SIGNIFOR LAR (pasireotide) for injectable suspension Signifor

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What causes Cushing’s disease?

Cushing’s disease occurs when a benign pituitary adenoma secretes excess levels of adrenocorticotropic hormone (ACTH). This, in turn, causes the adrenal glands to secrete cortisol, resulting in excessive levels of circulating cortisol.1

What is the exaggerated cascade of ACTH overproduction?

Under normal conditions, circulating cortisol provides physiologic control through negative feedback inhibition on hypothalamic corticotropin-releasing hormone (CRH) and pituitary ACTH secretion.

In Cushing’s disease, the hypothalamic-pituitary-adrenal (HPA) feedback loop is disrupted, leaving CRH and ACTH production uncontrolled. Additionally, the pituitary adenoma becomes resistant to cortisol inhibition, continues to oversecrete ACTH, and stimulates the adrenal glands to produce excess cortisol.1

What are the signs and symptoms of Cushing’s disease?

Patients with Cushing’s disease are most likely to present with one or more of the signs and symptoms that result from elevated levels of cortisol or ACTH. These include sudden weight gain (especially with central obesity), hypertension, facial rounding, easy bruising, striae, glucose intolerance or diabetes mellitus, hyperlipidemia, decreased libido or impotence, menstrual disorders, osteopenia or osteoporosis, acne, hirsutism, recurrent opportunistic bacterial infections, and depression or psychosis.2

What is the role of somatostatin (SST) receptors in Cushing’s disease?

Somatostatin receptors are expressed in many tissues including neuroendocrine tumors such as ACTH-secreting pituitary adenomas. Corticotroph tumor cells from patients with Cushing’s disease frequently overexpress SST5, whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Binding and activating the SST receptors results in inhibition of ACTH secretion, which leads to decreased cortisol secretion.3

How does SIGNIFOR® LAR decrease cortisol levels?

SIGNIFOR LAR exerts its pharmacologic effect by binding to SST receptors. Of the 5 known human somatostatin receptor subtypes—SST1, SST2, SST3, SST4, and SST5—SIGNIFOR LAR binds with high affinity to four of the five. By targeting key SST receptors of pituitary adenoma cells, SIGNIFOR LAR decreases cortisol levels through inhibition of ACTH secretion.3

What is the pharmacologic profile of SIGNIFOR LAR?

SIGNIFOR LAR targets four of the five SST receptors. SIGNIFOR LAR has the highest binding affinity for SST5 and SST2, which regulate most ACTH secretion. SST5 is known to be the most overexpressed SST receptor in Cushing’s disease.3

References: 1. Lonser RR, Nieman L, Oldfield EH. J Neurosurg. 2017;126(2):404-417. 2. Kirk LF, Hash RB, Katner HP, et al. Am Fam Physician. 2000;62(5):1119-1127. 3. SIGNIFOR LAR (pasireotide) for injectable suspension, for intramuscular use [prescribing information]. Lebanon, NJ: Recordati Rare Diseases Inc.; 2020.

Indications and Usage

SIGNIFOR LAR (pasireotide) is a somatostatin analog indicated for the treatment of:

Important Safety Information

Warnings and Precautions

Indications and Usage

SIGNIFOR LAR (pasireotide) is a somatostatin analog indicated for the treatment of:

Important Safety Information

Warnings and Precautions

Adverse Reactions

Drug Interactions

Females and Males of Reproductive Potential

References: 1. Gatto F, Barbieri F, Arvigo M, et al. Biological and biochemical basis of the differential efficacy of first and second generation somatostatin receptor ligands in neuroendocrine neoplasms. Int J Mol Sci. 2019;20(16):3940. 2. Poullot A-G, Chevalier N. New options in the treatment of Cushing’s disease: a focus on pasireotide. Res Rep Endocr Disord. 2013;3:31-38. 3. SIGNIFOR LAR (pasireotide) for injectable suspension, for intramuscular use [prescribing information]. Lebanon, NJ: Recordati Rare Diseases Inc.; 2020. 4. Acromegaly. UCLA Health System. Accessed August 23, 2022. 5. Broder MS, Chang E, Cherepanov D, Neary MP, Ludlam WH. Incidence and Prevalence of Acromegaly in the United States: A Claims-Based Analysis. AACE Endocrine Practice. Published November 1, 2016. Accessed August 23, 2022. 6. Christofides EA. Clinical importance of achieving biochemical control with medical therapy in adult patients with acromegaly. Patient Prefer Adherence. 2016;10:1217-1225. 7. Acromegaly. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed August 23, 2022. 8. Carmichael JD, Bonert VS, Nu.o M, Ly D, Melmed S. Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis. J Clin Endocrinol Metab. 2014;99(5):1825-1833. 9. Carroll PV, Jenkins PJ. Acromegaly. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext [Internet]. South Dartmouth, MA:, Inc.; 2016 10. Giustina A, Barkhoudarian G, Beckers A, et al. Multidisciplinary management of acromegaly: A consensus. Rev Endocr Metab Disord. 2020;21(4):667-678. 11. Katznelson L, Laws ER Jr, Melmed S, et al. Endocrine Society Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933-3951. 12. Lavrentaki A, Paluzzi A, Wass JA, Karavitaki N. Epidemiology of acromegaly: review of population studies. Pituitary. 2017;20(1):4-9. 13. SOMATULINE® DEPOT (lanreotide) injection, for subcutaneous use [prescribing information]. Cambridge, MA: Ipsen Biopharmaceuticals, Inc.; 2019 14. SANDOSTATIN LAR DEPOT (octreotide acetate) for injectable suspension, for gluteal intramuscular use [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021. 15. Coopmans EC, Muhammad A, van der Lely AD, et al. How to position pasireotide LAR treatment in acromegaly. J Clin Endocrinol Metab. 2019;104(6):1978-1988. 16. Shanik MH, Cao PD, Ludlam WH. Historical response rates of somatostatin analogues in the treatment of acromegaly: a systematic review. Endocr Pract. 2016;22(3):350-356. 17. Casar-Borota O, Heck A, Schulz S, et al. Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in somatotroph adenomas assessed by monoclonal antibodies was reduced by octreotide and correlated with the acute and long-term effects of octreotide. J Clin Endocrinol Metab. 2013;98(11):E1730-E1739. 18. Silverstein JM. Hyperglycemia induced by pasireotide in patients with Cushing’s disease or acromegaly. Pituitary. 2016;19:536-543. 19. Zambre Y, Ling Z, Chen MC, et al. Inhibition of human pancreatic islet insulin release by receptor-selective somatostatin analogs directed to somatostatin receptor subtype 5. Biochem Pharmacol. 1999;57(10):1159-1164. 20. Singh V, Brendel MD, Zacharias S, et al. Characterization of somatostatin receptor subtype-specific regulation of insulin and glucagon secretion: an in vitro study on isolated human pancreatic islets. J Clin Endocrinol Metab. 2007;92(2):673-680. 21. Breitschaft A, Hu K, Hermosillo Res.ndiz K, Darstein C, Golor G. Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study. Diabetes Res Clin Pract. 2014;103(3):458-465. 22. Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013;98(8):3446-3453. 23. Gadelha MR, Bronstein MD, Brue T, et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(11):875-884. 24. Colao A, Bronstein MD, Freda P, et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab. 2014;99(3):791-799. 25. Gadelha MR, Gu F, Bronstein MD, et al. Risk factors and management of pasireotide-associated hyperglycemia in acromegaly. Endocr Connect. 2020;9(12):1178-1190. 26. American Diabetes Association. Standards of Medical Care in Diabetes-2020 Abridged for Primary Care Providers. Clin Diabetes. 2020;38(1):10-38. doi:10.2337/cd20-as01. 27. Samson SL, Gu F, Feldt-Rasmussen U, Zhang S, Yu Y, et al. Managing pasireotide-associated hyperglycemia: a randomized, open-label, Phase IV study. Pituitary. 2021;24(6):887-903.