Draft Policies - Prescription Drugs
Signifor LAR (pasireotide)
Comment Period Ends:11-02-2018
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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb strength of recommendation or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.
Signifor® LAR (pasireotide) injectable suspension, for intramuscular use, may be considered medically necessary for the treatment of adult patients with acromegaly who have had:
• An inadequate response to surgery, and/or
• For whom surgery is not an option.
Signifor® LAR (pasireotide) injectable suspension, for intramuscular use, may be considered medically necessary for the treatment of adult patients with Cushing’s disease when pituitary surgery:
• Is not an option, or
• Has not been curative.
Signifor® LAR (pasireotide) injectable suspension, for intramuscular use, may be considered medically necessary for carcinoid syndrome in adults, inadequately controlled with first generation somatostatin analogs in patients with metastatic neuroendocrine tumor of the digestive tract.
Signifor® LAR (pasireotide) injectable suspension, for intramuscular use, is considered experimental, investigational and/or unproven for all other indications.
NOTE 1: The following is noted on the Food and Drug Administration (FDA) Highlights of Prescribing Information: Signifor LAR should only be administered by a trained health professional.
Approval duration (initial and reauthorization): 12 months
Acromegaly is a rare hormonal disorder that occurs when the pituitary gland produces too much growth hormone (GH) during adulthood. The overproduction of growth hormone in most cases is due to a pituitary adenoma, a benign pituitary gland tumor. When GH is released into the bloodstream, the liver manufactures a hormone called insulin-like growth factor-1 (IGF-1). An excessive amount of IGF-1 can lead to atypical growth of skeletal and soft tissue. Physical changes can include an increase in size of extremities, examples include enlargement of hands, feet and face (protruding lower jaw and brow). Other symptoms may include headache, fatigue and vision impairment. Symptoms of acromegaly vary and may be gradual, due to the insidious onset; the condition may not be diagnosed immediately. Acromegaly could lead to serious life-threatening complications, therefore early diagnosis and treatment is important.
Tests used to help diagnose and monitor this disorder may include but are not limited to such tests as magnetic resonance imaging (MRI) of the brain, IGF-1 levels, prolactin, and growth hormone levels. Treatment may consist of surgical, medical and radiotherapeutic options or a combination of these therapies. Surgery to remove the pituitary tumor may be the initial treatment in patients with microadenomas. There are situations in which the tumor is unable to be removed completely; radiation or medical therapy may be used as adjunct to surgery.
Cushing’s disease is a subset of a larger condition called Cushing’s syndrome, which results when cortisol levels are increased by one of a number of possible causes. Cushing's syndrome, also called hypercortisolism, is a rare endocrine disorder. Cushing’s disease is commonly seen in adults between the ages of 20 and 50. The pituitary gland, at the base of the brain releases adrenocorticotropic hormone (ACTH). Adrenal glands, located at the top of each kidney produce cortisol. Cushing’s syndrome could be caused by several things including the use of cortisol-like glucocorticoids, or tumors. One type of tumor is an adenoma or noncancerous tumor that starts in the pituitary gland. This tumor causes the excessive releases of ACTH which leads to increased production of cortisol. Adenomas in other areas of the body can also increase cortisol production, (e.g. adrenal gland adenomas). Cortisol is a hormone, it affects development, metabolism, mood and other functions. Cushing’s syndrome includes a variety of symptoms to include, upper body obesity, fatigue and muscle weakness, high blood pressure, high blood sugar levels, increased amount of facial and body hair growth.
The treatment for Cushing's syndrome is contingent on the cause of excess cortisol. Treatments can include surgery, radiation, cortisol-reducing medications or chemotherapy. If the cause of the elevated cortisol levels is due to a pituitary adenoma, surgery to remove the tumor may be considered. Radiation therapy is also an option. The prognosis for those patients with Cushing's syndrome depends on the cause of the disease.
Carcinoid syndrome denotes a group of symptoms linked with carcinoid tumors, these are rare cancerous tumors that secrete certain chemicals such as serotonin into the bloodstream. Carcinoid tumors frequently occur in the lungs or the gastrointestinal tract. A small percentage of people with carcinoid tumors develop carcinoid syndrome. Normally the liver can reduce the effect of these chemicals, but in some cases cancer has spread to the liver and the chemicals are not neutralized, causing symptoms associated with carcinoid syndrome. These symptoms can include the following: skin flushing, facial skin lesions, diarrhea, difficulty breathing and rapid heartbeat. Treatment commonly focuses on the underlying carcinoid tumor and alleviating the symptoms associated with carcinoid syndrome, through medication.
The U.S. Food and Drug Administration (FDA) new drug application (NDA) for Signifor LAR (pasireotide) was approved December 15, 2014 for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option. In June 2018, the FDA approved a new indication to the product labeling for treatment of patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. Signifor LAR is an injectable suspension, for intramuscular use, (2) Signifor LAR is given by intramuscular injection every 4 weeks (every 28 days). Baseline evaluations are recommended prior to the initiation of Signifor LAR. (1)
The FDA’s Highlights of Prescribing information for Signifor LAR addresses the following warnings and precautions:
• Hyperglycemia and Diabetes;
• Bradycardia and QT Prolongation;
• Liver Test Elevations;
• Pituitary Hormone Deficiency(ies). (1)
The FDA’s Highlights of Prescribing information for Signifor LAR also notes that safety and effectiveness of Signifor LAR have not been established in pediatric patients.
The prescribing information also notes Signifor LAR must be administered by a trained healthcare professional. (1)
This medical policy was originally created in 2016 and has been updated with searches of the MEDLINE database. The most recent literature search was performed through August 8, 2018.
In a multicenter, double-blind randomized study to evaluate the safety and efficacy of Signifor LAR; patients with active acromegaly were randomized in a 1:1 ratio to Signifor LAR or another somatostatin analog active comparator. Three hundred fifty-eight patients who were naïve to drugs used to treat acromegaly were evaluated. Randomization was based on the patient’s prior pituitary surgical status (e.g., patients having at least one prior pituitary surgery vs. no prior pituitary surgery). One patient had a history of pituitary radiation therapy and 42% of patients had a prior pituitary surgery. Median time between diagnosis and trial participation was 6 months. Median growth hormone (GH) was 8.8 mcg/L (range: 0.8 – 200 mcg/L) and 10.1 mcg/L (range: 0.6 – 169.6 mcg/L) for Signifor LAR and active comparator, respectively at baseline. The efficacy endpoint noted was the proportion of patients with a mean GH level less than 2.5mcg/L and a normal insulin-like growth factor-1 (IGF-1) level at month 12 (age and sex adjusted). The proportion of patients achieving this level of control was 31.3% and 19.2% for Signifor LAR and active comparator, respectively. Biochemical control was achieved by month 3 in 30.1% of patients in the Signifor LAR arm. Ninety-eight percent of patients treated with Signifor LAR had either a reduction or no change in tumor volume from baseline assessed by magnetic resonance imaging (MRI) at month 12. The median (range) change in tumor volume was a reduction of 39.8% (-97.6% to 16.9%). (1)
In another study, a multicenter, randomized, 3-arm trial was performed in patients having acromegaly who were inadequately controlled on somatostatin analogs. In this trial, a total of 181 patients completed the 6-month trial. Patients were randomized to double-blind Signifor LAR 40mg (n=65) or Signifor LAR 60mg (n=65) or to continued open-label pre-trial somatostatin analog therapies at maximal or near maximal doses (n=68). Inadequate control was defined as a GH concentration of greater than 2.5 mcg/L (i.e., mean of 5 samples over 2 hours) and a sex-and age-adjusted IGF-1 level greater than 1.3 times the upper limit of normal. Patients were treated for at least 6 months prior to randomization with other somatostatin analogs. The maximum dose for one of the active comparators approved for use in the United States was not used in this multinational trial; approximately 75% of the population in the comparator group was receiving this active comparator. The percentage of patients with previous pituitary surgery in the Signifor LAR 40 mg and 60 mg arms and in the active control arm was 77%, 63% and 60%, respectively. Seven percent of patients in the active control arm and 3% of patients in the Signifor LAR groups and had prior radiation therapy. Median (range) time from diagnosis to participation in this trial was 50 (10-337) months, 55 (8-357) months, and 54 (8-357) months in the Signifor LAR 40 mg, 60 mg and the pre-trial therapy arms, respectively. At baseline, median (range) GH was 7.1 (1.0-200) mcg/L, 5.3 (1.4-113.8) mcg/L and 6.1 (1.0-92.4) mcg/L in the Signifor LAR 40 mg, 60 mg and the pre-trial therapy arms, respectively. The efficacy endpoint noted was the proportion of patients with a mean GH level less than 2.5 mcg/L and normal IGF-1 levels at week 24. The primary analysis compared Signifor LAR 40 mg and 60 mg to continued pretrial therapy (i.e., no change in treatment). At 6 months, the proportion of patients achieving biochemical control was 20.0% and 15.4% for Signifor LAR 60 mg and 40 mg, respectively. Seventy percent and 81 percent of patients treated with Signifor LAR 60 mg and 40 mg, respectively, had either a reduction or no change in tumor volume from baseline assessed by MRI at month 6. The median (range) change in tumor volume was a reduction of -10.4% (-74.5% to 19.4%) and -6.3% (-66.7% to 14.5%) from baseline for Signifor LAR 40 mg and 60 mg, respectively. (1)
Carcinoid Syndrome in Patients with Metastatic Neuroendocrine Tumor of the Digestive Tract
In 2015 Wolin et al. conducted a phase III study of patients with metastatic neuroendocrine tumors and carcinoid symptoms who were refractory to first-generation somatostatin analogues. (9) Adults were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Symptom control based on frequency of bowel movements and flushing episodes was the primary outcome. The secondary outcome was objective tumor response. A post hoc analysis included progression-free survival (PFS) information. The authors note that at the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27-1.97; P=0.53). Other results noted by the authors included tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89-4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 - not reached) with pasireotide versus 6.8 months (5.6 - not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20-0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs. 0%). The authors concluded among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.
In a Phase 3, randomized, double-blind, multicenter study, 150 patients with a screening mean urinary free cortisol level (mUFC) ≥ 1.5 and ≤ 5 x upper limits of normal (ULN), were randomized in a 1:1 ratio to receive a Signifor LAR starting dose of either 10 mg intramuscularly once every 28 days or 30 mg intramuscularly once every 28 days. (1) The purpose of this study was to evaluate the safety and efficacy of two dose regimens of Signifor LAR in patients with persistent or recurrent Cushing’s disease, or de novo patients who were not considered candidates for pituitary surgery, over a 12-month treatment period. The primary efficacy endpoint was the proportion of patients in each arm who were mUFC responders (mUFC ≤ ULN) after seven months of treatment, with or without up-titration at Month 4. The key secondary endpoint was the proportion of patients in each arm who were mUFC responders after seven months of treatment and who did not up-titrate the dose prior to Month 7. Other data evaluated as secondary endpoints included changes from baseline in 24-hour UFC, plasma adrenocorticotropic hormone (ACTH), and serum cortisol levels. Primary efficacy objectives were met for both dose groups. At Month 7, 39.2% (95% CI: 28.0, 51.2) of patients in the 10 mg arm and 40.8% (95% CI: 29.7, 52.7) of patients in the 30 mg arm were considered responders if they achieved a Month 7 mUFC ≤ 1xULN. At Month 12, 35.1% (26/74) of patients and 25.0% (19/76) of patients in the 10 mg and 30 mg starting dose groups, respectively, were considered responders. Key secondary efficacy objectives were met for both dose groups. Reductions were also noted in serum cortisol and plasma ACTH levels at Months 7 and 12 for each dose group.
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1. Department of Health and Human Services. Highlights of Prescribing Information for Signifor LAR (pasireotide) for injectable suspension, for intramuscular use (Reference ID: 4285411). Available at <http://www.accessdata.fda.gov> (accessed July 18, 2018).
2. Department of Health and Human Services New Drug Application (NDA)/Approval for Signifor LAR (pasireotide) for injectable suspension, for intramuscular use. Available at <http://www.accessdata.fda.gov> (accessed June 20, 2017).
3. Acromegaly-Mayo Clinic. Diseases and Conditions Acromegaly. Available at <http://www.mayoclinic.org> (accessed August 17, 2015).
4. Katnelson L, Atkinson John et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly-2011 Update. Endocrine Practice Vol 17 (Suppl 4) July/August 2011.
5. Katznelson L, Laws E R et al. Clinical Practice Guideline Acromegaly: An Enodcrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, November 2014, 99(11):3933-3951.
6. Colao A, Bronstein MD, Freda P, et al Pasireotide versus octreotide in acromegaly: a head-to- head superiority study. J Clin Endocrinol Metab. 2014 Mar; 99(3):791-9. PMID: 24423324.
7. Gadelha M.R., Bronstein, MD, Brue T, et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomized, phase 3 trial. Lancet Diabetes Endocrinol, 2014 Nov; 2(11):875-84. PMID: 25260838.
8. Pasireotide. In: IBM Micromedex® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Micromedex. Available at <http://www.micromedexsolutions.com> (accessed July 9, 2018).
9. Wolin E, Jarzab B, Eriksson B, et al. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015 Sep 3; 9:5075-86. PMID 26366058
10. National Institute of Diabetes and Digestive and Kidney Diseases. Acromegaly. Available at <https://www.niddk.nih.gov> (accessed June 26, 2017).
11. National Library of Medicine - PubMed Health. Acromegaly. Available at <https://www.ncbi.nlm.nig.gov> (accessed June 26, 2017).
12. Department of Health and Human Services New Drug Application (NDA)/Approval for Signifor LAR (pasireotide) for injectable suspension, for intramuscular use (Supplement Approval June 29, 2018). Available at <http://www.accessdata.fda.gov> (accessed July 18, 2018).
13. National Institute of Diabetes and Digestive and Kidney Diseases. Cushing’s Syndrome. Available at <https://www.niddk.nih.gov> (accessed August 7, 2018).
14. National Institute of Neurological Disorders and Stroke. Cushing’s Syndrome Information Page. Available at <https://www.ninds.nih.gov> (accessed August 7, 2018).
|Date||Reason TBD Document updated with literature review. The following was added to the Coverage section: 1) Clarification of adult patients was added to medically necessary criteria, and 2) Signifor® LAR (pasireotide) injectable suspension, for intramuscular use, may be considered medically necessary for the treatment of adult patients with Cushing’s disease when pituitary surgery: is not an option or, has not been curative 3) Approval duration (initial and reauthorization): 12 months. References 12-14 were added.|
|9/15/2017||Document updated with literature review. The following was added to the Coverage section: Signifor® LAR (pasireotide) injectable suspension, for intramuscular use, may be considered medically necessary for carcinoid syndrome, inadequately controlled with first generation somatostatin analogs in patients with metastatic neuroendocrine tumor of the digestive tract. Title changed to the following: Signifor® LAR (pasireotide)|
|11/1/2016||Reviewed. No changes.|
|1/1/2016||New medical document. Signifor® LAR (pasireotide) injectable suspension, for intramuscular use, may be considered medically necessary for the treatment of patients with acromegaly who have had: An inadequate response to surgery, and/or for whom surgery is not an option.|
|Title:||Effective Date:||End Date:|
|Signifor LAR (pasireotide)||09-15-2017||02-14-2019|
|Signifor LAR (pasireotide for injection suspension)||11-01-2016||09-14-2017|
|Signifor LAR (pasireotide for injection suspension)||01-01-2016||10-31-2016|