| Coverage Policy Manual | |
| Policy #: | 2015026 |
| Category: | Pharmacy |
| Initiated: | September 2015 |
| Last Review: | December 2023 |
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| Pasireotide (e.g., Signifor or Signifor LAR) | |
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| Description: |
Pasireotide (e.g., Signifor® and Signifor® LAR) is a somatostatin analog indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. Signifor® is administered by subcutaneous injection twice daily and Signifor® LAR is an IM injection administered once every 28 days.
The most common adverse reactions occurring in ≥20% of patients are diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus. The following testing is recommended prior to the initiation of pasireotide: fasting plasma glucose, hemoglobin A1c, liver tests, electrocardiogram (ECG), and gallbladder ultrasound, serum potassium and magnesium levels.
Other similar drugs to treat Cushing’s include corticorelin, ovine, mifepristone, RU-486, and off-label for cyproheptadine, metyrapone, and mitotane. The level of hyperglycemia is higher with pasireotide.
The following information is found from the National Institutes of Health on the National Library of Medicine website (https://www.nlm.nih.gov/medlineplus/ency/article/000348.htm).
Cushing disease (CD) is a condition in which the pituitary gland releases too much adrenocorticotropic hormone (ACTH). The pituitary gland is an organ of the endocrine system located at the base of the brain. CD is caused by a tumor or excess growth (hyperplasia) of the pituitary gland. A type of pituitary tumor called an adenoma is the most common cause. An adenoma is almost always benign (not a cancer).
With Cushing disease, the pituitary gland releases too much ACTH which stimulates production and release of cortisol, a stress hormone. Too much ACTH causes the adrenal glands to make too much cortisol. Cortisol is normally released during stressful situations. It controls the body's use of carbohydrates, fats, and proteins and also helps reduce the immune system's response to swelling (inflammation).
Treatment involves surgery to remove the pituitary tumor, if possible. After surgery, the pituitary gland may slowly start to work again and return to normal. During the recovery process, you may need cortisol replacement treatments. Radiation treatment of the pituitary gland may also be used if the tumor is not completely removed. If the tumor does not respond to surgery or radiation, you may need medicines to stop your body from making cortisol. If these treatments are not successful, the adrenal glands may need to be removed to stop the high levels of cortisol from being produced.
Untreated, Cushing disease can cause severe illness, even death. Removal of the tumor may lead to full recovery, but the tumor can grow back.
Other similar drugs have been used for a much longer period of time and include bromocriptine, lanreotide, octreotide, and pegvisomant. All of these drugs have similar adverse effects but the level of hyperglycemia is higher with pasireotide.
Regulatory Status
Signifor® was initially approved by the FDA in 2012 for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.
Signifor® LAR was initially approved by the FDA in 2012 for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.
On 6/2018 an indication was added for Signifor® LAR, for the treatment of patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
Effective December 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Pasireotide (e.g., Signifor® or Signifor® LAR) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative (FDA, 2020) when the following criteria are met (AACE, ES):
Dosage and Administration
Dosing per FDA Guidelines
Pasireotide (e.g., Signifor®) - The recommended initial dosage is either 0.6 mg or 0.9 mg by sub Q injection twice a day; recommended dosage range is 0.3 mg to 0.9 mg twice a day.
Pasireotide (e.g., Signifor) is available as an injection: 0.3 mg/mL, and 0.9 mg/mL in a single-dose ampule.
Pasireotide (e.g., Signifor® LAR) – For Cushing’s Disease, the recommended initial dose is 10 mg administered by intramuscular injection once every 4 weeks (every 28 days). Following 4 months of treatment with the initial dose of 10 mg once every 28 days, the dose may be increased for patients who have not normalized 24-hr urinary free cortisol (UFC and who tolerate this dose, up to a maximum dose of 40 mg once every 28 days. Signifor LAR must be administered by a health care professional, only by IM injection in the right or left gluteus.
Pasireotide (e.g., Signifor LAR) is available for in injectable suspension: 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg powder in a vial to be reconstituted with the provide 2 mL diluent.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Pasireotide (e.g., Signifor® or Signifor® LAR), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes including but not limited to acromegaly.
For members with contracts without primary coverage criteria Pasireotide (e.g., Signifor® or Signifor® LAR), for any indication or circumstance not described above, is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective December 2022 to November 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Pasireotide (e.g., Signifor® or Signifor® LAR) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative (FDA, 2020) when the following criteria are met (AACE, ES):
Dosage and Administration
Pasireotide (e.g., Signifor®) - The recommended initial dosage is either 0.6mg or 0.9mg by sub Q injection twice a day; recommended dosage range is 0.3mg to 0.9 mg twice a day.
Pasireotide (e.g., Signifor) is available as an injection: 0.3 mg/mL, and 0.9 mg/mL in a single-dose ampule.
Pasireotide (e.g., Signifor® LAR) – For Cushing’s Disease, the recommended initial dose is 10 mg administered by intramuscular injection once every 4 weeks (every 28 days). Following 4 months of treatment with the initial dose of 10 mg once every 28 days, the dose may be increased for patients who have not normalized 24-hr urinary free cortisol (UFC and who tolerate this dose, up to a maximum dose of 40mg once every 28 days. Signifor LAR must be administered by a health care professional, only by IM injection in the right or left gluteus.
Pasireotide (e.g., Signifor LAR) is available for in injectable suspension: 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg powder in a vial to be reconstituted with the provide 2 mL diluent.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Pasireotide (e.g., Signifor® or Signifor® LAR) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to treat any disorder other than Cushing’s disease, including but not limited to acromegaly.
For members with contracts without primary coverage criteria Pasireotide (e.g., Signifor® or Signifor® LAR) is considered investigational when used to treat any disorder other than Cushing’s disease.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective December 2019 to November 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Pasireotide (Signifor® or Signifor® LAR) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative (FDA, 2020) when the following criteria are met (AACE, ES):
Dosage and Administration
Signifor® - The recommended initial dosage is either 0.6mg or 0.9mg by sub Q injection twice a day; recommended dosage range is 0.3mg to 0.9 mg twice a day.
Signifor® LAR – For Cushing’s Disease, the recommended initial dose is 10 mg administered by intramuscular injection once every 4 weeks (every 28 days). Following 4 months of treatment with the initial dose of 10 mg once every 28 days, the dose may be increased for patients who have not normalized 24-hr urinary free cortisol (UFC and who tolerate this dose, up to a maximum dose of 40mg once every 28 days. Signifor LAR must be administered by a health care professional, only by IM injection in the right or left gluteus.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Pasireotide (Signifor® or Signifor® LAR) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to treat any disorder other than Cushing’s disease, including but not limited to acromegaly.
For members with contracts without primary coverage criteria Pasireotide (Signifor® or Signifor® LAR) is considered investigational when used to treat any disorder other than Cushing’s disease.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective December 2018 to November 2019
Pasireotide (Signifor® or Signifor® LAR) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative when the following criteria are met:
Pasireotide (Signifor® or Signifor® LAR) does not meet member benefit certificate primary coverage criteria to treat any disorder other than Cushing’s disease, including but not limited to acromegaly.
For members with contracts without primary coverage criteria Pasireotide (Signifor® or Signifor® LAR) is considered investigational and/or not medically necessary when used to treat any disorder other than Cushing’s disease. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Dosage and Administration
Signifor® - The recommended initial dosage is either 0.6mg or 0.9mg by sub Q injection twice a day; recommended dosage range is 0.3mg to 0.9 mg twice a day.
Signifor® LAR – For Cushing’s Disease, the recommended initial dose is 10 mg administered by intramuscular injection once every 4 weeks (every 28 days). Following 4 months of treatment with the initial dose of 10 mg once every 28 days, the dose may be increased for patients who have not normalized 24-hr urinary free cortisol (UFC and who tolerate this dose, up to a maximum dose of 40mg once every 28 days. Signifor LAR must be administered by a health care professional, only by IM injection in the right or left gluteus.
Effective Prior to September 2018
The use of pasireotide (Signifor) meets primary coverage criteria for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative when the following criteria are met:
The use of pasireotide to treat any disorder other than Cushing’s disease, including but not limited to acromegaly, does not meet primary coverage criteria due to lack peer-reviewed medical literature describing safety and effectiveness.
For contracts without primary coverage criteria the use of pasireotide is considered investigational when used to treat any disorder other than Cushing’s disease.
There are a number of ongoing clinical trials using pasireotide to treat various other conditions at (www.clinicaltrials,gov ).
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| Rationale: |
The FDA approved labeling cites a 12 month phase 3 study of Pasireotide in Cushing’s disease (Colao et al, 2012) in which 162 adults with confirmed persistent or recurrent Cushing’s disease or newly diagnosed disease if not candidates for surgery. Exclusion criteria included pituitary irradiation within the previous 10 years, compression of the optic chiasm causing visual-field defects, symptomatic cholelithiasis, or glycated hemoglobin. Patients were assigned to 600 µg or 900 µg twice daily. Patients with a urinary free cortisol level not exceeding the baseline level at month 3 continued to receive their randomly assigned dose through month 6. Study assignments were revealed to all other patients at month 3 and the doses were increased by 300 µg twice daily. At month 6 patients entered an open-label phase through month 12. If the urinary free cortisol level was above the upper limit of normal the dose could be increased by 300 µg twice daily (maximum dose 1200 µg at any time). At baseline 78% of patients had moderate-to-very-severe hypercortisolism. The median urinary free cortisol level decreased by approximately 50% by month two in both treatment groups and remained stable. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the limit of the normal ranges than in patients with higher baseline levels. Most patients, approximately 90%, whose hypercortisolism was uncontrolled at months 1 and 2 continued to have uncontrolled hypercortisolism at months 6 and 12. The reduction in urinary free cortisol level was accompanied by reduction in serum cortisol and plasma corticotropin levels. Body weight, systolic and diastolic blood pressure and, and LDL cholesterol levels were significantly reduced and scores for health-related quality of life improved.
The 2014 Endocrine Society Guidelines for Acromegaly make no mention of pasireotide.
The AACE Guidelines for Acromegaly, not updated since 2011, do not mention pasireotide.
Sheppard et al. reported results of an extension study involving 120 patients (core study n=358 x 12 months). These patients continued to receive their randomized therapy: pasireotide LAR (n=74) or octreotide LAR (n=46). At month 25 biochemical control (GH <2.5 µg/L and normal IGF-1) was achieved by 48.6% and 45.7% of patients in the pasireotide LAR and octreotide LAR arms respectively. In total, 74.7% of pasireotide LAR and 71.6% of octreotide LAR patients had tumor volume decrease ≥ 20% from baseline to month 26. Most adverse effects were mild or moderate. Hyperglycemia-related AEs were seen in 62.9 and 25.0% of pasireotide LAR and octreotide LAR patients, respectively. The safety profile of pasireotide LAR is typical of a somatostatin analogue, except for the frequency and degree of hyperglycemia.
Signifor® LAR for Cushing’s disease
A Phase 3, randomized, double-blind multicenter study was conducted to evaluate the safety and efficacy of two dose regimens of SIGNIFOR LAR over a 12-month treatment period in patients with persistent or recurrent Cushing’s disease or de novo patients who were not considered candidates for pituitary surgery.
The study enrolled 150 patients with a screening mean urinary free cortisol level (mUFC) ≥1.5 and ≤5 x ULN, who 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. Randomization was stratified by values of mUFC at screening (1.5 to < 2xULN versus 2 to 5xULN, respectively).
After twelve months of treatment (core phase), patients had the option to enter an extension to continue to receive SIGNIFOR LAR if they benefited from treatment. 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. The pre-specified boundary of the lower limit of the 95% confidence interval for efficacy for both the primary and key secondary endpoints was 15%. Patients with missing mUFC assessment at Month 7 were classified as non-responders. Other secondary endpoints included changes from baseline in 24-hour UFC, plasma ACTH, and serum cortisol levels. All analyses were conducted based on the randomized dose groups.
The study met the primary efficacy objective for both dose groups. Patients were considered responders if they remained on treatment until at least Month 7 and achieved a Month 7 mUFC ≤ 1xULN, regardless of up titration at Month 4. The proportion of patients with mUFC response at Month 7 was 39.2% (95% CI: 28.0, 51.2) in the 10 mg arm and 40.8% (95% CI: 29.7, 52.7) in the 30 mg arm. The responder rate at Month 12 was 35.1% (26/74) and 25.0% (19/76) in the 10 mg and 30 mg starting dose groups, respectively.
There are a number of ongoing clinical trials using pasireotide to treat various other conditions at (www.clinicaltrials,gov ).
2017 Update
A literature search conducted through August 2017 did not reveal any new information that would prompt a change in the coverage statement.
2018 Update
A literature search conducted through December 2018 did not reveal any new information that would prompt a change in the coverage statement.
2019 Update
The efficacy and safety of subcutaneous pasireotide have been evaluated in a Phase III trial. The safety and efficacy results are from a multinational, expanded-access study of pasireotide sc in patients with Cushing's disease (CD) in a real-world setting (clinicaltrials.gov, identifier: NCT01582061).
Adults with active CD previously untreated with pasireotide were enrolled; pasireotide sc was initiated at 600 μg twice daily or 900 μg bid. Pasireotide dose could be adjusted in 300 μg increments/decrements to a maximum of 900 μg bid or minimum of 300 μg bid for sustained urinary free cortisol (UFC) normalization/tolerability issues. The primary objective was to document the safety of pasireotide sc in patients with CD. Key secondary objectives were to assess the proportion of patients with mean UFC (mUFC) not exceeding the upper limit of normal (ULN) and changes from baseline in clinical signs/symptoms and quality of life (QoL) to weeks 12, 24, and 48.
One hundred and four patients received pasireotide. Forty patients completed the study. The most common reasons for premature discontinuation of pasireotide were unsatisfactory therapeutic effect and adverse events. Drug-related grade 3/4 AEs or drug-related serious AEs were documented in 42 patients, most commonly diabetes mellitus and hyperglycemia. All patients experienced ≥1 AE and most reported ≥1 drug-related AE; six patients discontinued treatment because of hyperglycemia-related AEs. At weeks 12, 24, and 48, respectively, 36/66, 22/46, and 9/21 evaluable patients had normalized mUFC levels. Clinical signs/symptoms and QoL were also improved.
In an international, real-world, clinical-practice setting, pasireotide sc was generally well-tolerated, effectively reduced UFC and improved clinical signs and QoL in patients with CD. (Fleseriu M, et al., 2019).
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2020. No new literature was identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
In the multinational, randomized, double-blind, Phase 3 B2305 study of patients with Cushing's disease (CD; ClinicalTrials.gov identifier NCT00434148), pasireotide substantially decreased urinary-free cortisol (UFC) levels, decreased mean corticotroph tumor volume, and improved clinical signs of disease. The current post hoc analysis further assesses the effects of pasireotide on corticotroph pituitary tumor volume.
Patients enrolled in the B2305 study had persistent or recurrent CD or newly diagnosed CD but were not surgical candidates. Enrollees were randomized to receive subcutaneous pasireotide, either 600-μg or 900-μg twice daily. Tumor volume was assessed independently at months 6 and 12 by 2 blinded radiologists and compared with baseline value and UFC response.
Of 162 patients enrolled in the trial, 53 had measurable tumor volume data and were included in the post hoc analysis. Reductions in tumor volume were both dose and time dependent. Tumor volume reduction was more frequently observed at month 6 in the 900-μg group (75%) than in the 600-μg group (44%). Similarly, at month 12 (n = 32), tumor volume reduction was observed more frequently in the 900-µg group (89%) than in the 600-µg group (50%). Control of UFC levels was not required for reduction of tumor volume. No relationship was noted between baseline tumor size and change in tumor size.
Measurable decreases in pituitary tumor volume were observed in a large proportion of patients with CD and measurable tumor volume who were enrolled in the trial and treated with subcutaneous pasireotide; this decrease was not correlated with UFC control. (Lacroix A, Gu F, Schopohl J, et. al., 2020)
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.
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| CPT/HCPCS: | |
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| References: |
Colao A, Petersenn S, et al.(2012) A 12-month phase 3 study of pasireotide in Cushing's disease. NEJM, 2012; 366:914-24. Fleseriu M, Iweha C, Salgado L, et al.(2019) Safety and Efficacy of Subcutaneous Pasireotide in Patients With Cushing's Disease: Results From an Open-Label, Multicenter, Single-Arm, Multinational, Expanded-Access Study. Front Endocrinol (Lausanne). 2019;10:436. Published 2019 Jul 16. doi:10.3389/fendo.2019.00436 Katznelson L, Atkinson J, et al.(2011) American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis & Treament of Acromegaly-2011 Update. Endocrine Practice, 2011; Vol 17(Suppl4). Katznelson L, Laws ER Jr, et al.(2014) Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2014; 99:3933-51. Lacroix A, Gallardo W, Pivonello R, et al.(2018) Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 month clinical trial. Lancet Diabetes Endoncrinol. 2018 Jan;6(1):17-26. doi: 10.1016/S2213-8587(17)30326-1. Epub 2017 Oct 12. Lacroix A, Gu F, Schopohl J, Kandra A, Pedroncelli AM, Jin L, Pivonello R.(2020) Pasireotide treatment significantly reduces tumor volume in patients with Cushing's disease: results from a Phase 3 study. Pituitary. 2020 Jun;23(3):203-211. doi: 10.1007/s11102-019-01021-2. PMID: 31875276; PMCID: PMC7181422. McKeage K.(2015) Pasireotide in acromegaly: A review. Drugs, 2015; 75:1039-48. Samson SL.(2015) Pasireotide in acromegaly: An overview of current mechanistic and clinical data. Neuroendocrinol, 2015; 102-8-17. Sheppard M, Bronstein MD, et al.(2015) Paireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double-blind, multicenter Phase III study. Pituitary, 2015; 18:385-394. SIGNIFOR® (pasireotide)(2020) [package insert]. East Hanover, NJ, Novartis Pharmaceuticals Corporation; 2020 SIGNIFOR® LAR (pasireotide)(2020) [package insert]. Lebanon, NJ, Recordati Rare Disease, Inc.; 2020 Webb SM, Ware JE, et al.(2014) Treatment effectiveness of pasireotide on health-related quality of life in patients with Cushing's disease. Eur J Endocrinol, 2014; 171:89-98. |
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association. |
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