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Prescribing Information
SIGNIFOR LAR (pasireotide) for injectable suspension
For US Healthcare Professionals Only

SIGNIFOR LAR (pasireotide) for injectable suspension Signifor

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FAQs

What causes acromegaly?

Acromegaly is a rare, chronic disease characterized by hypersecretion of growth hormone (GH) from benign somatotrophic adenomas. Hypersecretion of GH, in turn, stimulates overproduction of insulin-like growth factor 1 (IGF-1) from the liver and systemic tissues.1,2

What are the signs and symptoms of acromegaly?

The effects of increased levels of GH and IGF-1 on many organs result in the clinical manifestations of acromegaly that lead to a multisystem disease associated with physical disfigurement, comorbidities, and premature mortality. Patients with acromegaly may develop cardiovascular comorbidities such as hypertension and cardiomyopathy, insulin resistance, sleep apnea, and neoplasia such as colon polyps.1

Classic signs and symptoms include prominent brow ridge, a widening of the space between the teeth, and soft-tissue changes. Patients may complain of excessive perspiration, soft-tissue swelling, large-joint osteoarthritis, and carpal tunnel syndrome.1

What is the role of somatostatin (SST) receptors in acromegaly?

Somatostatin receptors are expressed in many tissues including neuroendocrine tumors such as GH-secreting pituitary adenomas. There are 5 known human SST receptor subtypes: SST1, SST2, SST3, SST4, and SST5. These receptor subtypes are expressed in different tissues under normal physiologic conditions. SST analogs bind to SST receptors with different potencies.3

How does SIGNIFOR LAR decrease GH levels?

SIGNIFOR LAR exerts its pharmacologic effect by binding to SST receptors. Of the 5 known human SST receptor subtypes, SIGNIFOR LAR binds with high affinity to four of the five. SIGNIFOR LAR binds with the highest affinity to SST2 and SST5 subtype receptors, which may be relevant for inhibition of GH secretion. In vivo studies show that SIGNIFOR LAR lowers GH and IGF-1 levels in patients with acromegaly.3

How is SIGNIFOR LAR administered?

SIGNIFOR LAR for injectable suspension is administered by a trained healthcare professional, such as a physician or nurse, as an intramuscular injection into the right or left gluteal muscle. The long-acting formulation achieves 28 days of medication release with one injection, allowing SIGNIFOR LAR to be administered once every 4 weeks.3

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References: 1. Christofides EA. Patient Prefer Adherence. 2016;10:1217-1225. 2. Carmichael JD, Bonert VS, Nuño M, et al. J Clin Endocrinol Metab. 2014;99(5):1825-1833. 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 patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

IMPORTANT SAFETY INFORMATION

Hyperglycemia, Diabetes, and Ketoacidosis: SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. Monitor glucose levels as clinically appropriate during therapy. There have been postmarketing cases of ketoacidosis with SIGNIFOR LAR in patients with or without history of diabetes. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia. Patients who develop significant hyperglycemia on SIGNIFOR LAR may require initiation of anti-diabetic treatment or adjustment in their current anti-diabetic treatment. The optimal treatment for the management of SIGNIFOR LAR-induced hyperglycemia is not known. If hyperglycemia cannot be controlled despite medical management, reduce the dose or discontinue SIGNIFOR LAR. Patients who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of diabetes history. If ketoacidosis is suspected, discontinue SIGNIFOR LAR and promptly evaluate and treat the patient.

INDICATIONS AND USAGE

SIGNIFOR LAR® (pasireotide) is a somatostatin analog indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

IMPORTANT SAFETY INFORMATION

Hyperglycemia, Diabetes, and Ketoacidosis: SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. Monitor glucose levels as clinically appropriate during therapy. There have been postmarketing cases of ketoacidosis with SIGNIFOR LAR in patients with or without history of diabetes. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia. Patients who develop significant hyperglycemia on SIGNIFOR LAR may require initiation of anti-diabetic treatment or adjustment in their current anti-diabetic treatment. The optimal treatment for the management of SIGNIFOR LAR-induced hyperglycemia is not known. If hyperglycemia cannot be controlled despite medical management, reduce the dose or discontinue SIGNIFOR LAR. Patients who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of diabetes history. If ketoacidosis is suspected, discontinue SIGNIFOR LAR and promptly evaluate and treat the patient.

Bradycardia and QT Prolongation: Bradycardia has been reported with the use of SIGNIFOR LAR. Patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia, high grade heart block, or concomitant use of drugs associated with bradycardia, should be monitored. Adjustments in the dose of drugs known to slow the heart rate (e.g., beta-blockers, calcium channel blockers) and correction of electrolyte disturbances may be necessary when initiating or during the course of SIGNIFOR LAR treatment. In cardiac electrophysiology studies with pasireotide via subcutaneous route, QT prolongation occurred at therapeutic and supra-therapeutic doses. Use with caution in patients at significant risk; evaluate ECG and electrolytes prior to dosing and periodically while on treatment. Hypokalemia or hypomagnesemia must be corrected prior to initiating SIGNIFOR LAR and should be monitored periodically during therapy.

Liver Test Elevations: Increases in liver enzymes have been observed with SIGNIFOR LAR. Evaluate liver enzyme tests prior to and during treatment.

Cholelithiasis and Complications of Cholelithiasis: There have been reports of cholelithiasis resulting in complications including cholecystitis or cholangitis and requiring cholecystectomy in patients taking SIGNIFOR LAR. Monitor periodically. Discontinue SIGNIFOR LAR if complications of cholelithiasis are suspected and treat appropriately.

Pituitary Hormone Deficiency(ies): Suppression of anterior pituitary hormones may occur on SIGNIFOR LAR. Monitor for occurrence periodically and treat if clinically indicated.

Steatorrhea and Malabsorption of Dietary Fats: New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur. If new occurrence or worsening of these symptoms are reported, evaluate for potential pancreatic exocrine insufficiency.

The most common adverse reactions occurring in ≥ 20% of patients with acromegaly were diarrhea, hyperglycemia, cholelithiasis, and diabetes mellitus.

To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions

Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy.

SIGNIFOR LAR® (pasireotide) for injectable suspension, for intramuscular use, is available as 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg powder in a vial to be reconstituted with the provided 2 mL diluent.

Please see the accompanying full Prescribing Information and Patient Information.

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. https://www.uclahealth.org/medical-services/surgery/endocrine-surgery/patient-resources/patient-education/endocrine-surgery-encyclopedia/acromegaly. 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. https://www.endocrinepractice.org/article/S1530-891X(20)35591-9/pdf. 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. https://www.niddk.nih.gov/health-information/endocrine-diseases/acromegaly. 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: MDText.com, 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.