PHARMACY POLICY – 5.01.553 Myalept® (metreleptin)

Effective Date: Aug. 1, 2021 RELATED MEDICAL POLICIES: Last Revised: July 13, 2021 None Replaces: N/A

Select a hyperlink below to be directed to that section.

POLICY CRITERIA | DOCUMENTATION REQUIREMENTS | CODING RELATED INFORMATION | EVIDENCE REVIEW | REFERENCES | HISTORY

∞ Clicking this icon returns you to the hyperlinks menu above.

Introduction

Lipodystrophy is a condition in which there is little or no fat tissue in the body. If a person is born with the condition, it’s known as congenital lipodystrophy. Acquired lipodystrophy refers to the condition when it’s not inherited. Acquired lipodystrophy can arise because of medications, problems with the immune system, or for an unknown reason. A lack of body fat results in low levels of the hormone leptin. Leptin controls specific process in the body, and not having enough of this hormone can lead to other health problems, like too much fat in the blood and high blood sugar. Myalept® is a drug that can be used in some cases to treat low levels of leptin. This policy describes when this drug may be considered medically necessary.

Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.

Policy Coverage Criteria

Drug Medical Necessity Myalept® (metreleptin) SC Myalept® (metreleptin) may be considered medically necessary as an adjunct to diet to treat the complications of leptin deficiency in patients with congenital or acquired lipodystrophy when the following criteria are met: • Patient has a confirmed diagnosis of leptin deficiency AND • Documentation that Myalept® (metreleptin) is being used along with a doctor-recommended diet for generalized lipodystrophy AND • Patient has one of the following metabolic abnormalities at baseline: o Diabetes mellitus and an HbA1c ≥ 7% with optimized insulin therapy o Fasting triglyceride values of ≥ 250 mg/dL after treatment with two or more lipid lowering agents AND • Myalept® (metreleptin) is prescribed by or in consultation with an endocrinologist AND • The dose prescribed is ≤ 10 mg once daily

Drug Investigational Myalept® (metreleptin) Use of Myalept® (metreleptin) for all other indications is considered investigational.

Length of Approval Approval Criteria Initial authorization Myalept® (metreleptin) may be approved up to 12 months. Re-authorization criteria Future re-authorization of Myalept® (metreleptin) may be approved up to 12 months as long as the drug-specific coverage criteria are met, chart notes document the patient is

tolerating therapy, and there is a decrease in HbA1c and/or fasting triglyceride levels from baseline.

Page | 2 of 12 ∞ Documentation Requirements The patient’s medical records submitted for review for all conditions should document that medical necessity criteria are met. The record should include the following: • Office visit notes that contain the diagnosis, relevant history, physical evaluation, patient specific diet, prescribed dose, and documented metabolic abnormality

Coding

N/A

Related Information

Benefit Application

This drug is managed through the Pharmacy benefit.

Evidence Review

Description

Disease Characteristics & Pathophysiology

Lipodystrophy is a group of clinically heterogeneous metabolic disorders that are either acquired or inherited and result in loss of adipose tissue. This leads to disruption of various metabolic pathways. The disease is classified primarily based on 2 factors: whether it is genetic or acquired and whether fat loss is generalized or partial. Therefore, there are 4 major classifications:

• Congenital generalized lipodystrophy (CGL), also known as Berardinelli–Seip syndrome

• Familial partial lipodystrophy (FPL)

Page | 3 of 12 ∞ • Acquired generalized lipodystrophy (AGL)

• Acquired partial lipodystrophy (APL), also known as Barraquer–Simons syndrome

This general classification scheme is not inclusive of all lipodystrophies because rare lipodystrophies, such as mandibuloacral dysplasia, neonatal progeria, and atypical progeria, may not fit exactly into one of the 4 main subgroups. Further, one patient may fall into more than 1 main subgroups.

Many genetic mutations have been identified in congenital and familial lipodystrophies, such as AGPAT2, seipin, LMNA, PPARγ, ZMPSTE24, and LMNB2. These mutations can follow autosomal recessive (AGPAT2, seipin) or autosomal dominant (LMNA) inheritance patterns. Acquired lipodystrophies can be autoimmune-associated. Patients with CGL, AGL, and APL often present with metabolic abnormalities during childhood or adolescence, whereas those with FPL tend to present later in adolescence and adulthood.

Adipose tissue is an endocrinologically active tissue as it secretes multiple hormones (leptin and adiponectin) and cytokines. Leptin is a key regulator in energy homeostasis as well as fat and glucose metabolism. The relative leptin deficiency that occurs as a result of loss of adipose tissue has been implicated as a key pathogenic mechanism underlying lipodystrophy. Lipodystrophy is associated with deposition of fat in ectopic locations (eg, liver and muscle) and metabolic abnormalities (eg, insulin resistance, hypertriglyceridemia, and diabetes).

Common clinical complications and manifestations of lipodystrophy include:

• Insulin-resistant diabetes mellitus and resulting complications

• Severe hypertriglyceridemia, which may lead to acute pancreatitis

• Hepatic steatosis or steatohepatitis which may progress to cirrhosis

• Proteinuric nephropathies, which may lead to renal failure

• Severe cardiovascular complications, such as premature atherosclerotic disease and hypertrophic cardiomyopathy

• Reproductive and hormonal abnormalities in women

• Increased appetite leading to hyperphagia

Page | 4 of 12 ∞ Epidemiology and Risk Factors

Lipodystrophy is a rare disease. According to a 2004 review, approximately 800 cases of lipodystrophy (CGL, FPL, AGL, and APL, excluding HIV-related lipodystrophy) have been reported in the literature. Because of the rarity of the condition, epidemiologic data for this disease are not available.

Clinical Presentation

The clinical presentation of lipodystrophy varies by type of lipodystrophy and from patient-to- patient. Extreme loss of subcutaneous fat is apparent from birth in CGL, while it becomes apparent at puberty in patients with FPL. In APL patients, there is loss of fat from the face, neck, arms, and trunk, but legs are spared. In AGL patients, there is generalized loss of fat associated with tender subcutaneous nodules along with autoimmune or other diseases. Affected patients are predisposed to insulin resistance and its attendant complications, such as diabetes mellitus, dyslipidemia, hepatic steatosis, and acanthosis nigricans. Features of polycystic ovary syndrome that include hirsutism, oligoamenorrhea, and polycystic ovaries may develop in affected women. The impact of the disease on physical appearance can cause severe psychological distress in many patients.

Diagnosis

Generalized lipodystrophies are easily detected clinically and are usually diagnosed by pediatricians because of the characteristic features from birth onwards. Partial lipodystrophies, on the other hand, are more difficult to recognize, only causing metabolic abnormalities later in life. Because many metabolic features of partial lipodystrophy resemble those of metabolic syndrome and/or type 2 diabetes mellitus, patients with FPL are often misdiagnosed. The only clinical signs that are unique to such patients are lipoatrophy and the onset of severe metabolic abnormalities.

The American Association of Clinical Endocrinologist has recently published a consensus statement for diagnosis of lipodystrophy. This consensus statement describes the clinical approach for diagnosis of lipodystrophy. These statements only summarize certain clinical features that may arouse suspicion of lipodystrophy but are not definitive of a diagnosis.

Page | 5 of 12 ∞ American Association of Clinical Endocrinologist Criteria That Raise Clinical Suspicion of Lipodystrophy

Core clinical characteristic for lipodystrophy:

• Loss or absence of subcutaneous body fat in a partial or generalized fashion

Core clinical characteristic for Familial partial lipodystrophy:

• Loss of subcutaneous body fat, typically occurring around or shortly after puberty, occurring in the extremities and/or gluteal region with sparing of fat loss or accumulation of excess fat in the face and neck or intra-abdominal area

Supportive clinical characteristics for lipodystrophy:

• Presence of diabetes with evidence of severe insulin resistance

• Diabetes mellitus with requirement for high doses of insulin

• Ketosis-resistant diabetes

• Other evidence of severe insulin resistance

• Acanthosis nigricans

• PCOS or PCOS-like symptoms (hyperandrogenism, oligomenorrhea, and/or polycystic ovaries)

• Presence of hypertriglyceridemia

• Severe hypertriglyceridemia (≥500 mg/dL)

• Triglyceride levels that are nonresponsive to therapy and/or modifications to diet (≥250 mg/dL)

• History of pancreatitis associated with hypertriglyceridemia

• Evidence of hepatic steatosis or steatohepatitis

• Hepatomegaly and/or elevated transaminases in the absence of a known cause of liver disease (eg, viral hepatitis) may be consistent with nonalcoholic fatty liver disease

• Radiographic evidence of hepatic steatosis (eg, on ultrasound or computed tomography)

• Family history of similar physical appearance and/or history of fat loss

Page | 6 of 12 ∞ • Prominent muscularity and phlebomegaly (enlarged veins) in the extremities

• Disproportionate hyperphagia (cannot stop eating, waking up to eat, fighting for food)

• Secondary hypogonadism in a male or primary/secondary amenorrhea in a female patient

Therapeutic Options

The primary goal of treatment in patients with lipodystrophies is to prevent morbidity and mortality as a result of diabetes mellitus, recurrent episodes of acute pancreatitis and cirrhosis.

Current treatment options for lipodystrophies include antidiabetic and lipid-lowering medications. These treatment options may address the metabolic abnormalities associated with lipodystrophy, but not the underlying pathophysiologic abnormalities. Further, these treatments are often rendered marginally effective by the severity of the abnormalities observed in patients with lipodystrophy.

Hypertriglyceridemia and hyperglycemia should be managed by lifestyle change. Low fat diet, regular exercise, aggressive glycemic controls are recommended. If hypertriglyceridemia persists despite changes in diet, regular exercise, and maintenance of euglycemia, patients should be treated with fibrates and high doses of fish oils containing n-3 polyunsaturated fats. Aggressive glycemic control is pivotal for the prevention of the long-term complications of diabetes. Oral hypoglycemic drugs, particularly metformin, which may additionally reduce appetite, induce weight loss, and improve the polycystic ovary syndrome and hepatic steatosis, is a particularly attractive therapeutic choice. Insulin may also be used if hyperglycemia is not adequately controlled by oral hypoglycemia agents. Estrogens, whether taken for contraception, polycystic ovary syndrome, or postmenopausal symptoms, may exacerbate hypertriglyceridemia and should be avoided. Patients with hypertriglyceridemia and hepatic steatosis should be advised to avoid drinking alcohol.

Rationale

Efficacy of metreleptin consists entirely of small observational studies. The largest was an NIDDK sponsored open-label single-arm study of patients with generalized lipodystrophy (non-HIV- related) and diabetes, insulin resistance, or hypertriglyceridemia. There is some question about the size of the study, since the original publication reported 55 subjects (Chan, 2011), but a

Page | 7 of 12 ∞ more recent abstract lists 64 and the prescribing information says 48. It is not clear why some patients were excluded from the FDA-approved label.

Treatment with metreleptin reduced mean HbA1c from baseline at 4 months -1.2% (95% CI, -1.6 to -0.8) (n=40) and at 3 years -2.1% (95% CI, -3.2 to -1.1) (n=18). Among all patients, the change in triglycerides from baseline to 4 months was -44.4 mg/dL (95% CI, -58.8 to -29.9) (n=40) and at 3 years it was -35.4 mg/dL (95% CI, -64.1 to -6.7) (n=19). These subjects were a heterogeneous group with varying type and level of metabolic abnormalities at baseline. In subgroups of patients whose HbA1c and triglyceride levels were elevated at baseline, the HbA1c reduction at 4 months and 3 years were -1.4 (95% CI, -1.8 to -0.9) and -2.6 (95% CI, -3.8 to -1.3) (n=14). The mean reduction in triglycerides among patients with elevated levels at baseline at 4 months and 3 years were -44.4 mg/dL (95% CI, -58.8 to -29.9) (n=30) and -51.2 mg/dL (95% CI, - 87.5 to -14.8) (n=13), respectively. There was greater response in patients with elevated HbA1c and triglycerides at baseline. These results were consistent with those from smaller studies.

Due to the subjects’ heterogeneity and the absence of a control group, it is difficult to quantify the true treatment effect of metreleptin. Changes in concomitant medications, diet or exercise may have confounded the results. Eighty four percent of patients displayed immunogenicity and expressed anti-metreleptin antibodies. Anti-metreleptin antibodies with neutralizing activity are associated with loss of endogenous leptin activity as well as loss of metreleptin efficacy, as occurred in 6% of study patients.

Most common adverse reactions in clinical trials were headache (13%), hypoglycemia (13%), decreased weight (13%) and abdominal pain (10%). T-cell lymphoma has been reported in 2 patients (4%). Both patients had immunodeficiency and severely abnormal bone marrow biopsy specimens at baseline. However, there was one case of anaplastic large cell lymphoma in a patient receiving metreleptin who did not have hematological abnormalities before treatment. Eighty four percent of patients displayed immunogenicity and expressed anti-metreleptin antibodies. Anti-metreleptin antibodies with neutralizing activity associated with adverse events consistent with loss of endogenous leptin activity and/or loss of metreleptin efficacy. Severe infection and/or worsening metabolic control have been reported as a result of anti-metreleptin antibodies (increases in HbA1c and/or triglycerides) and observed in 6% of patients. For these two specific reasons metreleptin is only available through the MYALEPT REMS program. There were cases of acute pancreatitis in 5 patients (9%). All of these patients had a history of pancreatitis and severe hypertriglyceridemia. Chronic renal adverse events reported in 5 patients (9%), all of whom had a history of renal disease at baseline. Elevated LFT or events of liver disease are reported in 4 patients (7%). Given the small number of patient exposures, it is difficult to assess the probability of other less common but serious adverse events occurring.

Page | 8 of 12 ∞ 2015 Update

A literature search from January 1, 2014, to June 28, 2015, was conducted. No new studies were found that would affect this policy.

2016 Update

A literature search from July 1, 2015, to December 6, 2016, was conducted. No new studies were found that would affect this policy. Additional reference included.

2017 Update

A literature search from July 1, 2016 to November 1, 2017 was conducted. No new studies were found that would affect this policy.

2018 Update

A literature search from November 1, 2017, to October 31, 2018, was conducted. No new studies were found.

2019 Update

Reviewed Myalept® (metreleptin) prescribing information and conducted a literature search from November 1, 2018, through November 30, 2019. No new information was identified that would require changes to this policy.

2020 Update

Reviewed Myalept® (metreleptin) prescribing information and conducted a literature search from December 1, 2019, through September 30, 2020. No new information was identified that would require changes to this policy.

Page | 9 of 12 ∞ 2021 Update

Reviewed Myalept® (metreleptin) prescribing information and updated policy based on FDA- approved indication for Myalept® and clinical studies referenced. Per prescribing information Myalept® is indicated as an adjunct to diet and the patient is to follow a doctor-recommended diet for generalized lipodystrophy. Updated requirements for the metabolic abnormalities

adding HbA1c and triglyceride values based on the clinical studies. Added requirement drug is prescribed by or in consultation with an endocrinologist and added a daily dose limit of 10 mg/day which is the maximum dose listed in the prescribing information. For the re- authorization criteria added specific requirements that the patient is tolerating therapy and that there is a decrease in HbA1c and/or fasting triglyceride levels from baseline.

References

1. Myalept® (metreleptin) prescribing information. Aegerion Pharmaceuticals, Inc.; Cambridge, MA. Revised September 2020.

2. Chan JL, Lutz K, Cochran E, et al. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr Pract. Nov-Dec 2011;17(6):922-932. PMID 22068254

3. Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. Feb 21 2002;346(8):570-578. PMID 11856796

4. Javor ED, Cochran EK, Musso C, Young JR, Depaoli AM, Gorden P. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes. Jul 2005;54(7):1994-2002. PMID 15983199

5. Ebihara K, Kusakabe T, Hirata M, et al. Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab. Feb 2007;92(2):532-541. PMID 17118991

6. Beltrand J, Beregszaszi M, Chevenne D, et al. Metabolic correction induced by leptin replacement treatment in young children with Berardinelli-Seip congenital lipoatrophy. Pediatrics. Aug 2007;120(2):e291-296. PMID 17671040

7. Oral EA NA, Hakim B, Miller S, Shan K, Irani B, Lutz K, Chan JL. Metabolic Effects of Metreleptin Treatment in Familial Partial Lipodystrophy (FPL) (Abstract). 94th Annual Meeting and Expo of the Endocrine Society. 2012: 3(3): MON-246

8. Simha V, Subramanyam L, Szczepaniak L, et al. Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety. J Clin Endocrinol Metab. Mar 2012;97(3):785-792. PMID 22170723

9. Safar Zadeh E, Lungu AO, Cochran EK, et al. The liver diseases of lipodystrophy: the long-term effect of leptin treatment. J Hepatol. Jul 2013;59(1):131-137. PMID 23439261

10. Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. Oct 27 1999;282(16):1568-1575. PMID 10546697

11. Shetty GK, Matarese G, Magkos F, et al. Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet. Eur J Endocrinol. Aug 2011;165(2):249-254. PMID 21602313

Page | 10 of 12 ∞ 12. Ravussin E, Smith SR, Mitchell JA, et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring). Sep 2009;17(9):1736-1743. PMID 19521351

13. Moon HS, Matarese G, Brennan AM, et al. Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance. Diabetes. Jun 2011;60(6):1647-1656. PMID 21617185

14. Lee JH, Chan JL, Sourlas E, Raptopoulos V, Mantzoros CS. Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy. J Clin Endocrinol Metab. Jul 2006;91(7):2605-2611. PMID 16636130

15. Magkos F, Brennan A, Sweeney L, et al. Leptin replacement improves postprandial glycemia and insulin sensitivity in human immunodeficiency virus-infected lipoatrophic men treated with pioglitazone: a pilot study. Metabolism. Jul 2011;60(7):1045- 1049. PMID 21081243

16. Chou SH, Chamberland JP, Liu X, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A. Apr 19 2011;108(16):6585-6590. PMID 21464293

17. Long-Term Efficacy of Leptin Replacement in Treatment of Lipodystrophy (Protocol 02-DK-0022). Available at: https://www.ncbi.nlm.nih.gov/pubmed/15983199 Accessed June 24, 2021.

18. Garg A. Acquired and inherited lipodystrophies. N Engl J Med. Mar 18 2004;350(12):1220-1234. PMID 15028826

19. Chan JL, Oral EA. Clinical classification and treatment of congenital and acquired lipodystrophy. Endocr Pract. Mar-Apr 2010;16(2):310-323. PMID 20061300

20. Haque WA, Shimomura I, Matsuzawa Y, Garg A. Serum adiponectin and leptin levels in patients with lipodystrophies. J Clin Endocrinol Metab. May 2002;87(5):2395. PMID 11994394

21. Oral EA, Chan JL. Rationale for leptin-replacement therapy for severe lipodystrophy. Endocr Pract. Mar-Apr 2010;16(2):324-333. PMID 20061299

22. Handelsman Y, Oral EA, Bloomgarden ZT, et al. The clinical approach to the detection of lipodystrophy - an AACE consensus statement. Endocr Pract. Jan-Feb 2013;19(1):107-116. PMID 23435042

23. Chou K, Perry CM. Metreleptin: first global approval. Drugs. Jun 2013;73(9):989-997. PMID 23740412

24. PMGroup Worldwide Ltd. Amylin and Takeda halt obesity drug study. Available at: http://www.pmlive.com/pharma_news/amylin_and_takeda_halt_obesity_drug_study_266050 Accessed June 24, 2021.

25. Chan JL, Wong SL, Orlova C, Raciti P, Mantzoros CS. Pharmacokinetics of recombinant methionyl human leptin after subcutaneous administration: variation of concentration-dependent parameters according to assay. J Clin Endocrinol Metab. Jun 2007;92(6):2307-2311. PMID 17405837

26. Chan JL, Wong SL, Mantzoros CS. Pharmacokinetics of subcutaneous recombinant methionyl human leptin administration in healthy subjects in the fed and fasting states: regulation by gender and adiposity. Clin Pharmacokinet. 2008;47(11):753-764. PMID 18840030

27. Brown RJ, et al. The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline. J Clin Endocrinol Metab. October, 2016; jc20162466. [Epub ahead of print].

28. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr Pract. 2011 Nov-Dec: 17(6): 922- 932. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498767/ Accessed June 24, 2021.

History

Page | 11 of 12 ∞ Date Comments 06/09/14 New policy, add to Prescription Drug section. Metreleptin (Myalept®) may be considered medically necessary for treatment of congenital or acquired lipodystrophy when all criteria are met; all other uses are considered investigational. Approved by P&T Committee on May 22, 2014.

07/14/15 Annual Review. Policy updated with literature review. No change to policy statement.

01/01/17 Annual Review, approved December 13, 2016. Policy updated with literature review. No changes made to the policy statement. Additional reference included.

12/01/17 Annual Review, approved November 14, 2017. Updated Myalept criteria. One reference was added.

12/01/18 Annual Review, approved November 21, 2018. No new studies found.

01/01/20 Annual Review, approved December 10, 2019. No changes to policy statement.

12/01/20 Annual Review, approved November 3, 2020. No changes to policy statement.

08/01/21 Annual Review, approved July 13, 2021. Updated criteria removing requirement the diagnosis of leptin deficiency is by an endocrinologist. Added requirement drug is used as an adjunct to diet, updated requirements for the metabolic abnormalities, added requirement drug is prescribed by or in consultation with an endocrinologist, and added a daily dose limit. Updated the re-authorization criteria to document the

patient is tolerating therapy and that there is a decrease in HbA1c and/or fasting triglyceride levels from baseline.

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). ©2021 Premera All Rights Reserved.

Scope: Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Page | 12 of 12 ∞

Discrimination is Against the Law Oromoo (Cushite): Beeksisni kun odeeffannoo barbaachisaa qaba. Beeksisti kun sagantaa Premera Blue Cross complies with applicable Federal civil rights laws and yookan karaa Premera Blue Cross tiin tajaajila keessan ilaalchisee does not discriminate on the basis of race, color, national origin, age, odeeffannoo barbaachisaa qabaachuu danda’a. Guyyaawwan murteessaa disability, or sex. Premera does not exclude people or treat them differently ta’an beeksisa kana keessatti ilaalaa. Tarii kaffaltiidhaan deeggaramuuf because of race, color, national origin, age, disability or sex. yookan tajaajila fayyaa keessaniif guyyaa dhumaa irratti wanti raawwattan jiraachuu danda’a. Kaffaltii irraa bilisa haala ta’een afaan keessaniin Premera: odeeffannoo argachuu fi deeggarsa argachuuf mirga ni qabaattu. • Provides free aids and services to people with disabilities to communicate Lakkoofsa bilbilaa 800-722-1471 (TTY: 800-842-5357) tii bilbilaa. effectively with us, such as: • Qualified sign language interpreters Français (French): • Written information in other formats (large print, audio, accessible Cet avis a d'importantes informations. Cet avis peut avoir d'importantes electronic formats, other formats) informations sur votre demande ou la couverture par l'intermédiaire de • Provides free language services to people whose primary language is not Premera Blue Cross. Le présent avis peut contenir des dates clés. Vous English, such as: devrez peut-être prendre des mesures par certains délais pour maintenir votre couverture de santé ou d'aide avec les coûts. Vous avez le droit • Qualified interpreters d'obtenir cette information et de l’aide dans votre langue à aucun coût. • Information written in other languages Appelez le 800-722-1471 (TTY: 800-842-5357).

If you need these services, contact the Civil Rights Coordinator. Kreyòl ayisyen (Creole):

Avi sila a gen Enfòmasyon Enpòtan ladann. Avi sila a kapab genyen If you believe that Premera has failed to provide these services or enfòmasyon enpòtan konsènan aplikasyon w lan oswa konsènan kouvèti discriminated in another way on the basis of race, color, national origin, age, asirans lan atravè Premera Blue Cross. Kapab genyen dat ki enpòtan nan disability, or sex, you can file a grievance with: avi sila a. Ou ka gen pou pran kèk aksyon avan sèten dat limit pou ka Civil Rights Coordinator - Complaints and Appeals kenbe kouvèti asirans sante w la oswa pou yo ka ede w avèk depans yo. PO Box 91102, Seattle, WA 98111 Se dwa w pou resevwa enfòmasyon sa a ak asistans nan lang ou pale a, Toll free 855-332-4535, Fax 425-918-5592, TTY 800-842-5357 san ou pa gen pou peye pou sa. Rele nan 800-722-1471 Email [email protected] (TTY: 800-842-5357).

You can file a grievance in person or by mail, fax, or email. If you need help Deutsche (German): filing a grievance, the Civil Rights Coordinator is available to help you. Diese Benachrichtigung enthält wichtige Informationen. Diese

Benachrichtigung enthält unter Umständen wichtige Informationen You can also file a civil rights complaint with the U.S. Department of Health bezüglich Ihres Antrags auf Krankenversicherungsschutz durch Premera and Human Services, Office for Civil Rights, electronically through the Blue Cross. Suchen Sie nach eventuellen wichtigen Terminen in dieser Office for Civil Rights Complaint Portal, available at Benachrichtigung. Sie könnten bis zu bestimmten Stichtagen handeln https://ocrportal.hhs.gov/ocr/portal/lobby.jsf, or by mail or phone at: müssen, um Ihren Krankenversicherungsschutz oder Hilfe mit den Kosten U.S. Department of Health and Human Services zu behalten. Sie haben das Recht, kostenlose Hilfe und Informationen in 200 Independence Avenue SW, Room 509F, HHH Building Ihrer Sprache zu erhalten. Rufen Sie an unter 800-722-1471 Washington, D.C. 20201, 1-800-368-1019, 800-537-7697 (TDD) (TTY: 800-842-5357). Complaint forms are available at http://www.hhs.gov/ocr/office/file/index.html. Hmoob (Hmong):

Tsab ntawv tshaj xo no muaj cov ntshiab lus tseem ceeb. Tej zaum Getting Help in Other Languages tsab ntawv tshaj xo no muaj cov ntsiab lus tseem ceeb txog koj daim ntawv thov kev pab los yog koj qhov kev pab cuam los ntawm Premera Blue This Notice has Important Information. This notice may have important Cross. Tej zaum muaj cov hnub tseem ceeb uas sau rau hauv daim ntawv information about your application or coverage through Premera Blue no. Tej zaum koj kuj yuav tau ua qee yam uas peb kom koj ua tsis pub Cross. There may be key dates in this notice. You may need to take action dhau cov caij nyoog uas teev tseg rau hauv daim ntawv no mas koj thiaj by certain deadlines to keep your health coverage or help with costs. You yuav tau txais kev pab cuam kho mob los yog kev pab them tej nqi kho mob have the right to get this information and help in your language at no cost. ntawd. Koj muaj cai kom lawv muab cov ntshiab lus no uas tau muab sau Call 800-722-1471 (TTY: 800-842-5357). ua koj hom lus pub dawb rau koj. Hu rau 800-722-1471 (TTY: 800-842-5357). አማሪኛ (Amharic): ይህ ማስታወቂያ አስፈላጊ መረጃ ይዟል። ይህ ማስታወቂያ ስለ ማመልከቻዎ ወይም የ Premera Blue Iloko (Ilocano): Cross ሽፋን አስፈላጊ መረጃ ሊኖረው ይችላል። በዚህ ማስታወቂያ ውስጥ ቁልፍ ቀኖች ሊኖሩ ይችላሉ። Daytoy a Pakdaar ket naglaon iti Napateg nga Impormasion. Daytoy a የጤናን ሽፋንዎን ለመጠበቅና በአከፋፈል እርዳታ ለማግኘት በተውሰኑ የጊዜ ገደቦች እርምጃ መውሰድ pakdaar mabalin nga adda ket naglaon iti napateg nga impormasion

ይገባዎት ይሆናል። ይህን መረጃ እንዲያገኙ እና ያለምንም ክፍያ በቋንቋዎ እርዳታ እንዲያገኙ መብት maipanggep iti apliksayonyo wenno coverage babaen iti Premera Blue አለዎት።በስልክ ቁጥር 800-722-1471 (TTY: 800-842-5357) ይደውሉ። Cross. Daytoy ket mabalin dagiti importante a petsa iti daytoy a pakdaar. Mabalin nga adda rumbeng nga aramidenyo nga addang sakbay dagiti Arabic): partikular a naituding nga aldaw tapno mapagtalinaedyo ti coverage ti) العربية salun-atyo wenno tulong kadagiti gastos. Adda karbenganyo a mangala iti يحوي ھذا اإلشعار معلومات ھامة . قد يحوي ھذا اإلشعار معلومات مھمة بخصوص طلبك أو daytoy nga impormasion ken tulong iti bukodyo a pagsasao nga awan ti التغطية التي تريد الحصول عليھا من خالل Premera Blue Cross. قد تكون ھناك تواريخ مھمة .(bayadanyo. Tumawag iti numero nga 800-722-1471 (TTY: 800-842-5357 في ھذا اإلشعار . وقد تحتاج التخاذ إجراء في تواريخ معينة للحفاظ على تغطيتك الصحية أو للمساعدة في دفع التكاليف . يحق لك الحصول على ھذه المعلومات والمساعدة بلغتك دون تكبد أية تكلفة . اتصل :(Italiano (Italian بـ(TTY: 800-842-5357) 800-722-1471 Questo avviso contiene informazioni importanti. Questo avviso può contenere 中文 (Chinese): informazioni importanti sulla tua domanda o copertura attraverso Premera 本通知有重要的訊息。 本通知可能有關於您透過 Premera Blue Cross 提交的 Blue Cross. Potrebbero esserci date chiave in questo avviso. Potrebbe 申請或保險的重要訊息。本通知內可能有重要日期。您可能需要在截止日期 essere necessario un tuo intervento entro una scadenza determinata per 之前採取行動，以保留您的健康保險或者費用補貼。您有權利免費以您的母 consentirti di mantenere la tua copertura o sovvenzione. Hai il diritto di ottenere queste informazioni e assistenza nella tua lingua gratuitamente. 語得到本訊息和幫助。請撥電話 。 800-722-1471 (TTY: 800-842-5357) Chiama 800-722-1471 (TTY: 800-842-5357).

037338 (07-2016) 日本語 (Japanese): Română (Romanian): この通知には重要な情報が含まれています。この通知には、 Premera Blue Prezenta notificare conține informații importante. Această notificare Cross の申請または補償範囲に関する重要な情報が含まれている場合があ poate conține informații importante privind cererea sau acoperirea asigurării ります。この通知に記載されている可能性がある重要な日付をご確認くだ dumneavoastre de sănătate prin Premera Blue Cross. Pot exista date cheie în aceast notificare. Este posibil s fie nevoie s ac iona i pân la anumite さい。健康保険や有料サポートを維持するには、特定の期日までに行動を ă ă ă ț ț ă termene limită pentru a vă menține acoperirea asigurării de sănătate sau 取らなければならない場合があります。ご希望の言語による情報とサポー asistența privitoare la costuri. Aveți dreptul de a obține gratuit aceste トが無料で提供されます。800-722-1471 (TTY: 800-842-5357)までお電話 informații și ajutor în limba dumneavoastră. Sunați la 800-722-1471 ください。 (TTY: 800-842-5357).

한국어 (Korean): Pусский (Russian): 본 통지서에는 중요한 정보가 들어 있습니다 . 즉 이 통지서는 귀하의 신청에 Настоящее уведомление содержит важную информацию. Это 관하여 그리고 Premera Blue Cross 를 통한 커버리지에 관한 정보를 уведомление может содержать важную информацию о вашем Premera Blue Cross. 포함하고 있을 수 있습니다 . 본 통지서에는 핵심이 되는 날짜들이 있을 수 заявлении или страховом покрытии через В настоящем уведомлении могут быть указаны ключевые даты. Вам, 있습니다. 귀하는 귀하의 건강 커버리지를 계속 유지하거나 비용을 절감하기 возможно, потребуется принять меры к определенным предельным 위해서 일정한 마감일까지 조치를 취해야 할 필요가 있을 수 있습니다 . срокам для сохранения страхового покрытия или помощи с расходами. 귀하는 이러한 정보와 도움을 귀하의 언어로 비용 부담없이 얻을 수 있는 Вы имеете право на бесплатное получение этой информации и 권리가 있습니다 . 800-722-1471 (TTY: 800-842-5357) 로 전화하십시오 . помощь на вашем языке. Звоните по телефону 800-722-1471 (TTY: 800-842-5357). ລາວ (Lao): Fa’asamoa (Samoan): ້ ້ ້ ້ ແຈ້ງການນີ ມີ ຂໍ ມູ ນສໍ າຄັ ນ. ແຈ້ງການນີ ອາດຈະມີ ຂໍ ມູ ນສໍ າຄັ ນກ່ ຽວກັບຄໍ າຮ້ອງສະ Atonu ua iai i lenei fa’asilasilaga ni fa’amatalaga e sili ona taua e tatau ໝັ ກ ຫືຼ ຄວາມຄຸ້ ມຄອງປະກັນໄພຂອງທ່ານຜ່ານ Premera Blue Cross. ອາດຈະມີ ona e malamalama i ai. O lenei fa’asilasilaga o se fesoasoani e fa’amatala ວັນທີ ສໍ າຄັ ນໃນແຈ້ງການນີ້ . ທ່ານອາດຈະຈໍ າເປັ ນຕ້ອງດໍ າເນີ ນການຕາມກໍ ານົ ດ atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e tau fia maua ເວລາສະເພາະເພື່ ອຮັກສາຄວາມຄຸ້ ມຄອງປະກັນສຸ ຂະພາບ ຫືຼ ຄວາມຊ່ວຍເຫືຼ ອເລື່ ອງ atu i ai. Fa’amolemole, ia e iloilo fa’alelei i aso fa’apitoa olo’o iai i lenei fa’asilasilaga taua. Masalo o le’a iai ni feau e tatau ona e faia ao le’i aulia le ້ ້ ຄ່ າໃຊ້ຈ່າຍຂອງທ່ານໄວ້ . ທ່ານມີ ສິ ດໄດ້ ຮັບຂໍ ມູ ນນີ ແລະ ຄວາມຊ່ວຍເຫືຼ ອເປັ ນພາສາ aso ua ta’ua i lenei fa’asilasilaga ina ia e iai pea ma maua fesoasoani mai ai ຂອງທ່ານໂດຍບໍ່ ເສຍຄ່ າ. ໃຫ້ໂທຫາ 800-722-1471 (TTY: 800-842-5357). i le polokalame a le Malo olo’o e iai i ai. Olo’o iai iate oe le aia tatau e maua atu i lenei fa’asilasilaga ma lenei fa’matalaga i legagana e te malamalama i 徶羶ែខមរ (Khmer): ai aunoa ma se togiga tupe. Vili atu i le telefoni 800-722-1471 (TTY: 800-842-5357). េសចកតជី ូនដណំ ឹងេនះ掶នព័ត៌掶ន架៉ ងស޶នំ។ ់ េសចកតីជូនដំណឹងេនះរបែហល ᾶ掶នព័ត៌掶ន架៉ ងសំ޶ន់អពំ ីទរមង់ ែបបបទ ឬζរ殶៉ បរង់ របសអ់ នក㾶មរយៈ Español (Spanish): Premera Blue Cross ។ របែហលᾶ掶ន ζលបរ េចិ ឆទសំ޶ន់េ俅កន ុងេសចកតជី ូន Este Aviso contiene información importante. Es posible que este aviso contenga información importante acerca de su solicitud o cobertura a ដណំ ងេនះ។ឹ អនករបែហលᾶរតវζរបេញូ ច ញសមត徶ពថ ដលក់ ណតំៃថ ់ ងᾶកច厶់ ស់ través de Premera Blue Cross. Es posible que haya fechas clave en este 侶侶 េដើមបីនងរកឹ 羶ទកζរ䮶侶ុ 殶៉ បរង់ សខ徶ពរបសុ ់អនក ឬរ厶កជ់ ំនួយេចញៃថល។ aviso. Es posible que deba tomar alguna medida antes de determinadas អនក掶នសទិ ធទទិ ួលព័ត掶នេ៌ នះ និងជំនួយេ俅កន ុង徶羶របស់អនកេ⮶យមនអសិ fechas para mantener su cobertura médica o ayuda con los costos. Usted លយេឡុ ើយ។ សូ មទូរស័ពទ 800-722-1471 (TTY: 800-842-5357)។ tiene derecho a recibir esta información y ayuda en su idioma sin costo alguno. Llame al 800-722-1471 (TTY: 800-842-5357).

ਪ ੰ ਜਾਬੀ (Punjabi): Tagalog (Tagalog): ਇਸ ਨ ੋ ਿਟਸ ਿਵਚ ਖਾਸ ਜਾਣਕਾਰੀ ਹੈ. ਇਸ ਨ ੋ ਿਟਸ ਿਵਚ Premera Blue Cross ਵਲ ƒ ਤੁਹਾਡੀ Ang Paunawa na ito ay naglalaman ng mahalagang impormasyon. Ang paunawa na ito ay maaaring naglalaman ng mahalagang impormasyon ਕਵਰਜੇ ਅਤ ੇ ਅਰਜੀ ਬਾਰ ੇ ਮਹ ੱ ਤਵਪਰਨੂ ਜਾਣਕਾਰੀ ਹ ੋ ਸਕਦੀ ਹ ੈ . ਇਸ ਨ ੋ ਿਜਸ ਜਵਚ ਖਾਸ ਤਾਰੀਖਾ . tungkol sa iyong aplikasyon o pagsakop sa pamamagitan ng Premera Blue ਹੋ ਸਕਦੀਆਂ ਹਨ ਜੇਕਰ ਤਸੀੁ ਜਸਹਤ ਕਵਰਜੇ ਿਰੱ ਖਣੀ ਹਵੋ ੇ ਜਾ ਓਸ ਦੀ ਲਾਗਤ ਜਿਵੱ ਚ ਮਦਦ ਦੇ Cross. Maaaring may mga mahalagang petsa dito sa paunawa. Maaring ਇਛ ੱ ੁਕ ਹ ੋ ਤ拓 ਤਹਾਨ ੁ ੰ ੂ ਅ ੰ ਤਮ ਤਾਰੀਖ਼ ਤ ƒ ਪਿਹਲ拓 ਕੁੱ ਝ ਖਾਸ ਕਦਮ ਚੱ ਕਣ ੁ ਦੀ ਲੋੜ ਹ ੋ ਸਕਦੀ ਹ ੈ ,ਤੁਹਾਨੰ ੂ mangailangan ka na magsagawa ng hakbang sa ilang mga itinakdang ਮਫ਼ਤੁ ਿਵੱ ਚ ਤ ੇ ਆਪਣੀ ਭਾਸ਼ਾ ਿਵ ੱ ਚ ਜਾਣਕਾਰੀ ਅਤ ੇ ਮਦਦ ਪਾਪਤ㘰 ਕਰਨ ਦਾ ਅਿਧਕਾਰ ਹੈ ,ਕਾਲ panahon upang mapanatili ang iyong pagsakop sa kalusugan o tulong na 800-722-1471 (TTY: 800-842-5357). walang gastos. May karapatan ka na makakuha ng ganitong impormasyon at tulong sa iyong wika ng walang gastos. Tumawag sa 800-722-1471 .(Farsi): (TTY: 800-842-5357) فارسی اين اعالميه حاوی اطالعات مھم ميباشد .اين اعالميه ممکن است حاوی اطالعات مھم درباره فرم :(ไทย (Thai تقاضا و يا پ وشش بيمه ای شما از طريق Premera Blue Cross باشد . به تاريخ ھای مھم در ั ประกาศนมข้ี ี ้อมลส ู ําคญ ั ประกาศนอาจม ้ี ีข ้อมลท ู ่ีส ําคญเก ั ่ียวกบการการสม ัครหร ั ือขอบเขตประกน اين اعالميه توجه نماييد .شما ممکن است برای حقظ پوشش بيمه تان يا کمک در پرداخت ھزينه . สขภาพของคุณผ ุาน ่ Premera Blue Cross และอาจมีก ําหนดการในประกาศนี ้ คณอาจจะต ุ ้อง ھای درمانی تان، به تاريخ ھای مشخصی برای انجام کارھای خاصی احتياج داشته باشيد شما حق اين را داريد که اين اطالعات و ک مک را به زبان خود به طور رايگان دريافت نماييد . برای کسب ี่ ดําเน ินการภายในกาหนดระยะเวลาท ํ ่ีแนนอนเพ ่ ่ือจะร ักษาการประกนส ัขภาพของค ุณหร ุ ือการช ่วยเหล ือท اطالعات با شماره 1471-722-800 (کاربران TTY تماس باشماره 5357-842-800) تماس มคี่้่าใชจาย คณม ุีิิ่ี้ัู้สทธทจะไดรบขอมลและความชวยเหล ่ ื้ีอนในภาษาของคณโดยไม ุ่มค ี่้่าใชจาย โทร برقرار نماييد . 800-722-1471 (TTY: 800-842-5357) Polskie (Polish): To og oszenie mo e zawiera wa ne informacje. To og oszenie mo e ł ż ć ż ł ż Український (Ukrainian): zawiera wa ne informacje odno nie Pa stwa wniosku lub zakresu ć ż ś ń Це повідомлення містить важливу інформацію. Це повідомлення świadczeń poprzez Premera Blue Cross. Prosimy zwrócic uwagę na може містити важливу інформацію про Ваше звернення щодо kluczowe daty, które mogą być zawarte w tym ogłoszeniu aby nie страхувального покриття через Premera Blue Cross. Зверніть увагу на przekroczyć terminów w przypadku utrzymania polisy ubezpieczeniowej lub ключові дати, які можуть бути вказані у цьому повідомленні. Існує pomocy zwi zanej z kosztami. Macie Pa stwo prawo do bezp atnej ą ń ł імовірність того, що Вам треба буде здійснити певні кроки у конкретні informacji we własnym języku. Zadzwońcie pod 800-722-1471 кінцеві строки для того, щоб зберегти Ваше медичне страхування або (TTY: 800-842-5357). отримати фінансову допомогу. У Вас є право на отримання цієї

інформації та допомоги безкоштовно на Вашій рідній мові. Дзвоніть за Português (Portuguese): номером телефону 800-722-1471 (TTY: 800-842-5357). Este aviso contém informações importantes. Este aviso poderá conter informações importantes a respeito de sua aplicação ou cobertura por meio Tiếng Việt (Vietnamese): do Premera Blue Cross. Poderão existir datas importantes neste aviso. Thông báo này cung cấp thông tin quan trọng. Thông báo này có thông Talvez seja necessário que você tome providências dentro de tin quan trọng về đơn xin tham gia hoặc hợp đồng bảo hiểm của quý vị qua determinados prazos para manter sua cobertura de saúde ou ajuda de chương trình Premera Blue Cross. Xin xem ngày quan trọng trong thông custos. Você tem o direito de obter esta informação e ajuda em seu idioma báo này. Quý vị có thể phải thực hiện theo thông báo đúng trong thời hạn e sem custos. Ligue para 800-722-1471 (TTY: 800-842-5357). để duy trì bảo hiểm sức khỏe hoặc được trợ giúp thêm về chi phí. Quý vị có quyền được biết thông tin này và được trợ giúp bằng ngôn ngữ của mình miễn phí. Xin gọi số 800-722-1471 (TTY: 800-842-5357).