted in urine, and only a small amount (1.6%) was excreted in feces.

Only a small part (5.2%) of the administered osilodrostat dose is excreted unchanged in urine; this indicates that metabolism is the main route of elimination of the drug from the human body.

Indications

Treatment of pituitary-derived Cushing’s disease when neurosurgical treatment is ineffective or not possible.

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

Administer Isturisa^®orally, with or without food.

Initiate therapy at the recommended starting dose of 2 mg twice daily.

Perform individual dose titration based on efficacy and tolerability.

Increase the dose in increments of 1-2 mg no more frequently than every 1-2 weeks.

Monitor 24-hour urinary free cortisol levels regularly to guide titration.

The typical maintenance dose range is 2 mg to 7 mg twice daily.

Do not exceed the maximum recommended dose of 30 mg twice daily.

For patients with moderate hepatic impairment (Child-Pugh B), initiate therapy at 1 mg twice daily.

For patients with severe hepatic impairment (Child-Pugh C), initiate therapy at 1 mg once daily in the evening; for the first titration step, increase to 1 mg twice daily.

No dose adjustment is required for patients with renal impairment.

Monitor for signs and symptoms of hypocortisolism and adrenal insufficiency throughout treatment.

If hypocortisolism is suspected, measure cortisol levels and consider a temporary dose reduction or interruption of therapy.

Resume therapy at a lower dose once cortisol levels are adequate and symptoms resolve.

Obtain an ECG before initiation, during the first week of therapy, and as clinically indicated thereafter to monitor the QT interval.

Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiation and monitor electrolytes periodically during treatment.

Adverse Reactions

Blood and lymphatic system disorders frequency unknown – neutropenia.

Endocrine disorders very common – adrenal insufficiency.

Metabolism and nutrition disorders very common – hypokalemia, decreased appetite.

Nervous system disorders very common – dizziness, headache; common – syncope.

Cardiac disorders very common – tachycardia, arterial hypotension.

Gastrointestinal disorders very common – vomiting, nausea, diarrhea, 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, edema; common – malaise.

Investigations: very common – increased blood testosterone concentration, increased blood ACTH concentration; common – QT interval prolongation on ECG, increased transaminase activity.

Contraindications

Hypersensitivity to osilodrostat, pregnancy, breastfeeding period, age under 18 years.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Osilodrostat may have harmful effects on the fetus.

A pregnancy test should be performed in women of childbearing potential before starting osilodrostat, they should be informed of the potential risk to the fetus and the need to use effective methods of contraception during treatment and for at least one week after its discontinuation.

Use in Hepatic Impairment

In patients with mild hepatic impairment (Child-Pugh class A), no dose adjustment is required.

In moderate hepatic impairment (Child-Pugh class B), the initial dose of osilodrostat should be 1 mg twice daily, and in severe hepatic impairment (Child-Pugh class C), treatment should be started with 1 mg once daily (in the evening), and as the first titration step, the dose should be increased to 1 mg twice daily.

Use in Renal Impairment

No dose adjustment is required in renal impairment.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Inhibition of cortisol synthesis by osilodrostat can lead to hypocorticism and related phenomena, such as cortisol withdrawal syndrome (appearance of clinical signs of hypocorticism when cortisol concentration decreases, which, however, has not fallen below the lower limit of reference values) and adrenal insufficiency (cortisol concentration below reference values).

During therapy, cortisol concentration should be monitored at regular intervals, as adverse events associated with hypocorticism may occur at any time during treatment and after treatment discontinuation.

Additional monitoring is recommended, especially in situations where the demand for cortisol increases, such as during stress and physical exertion, or during changes in concomitant pharmacotherapy, which may require adjustment of the osilodrostat dose.

It is recommended to use laboratory methods that do not show significant cross-reactivity with cortisol precursors, such as 11-deoxycortisol, the concentration of which may increase during treatment with osilodrostat.

Patients should be warned about the signs and symptoms of hypocorticism (such as nausea, vomiting, fatigue, abdominal pain, loss of appetite, dizziness).

If such symptoms are present, the patient should be closely monitored for arterial hypotension, hyponatremia, hyperkalemia and/or hypoglycemia.

If hypocorticism is suspected, cortisol concentration should be determined and consideration given to temporarily reducing the dose or temporarily discontinuing osilodrostat.

After discontinuation of osilodrostat, suppression of cortisol synthesis may persist for several months, regardless of the administered dose of osilodrostat, and may require additional monitoring.

If necessary, corticosteroid replacement therapy should be initiated.

After symptoms resolve, osilodrostat may be resumed at a lower dose provided that the cortisol concentration is above the lower limit of normal without glucocorticoid replacement therapy.

An ECG should be recorded before starting osilodrostat, during the first week of therapy, and thereafter as clinically indicated.

If the QTc interval value exceeds 480 ms before or during treatment with osilodrostat, consultation with a cardiologist is recommended.

Temporary dose reduction or interruption of administration may be required.

If hypokalemia, hypocalcemia, or hypomagnesemia are detected, they must be corrected before starting osilodrostat, and electrolyte levels should be periodically monitored during therapy.

Osilodrostat should be used with caution and the benefit-risk ratio should be carefully weighed in patients with risk factors for QT interval prolongation, such as: congenital long QT syndrome; serious cardiovascular diseases (including congestive heart failure, recent myocardial infarction, unstable angina, persistent ventricular tachycardia, severe conduction disorders and clinically significant bradyarrhythmias); concomitant use of drugs that prolong the QT interval.

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

Discontinuation of osilodrostat therapy should be considered in patients who experience invasive growth of a corticotropinoma during treatment, confirmed by MRI.

Caution is recommended and more careful monitoring should be carried out when using drugs that are potent inducers or inhibitors of isoenzymes concomitantly, when they are prescribed or discontinued during treatment with osilodrostat, as they may affect the systemic exposure of osilodrostat and increase the risk of adverse events (with increased exposure) or reduce the effectiveness of therapy (with decreased exposure).

Drug Interactions

Concomitant use of osilodrostat with other drugs affecting the QT interval may lead to QT interval prolongation in patients with known cardiac arrhythmias.

When switching to Osilodrostat from therapy with other drugs for the treatment of Cushing’s disease that are known to affect the QT interval, such as pasireotide or ketoconazole, a “washout” period should be provided.

Caution should be exercised when prescribing or discontinuing concomitant therapy with strong inhibitors of various enzymes during treatment with osilodrostat.

Caution should be exercised when prescribing or discontinuing concomitant therapy with strong inducers of various enzymes (e.g., rifampicin) during treatment with osilodrostat.

Since Osilodrostat and its main metabolite M34.5 may inhibit and/or induce various enzymes and transporter proteins, caution is generally recommended when co-administering osilodrostat with sensitive substrates of enzymes or transporter proteins that have a narrow therapeutic range.

When taking a single 50 mg dose of osilodrostat and a test drug mixture, Osilodrostat exhibited properties of a weak inhibitor of CYP2D6 and CYP3A4/5, an inhibitor of CYP2C19 (weak to moderate) and a moderate inhibitor of CYP1A2.

The AUC of dextromethorphan (a CYP2D6 substrate) when co-administered with osilodrostat increased 1.5-fold compared with monotherapy.

The AUC of midazolam (a CYP3A4 substrate) when co-administered with osilodrostat increased 1.5-fold compared with monotherapy.

The AUC of omeprazole (a CYP2C19 substrate) when co-administered with osilodrostat increased 1.9-fold compared with monotherapy.

However, signs of time-dependent inhibition were found in vitro, so the consequences of multiple administration are unclear.

Osilodrostat should be used with caution when co-administered with sensitive CYP2C19 substrates with a narrow therapeutic range.

The AUC of caffeine (a CYP1A2 substrate) increased 2.5-fold when co-administered with osilodrostat compared with monotherapy.

However, signs of CYP1A2 induction were found in vitro, so the consequences of multiple administration are unclear.

Osilodrostat should be used with caution when co-administered with sensitive CYP1A2 substrates with a narrow therapeutic range, such as theophylline and tizanidine.

Osilodrostat (30 mg twice daily), taken for 7 days before prescribing a combined oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel and for another 5 days concomitantly with it, did not have a clinically significant effect on the AUC and Cmax of ethinyl estradiol (geometric mean ratio: 1.03 and 0.88, respectively) and the AUC of levonorgestrel (geometric mean ratio: 1.02).

The Cmax of levonorgestrel was slightly outside the acceptable bioequivalence range.

The effects of longer prior and concomitant use have not been studied, and interaction studies with other hormonal contraceptives have not been conducted.

In vitro data for osilodrostat and its main metabolite M34.5 suggest that the drug is capable of both inhibiting and inducing CYP1A2, CYP2B6 and CYP3A4/5, and there is also the possibility of time-dependent inhibition of CYP2C19 and inhibition of CYP2E1 and UGT1A1.

It is possible that Osilodrostat may affect the systemic exposure of substrates of these enzymes.

In vitro data for osilodrostat and its main metabolite M34.5 suggest that the drug is capable of inhibiting the transporter proteins OATP1B1, OCT1, OCT2, OAT1, OAT3 and MATE1.

It is possible that Osilodrostat may affect the systemic exposure of sensitive substrates of these proteins.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.

Medical Disclaimer