PHARMACY POLICY – 5.01.612 Pharmacologic Treatment of Cystinosis
Effective Date: Oct. 1, 2020 RELATED MEDICAL POLICIES: Last Revised: Sept. 17, 2020 None Replaces: N/A
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POLICY CRITERIA | DOCUMENTATION REQUIREMENTS | CODING RELATED INFORMATION | EVIDENCE REVIEW | REFERENCES | HISTORY
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Introduction
Cystinosis is a rare, inherited disease that is caused by a change (mutation) in the CTNS gene. The CTNS gene provides instructions to help move an amino acid called cystine out of cells and into other areas of the body, like the digestive system, immune system, skeletal system, skin, and hair. Cystinosis occurs when cystine doesn’t move out of cells and instead builds up and forms crystals that cause cell death. Cystinosis slowly damages and destroys organs, including the kidneys, liver, eyes, muscles, and brain. The kidneys and the eyes are the organs that are most affected. Three types of cystinosis exist based on the age of onset and how severe the symptoms are: nephropathic (infancy), late-onset (teens to adults), and ocular, or “benign” (adults). Treatment of cystinosis is meant to remove cystine from the cells and delay any further damage to organs in the body. This policy describes when drugs used to treat cystinosis 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 Cystagon® (cysteamine Cystagon® (cysteamine bitartrate) may be considered bitartrate) capsules medically necessary for the treatment of adult and pediatric patients with nephropathic cystinosis when the following criteria are met: • Patient has a confirmed diagnosis of cystinosis by one of the following methods: o Elevated cystine content of peripheral blood leukocyte or fibroblasts OR o Cystine corneal crystals by the slit lamp examination OR o Confirmed mutation of the CTNS gene Procysbi® (cysteamine Procysbi® (cysteamine bitartrate) may be considered bitartrate) delayed-release medically necessary for the treatment of adult and pediatric capsules; delayed-release patients with nephropathic cystinosis when the following granules criteria are met: • Patient is 1 year of age or older AND • Patient has a confirmed diagnosis of cystinosis by one of the following methods: o Elevated cystine content of peripheral blood leukocyte or fibroblasts OR o Cystine corneal crystals by the slit lamp examination OR o Confirmed mutation of the CTNS gene AND • Patient has tried Cystagon® (cysteamine bitartrate) and has documentation of one of the following: o Inadequate response after 6-months of treatment OR o Had intolerance to use of Cystagon® (cysteamine bitartrate)
Page | 2 of 11 ∞ Drug Medical Necessity Cystadrops® (cysteamine Cystadrops® (cysteamine ophthalmic solution) may be ophthalmic solution) considered medically necessary for the treatment of corneal cystine crystal accumulation when the following criteria are met: • Patient has a confirmed diagnosis of cystinosis by one of the following methods: o Elevated cystine content of peripheral blood leukocyte or fibroblasts OR o Cystine corneal crystals by the slit lamp examination OR o Confirmed mutation of the CTNS gene Cystaran® (cysteamine Cystaran® (cysteamine ophthalmic solution) may be ophthalmic solution) considered medically necessary for the treatment of corneal cystine crystal accumulation when the following criteria are met: • Patient has a confirmed diagnosis of cystinosis by one of the following methods: o Elevated cystine content of peripheral blood leukocyte or fibroblasts OR o Cystine corneal crystals by the slit lamp examination OR o Confirmed mutation of the CTNS gene
Drug Investigational Cystagon® (cysteamine All other uses of Cystagon® (cysteamine bitartrate), Procysbi® bitartrate), (cysteamine bitartrate), Cystadrops® (cysteamine ophthalmic Procysbi® (cysteamine solution), and Cystaran® (cysteamine ophthalmic solution) for bitartrate), conditions not outlined in this policy are considered Cystadrops® (cysteamine investigational. ophthalmic solution), Cystaran® (cysteamine ophthalmic solution)
Page | 3 of 11 ∞ Length of Approval Approval Criteria Initial authorization All drugs listed in policy may be approved up to 6 months. Re-authorization criteria Future re-authorization of all drugs listed in policy may be approved up to 2 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 medication history
Coding
N/A
Related Information
Consideration of Age
The ages stated in this policy for which Cystagon® (cysteamine bitartrate), Procysbi® (cysteamine bitartrate), Cystadrops® (cysteamine ophthalmic solution), and Cystaran® (cysteamine ophthalmic solution) are considered medically necessary are based on the ages approved in the FDA labeling.
Benefit Application
This policy is managed through the Pharmacy benefit.
Page | 4 of 11 ∞
Evidence Review
Background
Cystinosis is a metabolic disease that results from mutations in the CTNS gene located at 17p13a. These mutations cause a defect in the transporter for cystine resulting in intracellular accumulation of cystine, which crystallizes and causes cell death. Cystinosis slowly destroys the organs in the body including the kidneys, liver, eyes, muscles and the brain. There are three types of cystinosis:
1. Infantile (nephropathic)
2. Late-onset (juvenile)
3. Adult (benign)
Cystinosis is an “orphan” disease that affects approximately 1 in 100,000 to 200,000. Cystinosis is an autosomal recessive genetic disease meaning both parents are carriers of the abnormal gene that leads to this condition but they themselves do not exhibit any of the symptoms of cystinosis.
Nephropathic cystinosis in untreated children is characterized by renal tubular Fanconi syndrome, poor growth, impaired glomerular function, and accumulation of cystine crystals leading to tissue destruction. Cysteamine therapy should be started as soon as the diagnosis of cystinosis is confirmed as it preserves renal function and improves growth in affected children. The administration of cysteamine directly treats the disease by reducing the intracellular cystine content. Cysteamine is an aminothiol that participates within lysosomes in a thiol-disulfide interchange reaction converting cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome in patients with cystinosis.
Summary of Evidence
Cystagon® (cysteamine bitartrate)
The National Collaborative Cysteamine Study (NCCS) treated 94 children (mainly from the United States) with nephropathic cystinosis with increasing doses of cysteamine HCl (mean dose 54 mg/kg/day) to attain white cell cystine levels of less than 2 nmol/½ cystine/mg protein 5 to 6 hours post-dose, and compared their outcome with an historical control group of 17 children
Page | 5 of 11 ∞ who had been in the placebo group of a randomized placebo-controlled trial of ascorbic acid. Cysteamine treated patients had been diagnosed at a mean age of 22 months and were a mean age of 46 months old at study entry; placebo patients had been diagnosed at about 29 months and were a mean age of about 52 months old at study entry. The principal measures of effectiveness were serum creatinine and calculated creatinine clearance and growth (height).
The average median white cell cystine level attained during treatment in the NCCS was 1.7 ± 0.2 nmol/½ cystine/mg protein. There were 70 cysteamine patients with baseline serum creatinine less than 2 mg/dL who were followed for at least a year and 17 placebo patients. Twelve of the 94 cysteamine treated patients required early dialysis or renal transplant. Median follow-up of cysteamine patients was over 32 months and 20% were followed more than 5 years. For the placebo group median follow-up was 20 months and only one was followed more than 24 months. Among cysteamine patients glomerular function was maintained over time despite the longer period of treatment and follow-up. Placebo treated patients, in contrast, experienced a gradual rise in serum creatinine. Height, corrected for age, was compared for treated patients with the height, at the various ages patients appeared, of the 143 patients initially screened for inclusion in the NCCS. Patients on treatment maintained growth (did not show increasing growth failure compared to normals) although growth velocity did not increase enough to allow patients to catch up to age norms. Renal tubular function was not affected by treatment.
Calculated creatinine clearances were evaluated for two groups of children, one with poor white cell cystine depletion and one with good white cell cystine depletion. The final mean creatinine clearance of the good depletion group was 20.8 ml/min/1.73 m2 greater than the mean for the poor depletion group, despite the older mean age of the good depletion group.
The Long Term Study, initiated in 1988, utilized both cysteamine HCl and phosphocysteamine (patient’s choice) in 46 patients who had completed the NCCS (averaging 6.5 years of treatment) and 93 new patients. Patients had cystinosis diagnosed by elevated white cell cystine (mean 3.63 nmol/½ cystine/mg). New patients and 46 continuing patients were required to have serum creatinine less than 3.0 mg/dL and 4.0 mg/dL, respectively. Patients were randomized to doses of 1.3 or 1.95 g/m2/day and stratified according to whether the serum creatinine was above 1.2 mg/dL or not. Doses could be raised if white cell cystine levels were approximately 2 nmol/½ cystine/mg protein and lowered due to intolerance.
Mean doses were 1.27 g/m2/day and 1.87 g/m2/day in the two groups and white cell cystine levels averaged 1.72 ± 1.65 nmol/½ cystine/mg protein and 1.86 ± 0.92 nmol/½ cystine/mg protein in the 1.3 and 1.95 g/m2/day groups, respectively. In new patients, a group similar in age to the NCCS group, serum creatinine was essentially unchanged over the period of follow-up (about half of the patients were followed for 24 months) and phosphocysteamine and cysteamine HCl had similar effects. The long-term follow-up group, about nine years old on
Page | 6 of 11 ∞ average at entry, stayed in the study (almost 80% were followed at least 2 years) and had essentially no change in renal function. In four studies of untreated cystinosis, renal death (need for transplant or dialysis) occurred at median age of less than 10 years. Both groups maintained height (although they did not catch up from baseline). There was no apparent difference between the two doses.
Safety
In three clinical trials, cysteamine or phosphocysteamine have been administered to 246 children with cystinosis. Causality of side effects is sometimes difficult to determine because adverse effects may result from the underlying disease.
The most frequent adverse reactions seen involve the gastrointestinal and central nervous systems. These are especially prominent at the initiation of cysteamine therapy. Temporarily suspending treatment, then gradual re-introduction may be effective in improving tolerance.
Adverse reactions were not collected systematically in the NCCS, but were often listed by investigators. The following rates may therefore be underestimated. The most common events (> 5%) were vomiting 35%, anorexia 31%, fever 22%, diarrhea 16%, lethargy 11%, and rash 7%.
Procysbi® (cysteamine bitartrate)
Procysbi is a delayed-release oral formulation of cysteamine bitartrate. Results demonstrated that at steady state, delayed-release cysteamine administered every 12 hours was noninferior to immediate-release cysteamine administered every 6 hours in depleting WBC cystine levels. As per the FDA per protocol analysis of 39 patients, the least-square-mean value of WBC cystine was 0.52 ± 0.06 nmol ½ cystine/mg protein after 12 hours under delayed-release cysteamine and 0.44 ± 0.06 nmol ½ cystine/mg protein after 6 hours under immediate-release cysteamine. Absolute difference of 0.08 ± 0.03 (95.8% CI: 0.01 to 0.15). This confidence interval did not include the non-inferiority margin of 0.30 nmol ½ cystine/mg protein. The analysis by the sponsor reported in the published paper included 38 patients in the per-protocol analysis and 41 patients in the ITT analysis. The results were not materially different in the sponsor analysis. The outcome of non-inferior WBC cystine levels was achieved at a lower average daily dose of delayed-release cysteamine (1513±477 mg/d) compared with immediate-release cysteamine (1801±511 mg/d).
Page | 7 of 11 ∞ Pharmacokinetic results shows that Cmax of a larger, single 12-hourly dose of delayed-release cysteamine compared with 2 consecutive 6-hourly doses of immediate-release cysteamine were not very different. As expected, the half-life of delayed-release cysteamine was longer than immediate-release cysteamine.
Results published as an abstract include 20-month data from 40 patients from the pivotal trial who enrolled into the extension phase. This study demonstrated that there was no change in the mean values for WBC cystine in the patients from study onset to the end of 20 months. After 20 months of treatment, the total daily dose of delayed-release cysteamine needed to achieve optimal WBC cystine levels was on average 72% of the initial immediate-release cysteamine dose. Kidney function was well preserved over the length of the study, as indicated by steady eGFR levels. The QOL outcomes measured using a generic instrument PedsQLTM version 4.08 improved significantly. From the study onset, the PedsQLTM scores improved significantly in all patients, including the Total Functioning Score (p < 0.001) and the Social Performance (p < 0.001).
Safety
The most commonly reported AEs were vomiting, abdominal pain/discomfort, headaches, nausea, diarrhea, anorexia/decreased appetite, breath odor, fatigue, dizziness, skin odor, and rash. The number of GI related AEs was 3-fold higher during the delayed-release cysteamine treatment period compared to the immediate-release cysteamine treatment period. PPI therapy was allowed as per the discretion of the patient and/or the physician during the immediate- release cysteamine treatment period, but was discontinued initially during the delayed-release cysteamine treatment period to maintain an optimal gastric pH environment for kinetics of the delayed-release formulation. Patient or study physician were given the option to restart PPI therapy. The use of PPI therapy was reduced by 87% during the delayed-release cysteamine treatment period, which could have potentially increased the incidence of GI related AEs.
More patients experienced an SAE with delayed-release cysteamine compared to immediate- release cysteamine (6 and 1 respectively). The investigators considered only 1 SAE as possibly related to delayed-release cysteamine treatment. SAEs were cervical femoral fracture from a fall, 1 elective knee surgery, 5 GI-related SAEs, and all SAEs were resolved by site investigator. No unexpected SAEs were reported in the Phase III trial or the extension phase of the study.
Serious adverse events such as skin and bone lesions that resemble clinical findings for Ehlers- Danlos syndrome, severe skin rashes such as erythema multiforme bullosa or toxic epidermal necrolysis, benign intracranial hypertension and neurological complications have been described
Page | 8 of 11 ∞ with use of immediate-release cysteamine. Therefore, caution about the possibility of such adverse reaction should be exercised with delayed-release cysteamine.
Cystaran® (cysteamine ophthalmic solution)
Clinical efficacy was evaluated in controlled clinical trials in approximately 300 patients. The primary efficacy end point was the response rate of eyes that had a reduction of at least 1 unit in the photo-rated Corneal Cystine Crystal Score (CCCS) at some time point during the study when baseline CCCS ≥1, or a lack of an increase of more than 1 unit in CCCS throughout the study when baseline CCCS <1.
Study 1 combined the data from three smaller studies. For eyes with a lower baseline of CCCS <1, the response rate was 13% (4/30) [95% CI: (4, 32)]. For eyes with a higher baseline of CCCS ≥1, the response rate was 32% (94/291) [95% CI: (27, 38)]. Study 2 evaluated ocular cystinosis patients who had a baseline of CCCS ≥1. The response rate was 67% (10/15) [95% CI: (38, 88)]. Study 3 also evaluated ocular cystinosis patients; for eyes with a baseline of CCCS ≥1, the response rate was 33% (3/9) [95% CI: (8, 70)].
Safety
The safety data described reflects exposure in controlled clinical trials of six months to 19 years duration in approximately 300 patients. The most frequently reported ocular adverse reactions occurring in ≥10% of patients were sensitivity to light, redness, and eye pain/irritation, headache and visual field defects.
Cystadrops® (cysteamine ophthalmic solution)
Clinical safety and efficacy of Cystadrops were assessed in two studies: a single-arm study conducted for 5 years (OCT-1) and a randomized controlled study conducted for 90 days (CHOC). In the OCT-1 study, 8 patients with cystinosis (2 males and 6 females) with a mean age of 12.1 ± 4.6 (range: 7.0 – 21.0) were enrolled and received a median of 4 drops/eye/day of Cystadrops. In CHOC study, 32 patients with cystinosis (15 males and 17 females) with a mean age of 17.1 ± 13.0 (range: 2.9 – 62.6) were enrolled and received a median of 4 drops/eye/day. Fifteen patients were exposed to Cystadrops and 16 were exposed to cysteamine hydrochloride 0.1% (control arm). Efficacy was assessed with In-Vivo Confocal Microscopy total score (IVCM
Page | 9 of 11 ∞ score) by quantifying the cystine crystals in the cornea. A decrease in IVCM total score from baseline indicated a reduction in corneal crystals. In the CHOC study, after 30 and 90 days of treatment with Cystadrops, 12% and 40% reduction in the total IVCM total score across all corneal layers was observed from baseline, respectively. Cystadrops demonstrated greater reduction compared to the control arm at 90 days. The average reduction in IVCM total score was 4.6 in the Cystadrops arm and 0.5 in the control arm, mean difference 3.8 (95% CI: (2.1, 5.6)). In the OCT-1 study, a mean decrease in corneal cystine crystal deposits of 30%, in comparison with baseline, was maintained over the 60-month period of the study.
Safety
The most common adverse reactions (≥ 10%) reported during clinical trials were eye pain, vision blurred, eye irritation, ocular hyperaemia, instillation site discomfort, eye pruritus, lacrimation increased, and ocular deposits.
2020 Update
Reviewed prescribing information for all drugs in policy and performed a review on the management of cystinosis. Added a new dosage form of Procysbi® to policy which are delayed- release granules. Added a new product called Cystadrops® (cysteamine ophthalmic solution) 0.37%, which requires less frequent administration of 4 times a day during waking hours than Cystaran® (cysteamine ophthalmic solution) 0.44%, which requires administration every waking hour.
References
1. Procysbi (cysteamine bitartrate) Prescribing Information. Horizon Pharma USA, Inc., Lake Forest, IL. February 2020.
2. Cystagon (cysteamine bitartrate) Prescribing Information. Mylan Pharmaceuticals Inc., Morgantown, WV. January 2019.
3. Cystadrops (cysteamine ophthalmic solution) Prescribing Information. Recordati Rare Diseases Inc., Lebanon, NJ. August 2020.
4. Cystaran (cysteamine ophthalmic solution) Prescribing Information. Leadiant Biosciences, Inc., Gaithersburg, MD. April 2020.
5. UpToDate. Cystinosis. Available at: http://www.uptodate.com/home/index.html. Accessed September 2020.
6. McDowell GA, Town MM, van't Hoff W, Gahl WA. Clinical and molecular aspects of nephropathic cystinosis. J Mol Med (Berl) 1998;76(5):295-302.
Page | 10 of 11 ∞ 7. Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med 2002;347(2):111-121.
8. Dohil R, Fidler M, Gangoiti JA, Kaskel F, Schneider JA, Barshop BA. Twice-daily cysteamine bitartrate therapy for children with cystinosis. J Pediatr 2010;156(1):71-75 e71-73.
9. Langman CB, Greenbaum LA, Sarwal M, et al. A randomized controlled crossover trial with delayed-release cysteamine bitartrate in nephropathic cystinosis: effectiveness on white blood cell cystine level and comparison of safety. Clin J Am Soc Nephrol: 2012(7):1112-1120.
History
Date Comments 10/01/19 New policy, approved September 10, 2019. Add to Prescription Drug section. Criteria added for Cystagon® (cysteamine bitartrate), Procysbi® (cysteamine bitartrate) and Cystaran® (cysteamine ophthalmic solution).
10/01/20 Annual Review, approved September 17, 2020. Added coverage criteria for Cystadrops (cysteamine ophthalmic solution) for the treatment of corneal cystine crystal accumulation. Added Procysbi (cysteamine bitartrate) delayed-release granules to policy.
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). ©2020 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.
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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架៉ ងសនំ។ ់ េសចកតីជូនដំណឹងេនះរបែហល ᾶ掶នព័ត៌掶ន架៉ ងសំន់អពំ ីទរមង់ ែបបបទ ឬζរ殶៉ បរង់ របសអ់ នក㾶មរយៈ Español (Spanish): Premera Blue Cross ។ របែហលᾶ掶ន ζលបរ េចិ ឆទសំន់េ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 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 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).