Warnings and Precautions: Hyperglycemia and Diabetes: SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. Patients with poor baseline glycemic control are at…+

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INDICATION: SIGNIFOR® LAR (pasireotide) for injectable suspension, for intramuscular use 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.

Disease Information

Epidemiology and Pathophysiology

What Is Acromegaly?

Acromegaly is a rare disease resulting from the hypersecretion of growth hormone. This hypersecretion is caused by a pituitary tumor.1 Overproduction of growth hormone (GH) by the pituitary is the underlying cause of many of the clinical signs and symptoms of acromegaly.2,3

The Pathophysiology of Acromegaly

The somatic growth and metabolic dysfunction associated with acromegaly result from excess secretion of GH and subsequent elevation of circulating and locally produced insulin-like growth factor-1 (IGF-1). In healthy individuals, GH secretion is under the dual regulation of growth hormone-releasing hormone (GHRH) and somatostatin, with variations in the secretion of somatostatin being the primary mode of regulation.2

The interaction of GHRH and somatostatin, as well as fluctuations in levels of somatostatin, regulate GH secretion.2 Hypersecretion of GH and IGF-1 may be caused primarily by GH-secreting adenoma(s) of the pituitary resulting from clonal expansion of a single mutated cell.4

GH-secreting tumors have a large number of receptors for somatostatin and, thus, are frequently responsive to therapy with analogues of somatostatin.5

How the hypothalamus and pituitary are related to somatic growth.

GH, growth hormone; GHRH, growth hormone-releasing hormone; IGF-1, insulin-like growth factor-1; SRIF, somatotropin-releasing inhibitory factor. Adapted with permission from Melmed.2

Diagnosis of Acromegaly

The Difficulty of Diagnosing Acromegaly

The difficulty of early diagnosis results from several challenges8:

  • Since symptoms develop gradually, time is required for them to be recognized by patients and physicians
  • Patients may exhibit a variety of different clinical signs and symptoms since they may have any combination of the common symptoms
  • Other conditions can produce the signs and symptoms of acromegaly and must, therefore, be ruled out

Tests Used In Diagnosing Acromegaly9

Several tests are useful in diagnosing and monitoring acromegaly. The most important are laboratory tests that measure the levels of GH and IGF-1 in the blood. IGF-1 levels are gender and age dependent, and are relatively stable throughout the day. In contrast, GH levels can fluctuate throughout the day depending on the patient's age, the time of day, and time since the last meal.

The Importance of Measuring GH Levels

Since GH is secreted sporadically throughout the day and has a short half-life, a single random GH test is considered to be of little value in diagnosing acromegaly.10 However, since elevation in GH is a basic abnormality in acromegaly, basal GH levels may be examined during the diagnostic phase, as well as during the ongoing monitoring of acromegalic patients. When acromegaly is suspected, an oral glucose tolerance test is used to evaluate the response of GH to "glucose challenge." In this test, 100 g of glucose are administered in an oral solution to a patient who has fasted overnight. Blood samples are obtained from the patient before ingestion of the glucose, then every 30 minutes afterwards for a total of 2 hours. The following results are observed10,13:

  • In healthy individuals, administration of glucose suppresses GH levels to <1 ng/mL for 1 to 2 hours13
  • In most acromegalic patients, GH levels remain elevated in the presence of glucose


Review the basics of biochemical control and help your patients understand why it's so important to control their levels of growth hormone (GH) and insulin-like growth factor (IGF-1).

Download Managing Acromegaly: Biochemical Control With Signifor LAR

The Role of Imaging In Diagnosis

When it has been established that a patient has elevated GH and IGF-1 levels, MRI or CT imaging is used to examine the pituitary. Imaging studies are used to determine the site and the size of the tumor, which aid in the planning of treatment options.9

MRI of a brain tumor located in the pituitary gland.

Example only, not actual patient.

The image above is an example of a magnetic resonance imaging (MRI) scan of an acromegalic patient with a macroadenoma, indicated by the arrows. A scan like this would be taken from the back (coronal view)11

Acromegaly Treatment Overview

While surgery is the first treatment choice, the role of pharmacologic agents has expanded as the need for tight biochemical control becomes clear.12


Follow two patients from diagnosis through treatment, while gaining insights on helping patients cope with and understand acromegaly.

Download Managing Acromegaly: Review of Two Cases

Surgery for Acromegaly

Surgery is the first course of action recommended for most patients. The goal of surgery is to remove the tumor and normalize GH and IGF-1 levels.9 If successful, hormone control is re-established. If not, medical therapy may be the next choice.12,13

Surgery Advantages13 Disadvantages13
Possible cure if tumor is completely removed
Possible GH and IGF-1 control, as well as symptom relief, even if resection is incomplete
Possible surgical complications

Medical Therapy With Somatostatin Analogues

Somatostatin analogues (SSAs) work by reducing the secretion of hormones that cause the symptoms of acromegaly.13


Radiotherapy involves the use of radiation to kill rapidly growing tumor cells. After radiation, tumors typically stop growing and may even begin to shrink; however, elevated hormone levels fall much more slowly.

Radiotherapy Advantages14 Disadvantages14
Reduces GH and IGF-1 levels
Relatively few side effects
Takes a long time to show effectiveness
Potential for pituitary and optic nerve damage
Risk of secondary malignancy


  1. Lancranjan I, Bruns C, Grass P, et al. Sandostatin LAR®: Pharmacokinetics, pharmacodynamics, efficacy, and tolerability in acromegalic patients. Metabolism. 1995;44(suppl 1):18-26.
  2. Melmed S. Acromegaly. N Engl J Med. 1990;322:966-977.
  3. Jane JA Jr, Thapar K, Laws ER Jr, et al. Acromegaly: historical perspectives and current therapy. J Neurooncol. 2001;54:129-137.
  4. Melmed S, Ho K, Klibanski A, Reichlin S, Thorner M. Clinical review 75: Recent advances in pathogenesis, diagnosis, and management of acromegaly. J Clin Endocrinol Metab. 1995;80:3395-3402.
  5. Lamberts SWJ, van der Lely A-J, de Herder WW, Hofland LJ. Octreotide. N Engl J Med. 1996;334:246-254.
  6. Acromegaly Therapy Consensus Development Panel. Consensus statement: benefits versus risks of medical therapy for acromegaly. Am J Med. 1994;97:468-473.
  7. Harris AG. Diagnosis of acromegaly. In: Daly AF, ed. Acromegaly and Its Management. Philadelphia, PA: Lippincott-Raven; 1996:38-48.
  8. Molitch ME. Clinical manifestations of acromegaly. Endocrinol Metab Clin North Am. 1992;21:597-614.
  9. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services website. Acromegaly. Available at: Accessed August 12, 2008.
  10. Maugans TA, Coates ML. Diagnosis and treatment of acromegaly. Am Fam Physician. 1995;52:207-213.
  11. Mercado M, Borges F, Bouterfa H, et al; on behalf of the SMS995B2401 Study Group. A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR® (long-acting repeatable octreotide) in the primary therapy of patients with acromegaly. Clin Endocrinol. 2007;66:859-868.
  12. Melmed S, Colao A, Barkan A, et al. Guidelines for acromegaly management: an update. J Clin Endocrinol Metab. 2009;94:1509-1517.
  13. AACE Acromegaly Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly—2011 update. Endocr Pract. 2011;17(suppl 4):1-44.
  14. Melmed S, Casanueva FF, Cavagnini F, et al; for the Acromegaly Treatment Consensus Workshop Participants. Guidelines for acromegaly management. J Clin Endocrinol Metab. 2002;87:4054-4058.

SIGNIFOR® LAR (pasireotide) for injectable suspension, for intramuscular use


SIGNIFOR LAR 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.


Warnings and Precautions:

  • Hyperglycemia and Diabetes: SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia.

    A majority of patients, including those with normal glucose tolerance, pre-diabetes and diabetes, experienced increased glucose levels within the first 2 to 3 months of treatment with SIGNIFOR LAR.

    Fasting plasma glucose and hemoglobin A1c should be assessed prior to starting treatment with SIGNIFOR LAR. In patients with poorly controlled diabetes mellitus, anti-diabetic treatment should be optimized before SIGNIFOR LAR treatment is started. Blood glucose monitoring should be done weekly for the first 3 months after initiating SIGNIFOR LAR and the first 4 to 6 weeks after dose increases. Periodic monitoring should continue thereafter, as clinically appropriate.

    Patients who develop significant hyperglycemia on SIGNIFOR LAR may require initiation of anti-diabetic therapy(ies) or adjustment in the dose or type of anti-diabetic therapy(ies) per standard of care. The optimal treatment for the management of SIGNIFOR LAR-induced hyperglycemia is not known. If hyperglycemia cannot be controlled, despite medical management, the dose of SIGNIFOR LAR should be reduced or discontinued.

    After treatment discontinuation, fasting plasma glucose and hemoglobin A1c should be assessed if indicated. Patients on anti-diabetic therapy discontinuing SIGNIFOR LAR may require more frequent blood glucose monitoring and anti-diabetic dose adjustment to mitigate the risk of hypoglycemia.

  • Bradycardia and QT Prolongation


    Bradycardia has been reported with the use of SIGNIFOR LAR. Patients with cardiac disease and/or risk factor 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.

    QT Prolongation

    SIGNIFOR LAR is associated with QT prolongation and should be used with caution in patients who are at significant risk of developing prolongation of the QT interval. A baseline ECG is recommended prior to initiating therapy with SIGNIFOR LAR 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. ALT or AST elevation greater than 3 times the upper limit of normal (ULN) were observed in 3% of patients and ALT or AST elevation greater than 5 times the upper limit of normal (ULN) were observed in 1% of patients treated with SIGNIFOR LAR.

    Assessment of liver function is recommended prior to treatment with SIGNIFOR LAR, and after the first 2 to 3 weeks, then monthly for 3 months. Thereafter, liver function should be monitored as clinically indicated. Patients who develop increased transaminase levels should be monitored until values return to pre-treatment levels. Treatment with SIGNIFOR LAR should be discontinued if signs or symptoms suggestive of clinically significant liver impairment develop.

  • Cholelithiasis: Cholelithiasis was reported in up to 33% of patients treated with SIGNIFOR LAR in clinical trials. Patients should be monitored periodically.
  • Pituitary Hormone Deficiency(ies): Suppression of pituitary hormones other than GH/IGF-1, may occur on SIGNIFOR LAR. Monitoring pituitary function (e.g., thyroid, adrenal, gonadal) prior to initiation of therapy with SIGNIFOR LAR, as well as periodically during treatment, as clinically appropriate, is recommended. Patients should be monitored for and instructed on the signs and symptoms of adrenal insufficiency during therapy. If adrenal insufficiency is suspected it should be confirmed and treated per standard of care with exogenous glucocorticoids at replacement doses.

Adverse Reactions

Adverse reactions associated with SIGNIFOR LAR and occurring in ≥20% of patients were diarrhea, cholelithiasis, hyperglycemia and diabetes mellitus.

Drug Interactions

Caution is advised when co-administering drugs that prolong the QT interval with SIGNIFOR LAR

The following drugs may require monitoring and possible dose adjustment when used with SIGNIFOR LAR: cyclosporine and bromocriptine



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