PHARMACY POLICY – 5.01.611 Pharmacologic Treatment of Cycle Disorders

Effective Date: Jan. 1, 2021 RELATED MEDICAL POLICIES: Last Revised: Dec. 1, 2020 None Replaces: N/A

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Introduction

When protein is eaten, the body breaks it down into amino acids, which help carry out bodily functions. Whatever is not needed by the body is then broken down by the liver and turned into waste products that are cleared out of the body through urine. One of these waste products is . Too much ammonia in the body is toxic. The liver changes ammonia into a non-toxic substance called urea using a series of specific protein molecules (). This process is called the . Urea cycle disorders are inherited and occur when the body can’t make one or more of the enzymes it needs to turn ammonia into urea. Ammonia builds up in the body and can lead to brain damage, coma, and even death. Urea cycle disorders most often affect infants, though they can affect children and adults. Treatment of urea cycle disorders is meant to reduce the amount of ammonia in the blood to safe levels. This policy describes when drugs used to treat urea cycle disorders 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 Generic sodium Generic may be considered medically phenylbutyrate necessary when the following criteria are met: • Generic sodium phenylbutyrate is used as adjunctive therapy Urea Cycle Pathway for the chronic management of patients with urea cycle Alternative disorders AND • Documented by genetic testing deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS) AND • Documented dietary protein restriction plan is in place Buphenyl® (sodium Buphenyl® (sodium phenylbutyrate) may be considered phenylbutyrate) medically necessary when the following criteria are met: • Buphenyl® is used as adjunctive therapy for the chronic Urea Cycle Pathway management of patients with urea cycle disorders Alternative AND • Patient has tried generic sodium phenylbutyrate first and has an inadequate response or intolerance to generic sodium phenylbutyrate (documentation required) AND • Documented by genetic testing deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS) AND • Documented dietary protein restriction plan is in place Carbaglu® () Carbaglu® (carglumic acid) may be considered medically necessary when the following criteria are met: Carbamoyl • Carbaglu® is used for the treatment of acute or chronic Synthetase 1 Activator AND • Documented by genetic testing deficiency of the hepatic N-acetylglutamate synthase (NAGS) Ravicti™ (glycerol Ravicti™ () may be considered phenylbutyrate) medically necessary when the following criteria are met:

Page | 2 of 10 ∞ Drug Medical Necessity Nitrogen Binding Agent • Ravicti™ is used as adjunctive therapy for the chronic management of patients with urea cycle disorders AND • Documented dietary protein restriction plan is in place AND • Patient has tried and failed generic sodium phenylbutyrate unless there is a contraindication to use of generic sodium phenylbutyrate

Drug Investigational Generic sodium All other uses of generic sodium phenylbutyrate, Buphenyl® phenylbutyrate, (sodium phenylbutyrate), Carbaglu® (carglumic acid), and Buphenyl® (sodium Ravicti™ (glycerol phenylbutyrate) for conditions not outlined phenylbutyrate), in this policy are considered investigational. Carbaglu® (carglumic acid), Ravicti™ (glycerol phenylbutyrate)

Length of Approval Approval Criteria Initial authorization All drugs listed in policy may be approved up to 12 months. Re-authorization criteria Future re-authorization of all drugs listed in policy may be approved up to 3 years as long as the drug-specific coverage criteria are met and chart notes demonstrate that the patient continues to show a positive clinical response to therapy.

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, and history

Page | 3 of 10 ∞ Coding

N/A

Related Information

Consideration of Age

The ages stated in this policy for which generic sodium phenylbutyrate, Buphenyl® (sodium phenylbutyrate), Carbaglu® (carglumic acid), and Ravicti™ (glycerol phenylbutyrate) are considered medically necessary are based on the ages approved in the FDA labeling.

Benefit Application

This policy is managed through the Pharmacy benefit.

Evidence Review

Background

Urea Cycle Disorders (UCDs) result from inherited deficiencies of enzymes or transporters including: N-acetylglutamate synthase (NAGS), carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate acid synthetase (AS), argininosuccinate acid lyase (ASL), or arginase (ARG). OTC is the most common enzyme deficiency of these disorders. These enzymes are responsible for the synthesis of urea from ammonia (NH3, NH4+). UCDs are rare genetic disorders, and its clinical manifestations are characterized by hyperammonemia and life- threatening hyperammonemic crises. Hyperammonemia-related neurologic injury ranges from lethal cerebral edema to mild cognitive impairment among individuals with milder genetic defects. The goal of management is to control ammonia levels and avoid hyperammonemic

Page | 4 of 10 ∞ crisis. Treatments are directed towards reducing ureagenesis through dietary protein restriction, , or citrilline supplementation, and administration of nitrogen-scavenging drugs.

The deficiency of the enzymes or transporters involved in UCDs varies from patient to patient, and some patients have a total or near total absence of activity of the first four enzymes of the urea cycle (OTC, CPS, AS, and ALS). These deficiencies lead to accumulation of ammonia and other precursor metabolites during the first few days of life. Some patients may have partial absence of the enzymes of the urea cycle, leading to a milder form of the disease. Patients may present with clinical manifestations across the lifespan, including as newborn/infants and in early childhood.

Most patients are diagnosed after presenting symptoms of hyperammonemia. If an elevated blood ammonia level is confirmed, and the results of other routine lab tests are consistent with a UCD diagnosis (normal anion gap, normal blood glucose, absence of liver disease), levels are tested to establish a specific diagnosis. The laboratory hallmark of a urea cycle disorder (UCD) is an elevated plasma ammonia concentration (>100 to 150 micromol/L).

The initial management of UCDs is to rehydrate and maintain good urine output without overhydrating. The next step is to remove nitrogen (ammonia) from the body using and/or hemodialysis. It is important to stop protein intake and minimize catabolism, as well as stimulate anabolism and uptake of nitrogen precursors by muscle. For chronic management of urea cycle disorders, if dietary protein restriction and/or amino acid supplementation cannot manage the disorder alone, then Buphenyl® (sodium phenylbutyrate) is the next option.

Summary of Evidence

Buphenyl® (sodium phenylbutyrate)

Previously, neonatal-onset disease was almost universally fatal within the first year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen-free analogs. However, with hemodialysis, use of alternative waste nitrogen pathways (sodium phenylbutyrate, , and sodium phenylacetate), dietary protein restriction, and, in some cases, essential amino acid supplementation, the survival rate in newborns diagnosed after birth but within the first month of life is almost 80%. Most deaths have occurred during an episode of acute hyperammonemic encephalopathy.

Patients with neonatal-onset disease have a high incidence of mental retardation. Those who had IQ tests administered had an incidence of mental retardation as follows: ornithine transcarbamylase deficiency, 100% (14/14 patients tested); argininosuccinic acid synthetase

Page | 5 of 10 ∞ deficiency, 88% (15/17 patients tested); and carbamylphosphate synthetase deficiency, 57% (4/7 patients tested). Retardation was severe in the majority of patients. In patients diagnosed during gestation and treated prior to any episode of hyperammonemic encephalopathy, survival is 100%, but even in these patients, most subsequently demonstrate cognitive impairment or other neurologic deficits. In late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase deficiency, who recover from hyperammonemic encephalopathy and are then treated chronically with sodium phenylbutyrate and dietary protein restriction, the survival rate is 98%. The two deaths in this group of patients occurred during episodes of hyperammonemic encephalopathy. However, compliance with the therapeutic regimen has not been adequately documented to allow evaluation of the potential for sodium phenylbutyrate and dietary protein restriction to prevent mental deterioration and recurrence of hyperammonemic encephalopathy if carefully adhered to. The majority of these patients tested (30/46 or 65%) have IQ's in the average to low average/borderline mentally retarded range. Reversal of preexisting neurologic impairment is not likely to occur with treatment and neurologic deterioration may continue in some patients. Even on therapy, acute hyperammonemic encephalopathy recurred in the majority of patients for whom the drug is indicated.

Safety

The assessment of clinical adverse events came from 206 patients treated with sodium phenylbutyrate. Adverse events (both clinical and laboratory) were not collected systematically in these patients but were obtained from patient-visit reports by the 65 co-investigators. Causality of adverse effects is sometimes difficult to determine in this patient population because they may result from either the underlying disease, the patient's restricted diet, intercurrent illness, or sodium phenylbutyrate. Furthermore, the rates may be underestimated because they were reported primarily by parent or guardian and not the patient.

In female patients, the most common clinical adverse event reported was amenorrhea/menstrual dysfunction (irregular menstrual cycles), which occurred in 23% of the menstruating patients. Decreased appetite occurred in 4% of all patients. Body odor (probably caused by the metabolite, phenylacetate) and bad taste or taste aversion were each reported in 3% of patients.

Carbaglu® (carglumic acid)

The efficacy of carglumic acid in the treatment of hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency was evaluated in a retrospective review of the clinical course of 23

Page | 6 of 10 ∞ NAGS deficiency patients who received carglumic acid treatment for a median of 7.9 years (range 0.6 to 20.8 years). Treatment with carglumic acid was divided in two regimens. For acute treatment, patients received a total daily dose of 100 to 250 mg/kg per day primarily administered in 2 to 4 divided doses for the first few days of treatment. For maintenance treatment, the dosage was reduced over time based upon biochemical and clinical responses. The clinical observations in the 23 patient case series were retrospective, unblinded and uncontrolled and preclude any meaningful formal statistical analyses of the data. However, short-term efficacy was evaluated using mean and median change in plasma ammonia levels from baseline to days 1 to 3. Persistence of efficacy was evaluated using long-term mean and median change in plasma ammonia level. Of the 23 NAGS deficiency patients who received treatment with carglumic acid, a subset of 13 patients who had both well documented plasma ammonia levels prior to carglumic acid treatment and after long-term treatment with carglumic acid were selected for analysis.

All 13 patients had abnormal ammonia levels at baseline. The overall mean baseline plasma ammonia level was 271 micromol/L. By day 3, normal plasma ammonia levels were attained in patients for whom data were available. Long-term efficacy was measured using the last reported plasma ammonia level for each of the 13 patients analyzed (median length of treatment was 6 years; range 1 to 16 years). The mean and median ammonia levels were 23 micromol/L and 24 micromol/L, respectively, after a mean treatment duration of 8 years.

Safety

Adverse reactions occurring in 2 or more patients treated with carglumic acid in the retrospective case series (≥ 10%) were vomiting (26%), abdominal pain (17%), pyrexia (17%), tonsillitis (17%), anemia (13%), diarrhea (13%), ear infection (13%), infections (13%), nasopharyngitis (13%) and decreased (13%).

Ravicti™ (glycerol phenylbutyrate)

Evidence for the efficacy of glycerol phenylbutyrate in treating urea cycle disorder consists of one multicenter, randomized, double-blind, double-dummy, placebo-controlled, cross-over, non-inferiority study. The phase 3 study assessed the non-inferiority of glycerol phenylbutyrate to sodium phenylbutyrate by evaluating blood ammonia levels in adult patients with UCDs from OTC, CPS, and AS who were being treated with sodium phenylbutyrate for control of their UCD. Adult patients ≥18 years of age with diagnoses of UCD were enrolled, an each of the patients had deficiencies including CPS, OTC, or AS, confirmed via enzymatic, biochemical, or genetic

Page | 7 of 10 ∞ testing. They were required to have controlled ammonia levels <100 μmol/L without signs and symptoms of hyperammonemia. The patients were not allowed to receive drugs known to increase ammonia levels, increase protein catabolism, or significantly affect renal clearance.

The sample size of 46 patients (only 44 patients were used in the analysis portion) were randomized equally to received placebo glycerol phenylbutyrate plus active sodium phenylbutyrate, or placebo sodium phenylbutyrate plus active glycerol phenylbutyrate for 14 days and then crossed over to receive the alternative treatment. The dose of glycerol phenylbutyrate was calculated to deliver the same amount of phenylbutyrate as each patient’s baseline sodium phenylbutyrate dose.

In both randomized groups, the patients received the same amount of phenylbutyrate throughout the study and followed a balanced diet in terms of protein and calorie intake. At the end of each treatment period (2 weeks), patients underwent repeated blood sampling over 24 hours for ammonia plasma and urine levels of metabolites, including phenylbutyrate and . The primary efficacy measure was daily ammonia exposure, assessed as 24- hour AUC. Non-inferiority was to be achieved if the upper 95% confidence interval (CI) for the ratio of the least squares means between glycerol phenylbutyrate and sodium phenylbutyrate was less than or equal to 1.25. The non-inferiority margin of 1.25 is consistent with FDA guidance on bioequivalence studies and corresponds to an absolute difference of approximately 9 umol/L for a patient with an ammonia at the upper limit of normal (35 umol/L), a clinically insignificant change.

When administered at the recommended dose levels sodium phenylbutyrate has been shown from clinical experience to be safe and effective in improving long-term survival in patients with UCDs (i.e., reducing the incidence of deaths due to hyperammonemic encephalopathy). However, compliance with sodium phenylbutyrate is difficult due to a high pill burden (up to 40 pills or 40 mL of dissolved powder daily for patients taking 20 g of sodium phenylbutyrate), foul taste, unpleasant odor, and high sodium content (approximately 2,300 mg/day for patients taking 20 g). All of these factors render sodium phenylbutyrate difficult to take, and compliance is suboptimal even for UCD patients with the most severe deficiency states, whose alternative is life-threatening hyperammonemia. Consequently, UCDs remains as a rare, serious and life- threatening condition with a not fully met medical need. Ravicti™ is an alternative therapy to sodium phenylbutyrate in patients with UCDs as it is expected to provide similar nitrogen- scavenging ability while eliminating the current issues of bad taste, odor, sodium content, and pill burden.

Forty patients who completed the short-term adult study and 11 patients who completed the short-term pediatric study enrolled in the long-term protocols; 26 additional, newly-enrolled adult and pediatric patients were also in the long-term protocol for a total of 77 UCD patients

Page | 8 of 10 ∞ (51 adult and 26 pediatric patients ages 6–17, including ARG, ASL, AS, CPS, and OTC subtypes). Mean ammonia values during long term treatment with glycerol phenylbutyrate were similar to the mean fasting values (time 0 or 24h) observed during the short-term controlled studies and well below the upper limit of normal (35 umol/L) for both pediatric and adult patients at each monthly visit, with monthly means approximately half the upper limit of normal and ranging from 6.3 (Month 9) to 29.6 μmol/L (Month 11).

Safety

The most common adverse events were mild gastrointestinal issues. Adverse events were reported by 61% and 51% of patients during glycerol phenylbutyrate and sodium phenylbutyrate treatment, respectively. The gastrointestinal disorders included diarrhea, flatulence, abdominal discomfort, dyspepsia, nausea, and oral discomfort. No clinically significant lab or ECG changes were observed. Headache, somnolence, lightheadedness, and confusion are all possible adverse reactions of glycerol phenylbutyrate. Phenylacetic acid exposure is associated with neurological toxicity at dose-dependent increases manifested by dysgeusia, hypoacusis, disorientation, and impaired memory. One patient experienced a hyperammonemic crisis and one patient withdrew early because of high ammonia and headache; both during sodium phenylbutyrate treatment. One patient had a serious adverse event including gastroenteritis on glycerol phenylbutyrate. There were no deaths during the study.

2020 Update

Reviewed prescribing information for all drugs. Updated Ravicti® (glycerol phenylbutyrate) criteria from tried and failed Buphenyl® (sodium phenylbutyrate) to tried and failed generic sodium phenylbutyrate to reflect the availability now of generic sodium phenylbutyrate.

References

1. Brusilow SW. may replace urea as a vehicle for waste nitrogen excretion. Pediatr Res. 1991;29(2):147-150.

2. Summar ML, Diagnosis, symptoms, frequency, and mortality of 260 patients with urea cycle disorders from a 21-year, multicenter study of acute hyperammonemic episodes. Acta Paediatrica 2008; 97:1420.

Page | 9 of 10 ∞ 3. Summar, Marshall M. "The Incidence of Urea Cycle Disorders." Molecular Genetics and 110.1-2 (2013): 179-80.

4. Buphenyl (sodium phenylbutyrate) Prescribing Information. Horizon Pharma USA, Inc., Lake Forest, IL. March 2018.

5. Carbaglu (carglumic acid) Prescribing Information. Recordati Rare Diseases Inc., Lebanon, NJ. September 2020.

6. Ravicti (glycerol phenylbutyrate) Prescribing Information. Horizon Pharma USA, Inc., Lake Forest, IL. November 2019.

History

Date Comments 10/01/19 New policy, approved September 10, 2019. Add to section. Criteria added for Buphenyl (sodium phenylbutyrate), Carbaglu (carglumic acid), and Ravicti (glycerol phenylbutyrate).

02/01/20 Interim Review, approved January 9, 2020. Added coverage criteria for generic sodium phenylbutyrate and updated coverage criteria for Buphenyl (sodium phenylbutyrate).

01/01/21 Annual Review, approved December 1, 2020. Updated Ravicti (glycerol phenylbutyrate) criteria from tried and failed Buphenyl (sodium phenylbutyrate) to tried and failed generic sodium phenylbutyrate.

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 | 10 of 10 ∞

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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).