Generic hydroxyurea or over-the-counter (OTC) L-glutamine, are available and recommended based on the limited evidence of Endari as discussed below.

Transcription

1 Subject: Endari (L-glutamine oral powder) Original Effective Date: 3/8/2018 Policy Number: MCP-305 Revision Date(s): Review Date: 3/8/2018 MCPC Approval Date: 3/8/2018 DISCLAIMER This Molina Clinical Policy (MCP) is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this MCP document and provide the directive for all Medicare members. RECOMMENDATIONS This policy addresses Endari (L-glutamine oral powder) for the treatment of patients 5 years of age and older with sickle cell disease (SCD) to reduce acute complications associated with the disease. All uses of Endari (L-glutamine oral powder) are considered not medically necessary in accordance to this policy. This coverage policy is subject to change based on research and medical literature, or at the discretion of Molina Healthcare. Molina Healthcare will be continue to evaluate and update this policy as relevant clinical evidence becomes available to determine whether Endari (L-glutamine oral powder) provides the impact on health outcomes or patient management. Generic hydroxyurea or over-the-counter (OTC) L-glutamine, are available and recommended based on the limited evidence of Endari as discussed below. LIMITATIONS/EXCLUSIONS: The use of Endari (L-glutamine oral powder) is not covered for all indications due to insufficient evidence to establish clinical effectiveness or superiority over standard L-glutamine dietary supplements. There is no high-quality evidence and no head-to-head studies from published clinical trials and peerreviewed literature evaluating the clinical safety and efficacy of this pharmaceutical grade L-glutamine oral powder versus over-the-counter L-glutamine, which is separately available as a nutritional supplement and widely available without a prescription at drugstores across the United States, although in much smaller doses than those the FDA recommends for sickle cell disease. There is also limited evidence from published clinical trials and lack of data supporting the long-term benefits, side-effect profile, or risks associated with pharmaceutical grade L-glutamine (Endari) over the various L-glutamine dietary supplements. In addition, there is also no head-to-head studies with hydroxyurea, the only previous drug treatment available for the management of SCD. Hydroxyurea is the preferred agent in the treatment of SCD and has been the mainstay of therapy for many years and is the most cost-effective for Molina members. Page 1 of 11

2 At this time, there are no guidelines relevant to L-glutamine (Endari) for SCD and no consensus from clinical experts to suggest that Endari is equivalent to, or should replace hydroxyurea therapy. Currently, it may be considered as add-on therapy in patients ages 5 years and older who have at least two sickle cell crises a year, despite maximally tolerated hydroxyurea doses, or as monotherapy for patients unable to tolerate hydroxyurea. Endari does not treat the underlying cause of SCD and has shown modest benefits in the reduction of sickle cell acute crisis (median 3 vs. median 4) and hospitalizations for sickle cell pain (median 2 vs. median 3). Furthermore, there are no headto-head studies with hydroxyurea, the only previous drug treatment available for the management of SCD. At the present time, the role of Endari may be considered as add-on therapy since approximately two-thirds of the participants in both arms (63%) also had been receiving hydroxyurea on a stable dose for at least three months and continued hydroxyurea during the pivotal phase 3 trial therefore, L-glutamine should not replace hydroxyurea therapy at this time. SUMMARY OF EVIDENCE/POSITION Sickle cell disease (SCD) is one of the most common genetic disorders in the world. Minniti 2013; Kanter 2013 SCD is an inherited blood disorder in which the red blood cells are abnormally shaped (in a crescent, or "sickle," shape). This restricts the flow in blood vessels and limits oxygen delivery to the body s tissues, leading to severe pain and organ damage. Approximately 100,000 Americans have sickle cell disease. CDC 2016 SCD is most common among people of African, Mediterranean and Asian descent. Kanter 2013 Patients with SCD are at risk for clot formation, infection, organ damage, Kanter 2013 retinopathy, stroke, and other complications. L-glutamine (Endari) was approved by the U.S. FDA in July 2017 for the treatment of patients 5 years of age and older with SCD to reduce acute complications associated with the disease. L-glutamine (Endari) is an amino acid and the first new drug approved in the U.S. to treat SCD in almost 20 years. Endari is a powder and is taken orally twice daily. Endari contains L-glutamine, an amino acid. L-glutamine is an amino acid that may increase the activity of nicotinamide adenine dinucleotide (NAD) synthesis, thereby countering the oxidant-dependent pathophysiology of sickle red blood cells. NAD redox potential is improved and nicotinamide adenine dinucleotide (reduced form) (NADH) levels are increased through increasing the availability of reduced glutamine. The proposed mechanism is reduced oxidative damage to sickled red blood cells, ultimately preventing reduced blood flow by decreasing clot formation. The FDA approval of L-glutamine (Endari) was supported by efficacy data from a 48-week randomized, double-blind, placebo-controlled, multicenter Phase III clinical trial evaluating the effects of Endari, prescription grade L-glutamine, as compared to placebo on 230 adults and children with SCD (NCT ). The 230 patients ranged in age from 5 to 58 years, with sickle cell anemia or sickle beta thalassemia who had at least two episodes of painful crises during the 12 months prior to screening were randomly assigned to receive oral L-glutamine 0.3 mg/kg a day or placebo (the food additive maltodextrin) for 48 weeks, followed by a three-week tapering period and a two- week follow-up period, for a total duration of up to 57 weeks. Efficacy was determined by a reduction in the number of sickle cell crises, defined as a visit to the emergency room/medical facility for SCD-related pain which was treated with a parenterally administered narcotic or parenterally administered ketorolac. In addition, occurrence of chest syndrome, priapism, and splenic sequestration were considered sickle cell crises. L-glutamine has shown modest benefits in the reduction of sickle cell acute crisis with a minimal toxicity profile. The results demonstrated that L-glutamine (Endari) reduced the frequency of sickle cell crises by 25% (median 3 vs. median 4), and hospitalizations by 33% for sickle cell pain (median 2 vs. median 3). Page 2 of 11

3 Additional findings showed a decrease in cumulative hospital days by 41% (median 6.5 days vs. median 11 days) and lower incidence of acute chest syndrome (ACS) by more than 60% (8.6% vs. 23.1%). Limitations of L-glutamine therapy that were reported include a low adherence to study medication with an average of 23% of study medication taken in the phase 3 trial. Of the 36.2% of patients in the L-glutamine group who dropped out of the study, only 2.7% reported an adverse drug reaction as the rationale for discontinuation. Other reasons for discontinuation from the study included consent withdrawal, patient relocation or logistical issues, noncompliance, and loss to follow-up. There are no head-to-head studies with hydroxyurea, the only previous drug treatment available for the management of sickle cell disease, and 63% of patients on the phase 3 trial were also taking hydroxyurea; approximately two-thirds of the participants in both arms also had been receiving hydroxyurea on a stable dose for at least three months and continued hydroxyurea during the trial. In the landmark trial for hydroxyurea in adult patients, hydroxyurea decreased median vaso-occlusive crises requiring hospitalization per year (2.5 vs. 4.5, p <.001), lengthened the median time to first vaso-occlusive crisis (3 vs. 1.5 months, p =.01), and decreased the incidence of acute chest syndrome (25 vs. 51, p <.001) compared to placebo. L-glutamine should not replace hydroxyurea therapy at this time, but it may be considered as add-on therapy in patients ages 5 years and older who have at least two sickle cell crises a year, despite maximally tolerated hydroxyurea doses, or as monotherapy for patients unable to tolerate hydroxyurea. The study was conducted in the United States. Subgroup analysis found that age, gender, and previous exposure to hydroxyurea therapy had no effect on the study results. There are no head-to-head studies evaluating the safety and efficacy of pharmaceutical grade L-glutamine and the various L-glutamine dietary supplements on the market. L-glutamine oral supplement is available as an OTC supplement. There are no head-to-head studies evaluating the safety and efficacy of pharmaceutical grade L-glutamine and the various L-glutamine dietary supplements on the market. There are no studies that compare L-glutamine to other treatment alternatives. The most common adverse reactions occurring in greater than 10% of patients treated with L-glutamine were constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain. Treatment discontinuation due to adverse reactions was reported in 2.7% (n=5) of patients receiving L-glutamine. These adverse reactions included one case each of hypersplenism, abdominal pain, dyspepsia, burning sensation, and hot flash. Limitations The study was conducted in a small patient population. Results were extracted from meeting abstracts, the prescribing information, and the briefing material used by the FDA's advisory committee. When data points differed between these sources, the most current document (PI) was used. Endari did not meet the trial's planned analysis initially and yielded a non-significant p value of versus the control comparator, maltodextrin. However, using a different analysis, Emmaus amended the statistical method that it claimed success with a p value and stated the results were highly statistically significant at Statistical considerations for the trial included assumptions of a 25% dropout rate and total accrual of 220 patients. Instead, the L-glutamine group had a discontinuation rate of 36.2% compared with 24.4% in the placebo group. Because of the imbalance, investigators employed various imputational methods to account for the difference. The reported outcomes showed a mean number of sickle-cell crises at 48 weeks was 3.2 in the L-glutamine group and 3.9 in the placebo group. Median values were 3.0 with L-glutamine and 4.0 with placebo, differences that achieved statistical significance (P=0.005). Hence, while the primary efficacy analysis was statistically significant in favor of treatment with L-glutamine, issues with data imputation and analysis overshadowed this finding, according to an FDA briefing document. FDA Briefing Document Page 3 of 11

4 Moreover, the discontinuation rate in this study was higher than anticipated (32% compared with the expected 25%), and there was a disparate rate of premature discontinuations between treatment arms (36% in the L-glutamine group vs. 24% in the placebo group). According to the briefing document, the data collected during the study were insufficiently detailed to allow reviewers to determine the reason(s) for the higher withdrawal rate in the L-glutamine arm. FDA Briefing Document CLASSIFICATION: Amino Acid; Gastrointestinal Agent, Miscellaneous FDA INDICATIONS SICKLE CELL DISEASE: To reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years and older. Available as: Carton of 60 packets: 5 g/packet (paper-foil-plastic laminate packets containing 5 g of L-glutamine powder) NOTE: Endari is an oral formulation of L-glutamine, an amino acid that has been sold in the U.S. since 2004 under the brand name NutreStore as a prescription nutritional supplement for patients with short bowel syndrome who are receiving specialized nutritional support along with a recombinant human growth hormone. NutreStore is also manufactured by Emmaus Medical. FDA Approved: July Orphan drug designation: Treatment of sickle cell disease The FDA Hematology and Oncologic Drugs Advisory Committee recommended approval of L-glutamine for the treatment of sickle cell disease on May 24, Endari received fast track designation from the FDA and was approved July 7, Black Box Warnings: None at the time of this writing REMS: No REMS is required for L-glutamine at the time of this writing COVERAGE EXCLUSIONS Endari (L-glutamine oral powder) for the treatment of to reduce the acute complications of sickle cell disease (SCD) is not covered for all indications. This coverage policy is subject to change based on research and medical literature, or at the discretion of Molina Healthcare. All other uses of Endari (L-glutamine oral powder) are considered experimental/investigational or not a covered benefit of this policy. This subject to change based on research and medical literature, or at the discretion of Molina Healthcare. *Pharmaceutical samples: The use of pharmaceutical samples (from the prescriber or manufacturer assistance program) will not be considered when evaluating the medical condition, prior prescription history, or as continuation of therapy. *FDA-approved indication does not, in itself, dictate coverage. Molina Clinical Policy may not recommend coverage for all FDA-approved indications. Please review this Policy in its entirety for indications covered by Molina Healthcare. Page 4 of 11

5 SUMMARY OF EVIDENCE Sickle cell disease (SCD) is an autosomal recessive genetic disorder caused by an abnormal form of hemoglobin called hemoglobin S (HbS) or sickle hemoglobin. SCD is a lifelong illness that causes significant morbidity and mortality. SCD is a group of chronic anemias with autosomal recessive inheritance caused by presence of 1 sickle hemoglobin gene, leading to > 50% production of hemoglobin S (HbS). HbS polymerizes when deoxygenated, distorting red blood cells and Dynamed 2017 causing a characteristic sickle shape. It is most common in individuals from or descended from Mediterranean countries, Africa, Middle East, India, Caribbean countries, and parts of Central and South America. The highest prevalence is in persons from Africa or of African descent. An estimated 100,000 individuals in the U.S. are living with SCD, according to the Centers for Disease Control and Prevention (CDC). SCD is most prevalent among people of African descent, occurring in approximately 1 of every 365 Black or African American babies born. In addition, approximately 1 in 13 Black or African American babies is born with sickle cell trait (SCT). Sickle cell trait (SCT) Persons with sickle cell trait (SCT) do not have sickle cell related health problems. They are considered carriers and can pass the HbS gene to their offspring. Sickle cell anemia is the most severe subtype, caused by homozygous inheritance of hemoglobin S (HbSS). It is usually diagnosed in childhood via universal newborn screening and requires lifelong management. Symptoms of SCD present during the first year of life, typically when the infant is 4 to 5 months of age (CDC). Other subtypes include: sickle cell trait (HbAS), an asymptomatic genetic carrier state sickle hemoglobin C disease (HbSC), a compound heterozygous anemia sickle beta thalassemia, a compound heterozygous anemia hemoglobin C disease (HbCC), a mild anemia Individuals with sickle cell trait are typically asymptomatic. Patients with sickle cell anemia may present with acute chest syndrome, anemia, severe musculoskeletal pain, and splenomegaly. Clinical course and disease severity may vary. Pain is a common symptom of sickle cell crises, and may present as chest, musculoskeletal, or abdominal pain. All infants born in the United States are screened at birth for sickle cell status as part of a unified newborn screening panel to identify cases and enable early management of disease. Diagnostic tests for suspected sickle cell disease include: complete blood count, peripheral blood smear, and hemoglobin electrophoresis or high performance liquid chromatography (HPLC) to detect hemoglobin S. Laboratory findings typical of sickle cell anemia include: Hemoglobin 6-8 g/dl (60-80 g/l), and normal or elevated mean corpuscular volume (MCV) Hemoglobin electrophoresis should be performed to confirm diagnosis using hemoglobin S > 90%, hemoglobin A 0%, and hemoglobin F typically < 10% Treatment for SCD are supportive care and preventive measures to reduce the incidence of vaso-occlusive crisis (VOC). SCD therapy involves proactive management of frequent acute and chronic complications. Goals are to reduce infection, pain episodes, thromboembolic complications, and other organ damage. Hydroxyurea (to improve blood flow) and blood transfusions (a source of normal hemoglobin) have been the primary disease modifying therapies. Recently, L- glutamine (Endari) was approved in the U.S. for patients five years and older to reduce severe complications associated with sickle cell disease. Allogeneic HSCT is the only potentially curative treatment for SCD; however, patient eligibility for HSCT is very limited due to substantial risks for transplant-related morbidity and mortality. Lack of appropriate donors is also an issue. Blood transfusions provide normal hemoglobin to patients with sickle cell disease. This lowers the percentage of circulating sickled red blood cells and reduces vascular changes and clotting (Yawn 2014). Transfusions are commonly used to treat sickle cell complications. They are also used perioperatively to reduce risk of vasoocclusive crisis, stroke, or acute chest syndrome. Exchange transfusions are sometimes used, based on the guidance of a specialist. With these transfusions, blood is removed from the patient, and replaced or exchanged with donor blood. Page 5 of 11

6 Hydroxyurea are indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in patients (in adults and in pediatric patients 2 years or older) with sickle cell anemia with recurrent moderate to severe painful crises. Therapy with the drug in this condition is not curative, and any beneficial effect will be maintained only as long as an effective regimen of hydroxyurea is continued. In addition, hydroxyurea therapy in patients with sickle cell anemia is prophylactic, and therefore the drug has no role in the treatment of a crisis in progress. Hydroxyurea is associated with serious adverse effects; use is typically limited to patients with recurrent moderate-to-severe painful crises. Because hydroxyurea is a cytotoxic agent, the possible risks of therapy with the drug, including long-term risks such as secondary neoplasms (e.g., leukemia), should be weighed carefully against the potential benefits in treating a nonmalignant disease such as sickle cell anemia. (AHFS 2018) Endari (L-glutamine oral powder) was approved by the U.S. FDA in July 2017 for the treatment of patients 5 years of age and older with sickle cell disease (SCD) to reduce acute complications associated with the disease. L- glutamine (Endari) is an amino acid and the first new drug approved in the U.S. to treat sickle cell disease in almost 20 years. Endari is a powder and is taken orally twice daily. CLINICAL TRIALS Emmaus has completed three clinical trials that assessed the effectiveness of Endari in treating sickle cell anemia and sickle cell thalassemia. The first, which ended in 2008, was a Phase 2 double-blind and placebo-controlled study (NCT ) evaluating the number of sickle cell crises experienced by about 80 enrolled patients during 48 weeks of treatment. A second Phase 2 study (NCT ) that ended in 2009 evaluated the effectiveness of Endari, versus placebo, in 18 sickle cell anemia patients. Its focus was improvements in exercise endurance and breath, and the number of disease crises, as measured by pain levels and narcotics use, changes in energy and appetite, and hospital and emergency room visits over 28 days. A Phase 3 randomized, double-blind and placebo-controlled study (NCT ) evaluated the effects of Endari on the red blood cells of 230 adult and pediatric patients (ages 5 and older) with sickle cell anemia or sickle thalassemia. The U.S.-based trial, which concluded in 2014, compared 48 weeks of treatment with oral Endari or with maltodextrin, a food additive, for changes in sickle cell crises, hospitalizations and emergency room or medical visits, hematological parameters, and for adverse reactions. PIVOTAL TRIAL Phase III Safety and Efficacy Study of L-Glutamine to Treat Sickle Cell Disease or Sickle βo-thalassemia (Niihara Y, et al, 2014) Drug: L-glutamine vs Placebo Study Design: Randomized, Double-blind, Phase 3 Multicenter Study Study Funding: Emmaus Medical Subjects 230 patients (at least 5 years of age) with sickle cell anemia or sickle beta 0 -thalassemia and at least 2 documented episodes of sickle cell crises within 12 months prior to screening. Patients were 5 to 58 years of age (mean age, 22 years), 53.9% were female, 94% were black, approximately 3% were Hispanic; in both L-glutamine and placebo groups, 66% had previously been treated with hydroxyurea, and the mean number of sickle cell crises in the year prior to screening was 4. Exclusion criteria: Included significant medical condition that required hospitalization (other than sickle cell crisis) within 2 months of the screening visit; prothrombin time international normalized ratio (INR) greater than 2; serum albumin less than 3 g/dl; receipt of any blood products within 3 weeks of the screening visit; uncontrolled liver disease or renal insufficiency; current or previous use of any form of glutamine supplement within 30 days of the screening visit; or use of experimental antisickling medication/treatment within 30 days of the screening visit (with the exception of hydroxyurea in pediatric patients). Page 6 of 11

7 Intervention Patients were randomized (2:1) to treatment with either L-glutamine (n=152) or maltodextrin (placebo) (n=78). The dose of both drugs was 0.3 g/kg orally twice daily for 48 weeks. The dosage was increased in increments of 5 g based on weight. The upper limit for the daily dose of study medication was set at 30 g. At the baseline visit, patients were given verbal and written instructions for self-administration of the study medication; the powder for oral administration could be mixed with water or other non-heated beverages other than alcohol, or mixed with non-heated foods such as yogurt, applesauce, or cereal. Results Primary End Point(s) Median number of occurrences of sickle cell crises (i.e., visit to an emergency room/medical facility for sickle cell disease related pain requiring treatment with a parenterally administered narcotic or parenterally administered ketorolac, or the occurrence of chest syndrome, priapism, and splenic sequestration) during the 48-week treatment period was 3 with L-glutamine and 4 with placebo (P=0.008). The mean number of sickle cell crises at 48 weeks was 3.2 for L-glutamine compared with 3.9 for placebo (P = 0.005). However, while the primary efficacy analysis was statistically significant in favor of treatment with L-glutamine, issues with data imputation and analysis overshadowed this finding, according to an FDA briefing document. Secondary End Point(s) Median number of hospitalizations for sickle cell pain during the 48-week treatment period was 2 in the L-glutamine group and 3 in the placebo group (P=0.005). Median number of cumulative days in hospital was 6.5 days in the L-glutamine group and 11 days in the placebo group (P=0.022). Median time to first sickle cell crisis was 84 days (95% confidence interval [CI], 62 to 109) in the L-glutamine group and 54 days (95% CI, 31 to 73) in the placebo group. Acute chest syndrome occurred in 8.6% in the L-glutamine group and 23.1% in the placebo group. The recurrent crisis event time analysis produced an intensity rate ratio value of 0.75 (95% CI, 0.62 to 0.9 and 0.55 to 1.01 based on unstratified models using the Andersen-Gill and Lin-Wei-Yang-Ying methods, respectively) in favor of L-glutamine. Based on this analysis, the average cumulative crisis count was reduced by 25% from the L-glutamine group over the placebo group. Comments: The study was conducted in the United States. Subgroup analysis found that age, gender, and previous exposure to hydroxyurea therapy had no effect on the study results. Limitations The study was conducted in a small patient population. Statistical considerations for the trial included assumptions of a 25% dropout rate and total accrual of 220 patients. Instead, the L-glutamine group had a discontinuation rate of 36.2% compared with 24.4% in the placebo group. Because of the imbalance, investigators employed various imputational methods to account for the difference. The reported outcomes showed a mean number of sickle-cell crises at 48 weeks was 3.2 in the L-glutamine group and 3.9 in the placebo group. Median values were 3.0 with L-glutamine and 4.0 with placebo, differences that achieved statistical significance (P=0.005). Hence, while the primary efficacy analysis was statistically significant in favor of treatment with L-glutamine, issues with data imputation and analysis overshadowed this finding, according to an FDA briefing document. Moreover, the discontinuation rate in this study was higher than anticipated (32% compared with the expected 25%), and there was a disparate rate of premature discontinuations between treatment arms (36% in the L-glutamine group vs. 24% in the placebo group). According to the briefing document, the data collected during the study were insufficiently detailed to allow reviewers to determine the reason(s) for the higher withdrawal rate in the L-glutamine arm. Page 7 of 11

8 HAYES At the time of this writing in January 2018, a Hayes Technology assessment addressing Endari (Pharmaceutical Grade L- Glutamine) is not available; however a Prognosis Overview (a horizon scanning service that monitors emerging health technologies as they go through clinical trial development and the regulatory approval process) is available and published/updated on July CLINICAL PRACTICE GUIDELINES *Guidelines have not addressed the role of Pharmaceutical grade L-glutamine as of this writing in January 2018 National Heart, Lung, and Blood Institute. Evidence-based management of sickle cell disease: expert panel report, (2014) The only treatment previously available for the prevention of crises and organ damage associated with sickle cell disease was hydroxyurea or the use of chronic blood transfusions. Pharmaceutical grade L-glutamine was not available at the time this guideline was developed. DEFINITIONS NHLBI 2014 Acute Chest Syndrome One of the most common and severe complications of sickle cell disease; most common cause of death in patients with sickle cell disease. (Paul 2011) It is a sudden lung injury most often caused by an infection or clot (Miller 2012). Symptoms include chest pain, fever, rapid breathing, wheezing, and cough. This develops in 10% to 20% of patients admitted for a sickle cell crisis. (Miller 2012) Clinical features resemble pneumonia May develop suddenly, during hospitalization for a vaso-occlusive crisis, or after surgery (especially abdominal procedures) More common in patients with asthma or prior acute chest syndrome event Typical presentation includes sudden onset of signs and symptoms associated with lower respiratory tract disease, including: cough, shortness of breath, rales Children typically present with fever but adults are often afebrile Signs of severe acute chest syndrome event include Multilobe disease Inability to maintain oxygen saturation > 95% with supplemental oxygen Increased difficulty breathing Pleural effusions No distinctive laboratory features, but rapid decrease in hemoglobin below baseline value often occurs Therapy for acute chest syndrome includes fluids, analgesics, broad-spectrum antibiotics, and oxygen. Transfusions are sometimes used for severe respiratory distress. Pre-operative transfusions and incentive spirometry during sickle cell crisis hospitalizations may reduce the risk of acute chest syndrome. (Yawn 2014) References: Miller AC, Gladwin MT. Pulmonary complications of sickle cell disease. Am J Respir Crit Care Med 2012;185: Paul RN, Castro OL, Aggarwal A, Oneal PA. Acute chest syndrome: sickle cell disease. Eur J Haematol 2011;87: Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312: Page 8 of 11

9 NHLBI 2014 Splenic sequestration Characterized by sudden enlargement of spleen, typically causing severe abdominal pain, with hemoglobin decrease 2 g/dl from baseline reticulocyte count and circulating nucleated red blood cells typically increased platelet count typically decreased Typically develops without warning or known cause More common in children aged < 5 years; in patients with sickle hemoglobin C disease and sickle betathalassemia, occurs in later childhood or adulthood 7%-30% lifetime prevalence in patients with sickle cell anemia Provide early education to parents of infants with regard to palpation of spleen symptoms of progressive anemia action for obtaining rapid evaluation and treatment Reference: National Institutes of Health, National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources. Evidence-based management of sickle cell disease. (NHLBI 2014) APPENDIX N/A CODING INFORMATION: THE CODES LISTED IN THIS CLINICAL POLICY ARE FOR INFORMATIONAL PURPOSES ONLY. LISTING OF A SERVICE OR DEVICE CODE IN THIS POLICY DOES NOT IMPLY THAT THE SERVICE DESCRIBED BY THIS CODE IS A COVERED OR NON-COVERED. COVERAGE IS DETERMINED BY THE BENEFIT DOCUMENT. THIS LIST OF CODES MAY NOT BE ALL INCLUSIVE AND INCLUSION OR EXCLUSION OF ANY CODES DOES NOT GUARANTEE COVERAGE. PROVIDERS SHOULD REFERENCE THE MOST UP-TO-DATE SOURCES OF PROFESSIONAL CODING GUIDANCE PRIOR TO THE SUBMISSION OF CLAIMS FOR REIMBURSEMENT OF COVERED SERVICES. CPT NA HCPCS Description Description *CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS). Page 9 of 11

10 REFERENCES PACKAGE INSERT, FDA, DRUG COMPENDIA Endari (L-glutamine) oral powder package insert. Torrance, CA: Emmaus Medical, Inc.; 2017 July. Hydroxyurea Prescribing information. Bristol-Myers Squibb Company Princeton, New Jersey Drug Facts and Comparisons. Facts and Comparisons eanswers [online]. Clinical Drug Information LLC, Available from Wolters Kluwer Health, Inc. [via subscription only] Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; URL: Updated periodically. [via subscription only] DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated periodically. Lexi-Comp ONLINE with AHFS, Hudson, Ohio: Lexi-Comp, Inc.; 2017; Updated periodically. [via subscription only] DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services Record No , Sickle cell disease in adults and adolescents; [updated 2017 May 17, cited January 2017]; [about 18 screens]. Available from Registration and login required. Emmaus Life Sciences. FDA advisory committee recommends approval of Endari from Emmaus Life Sciences for the treatment of sickle cell disease [news release]. Published May 24, Accessed January Farrell AT. NDA approval letter: Endari (L-glutamine NDA ). Food and Drug Administration website. Published July 7, Accessed January ClinicalTrials.gov A phase III, prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter study of l glutamine therapy for sickle cell anemia and sickle ß0-thalassemia. Available at: CDC. Sickle cell disease: data and statistics. Updated August 31, Available at: Accessed January U.S. Food and Drug Administration. FDA approved L-glutamine powder for the treatment of sickle cell disease. U.S. Food and Drug Administration: Approved Drugs. July 7, 2017; Available at: Accessed January U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Oral L-glutamine powder NDA , May 24, Available at: mmittee/ucm pdf. Accessed January Sickle cell disease. Genetics Home Reference. August 2012; Page 10 of 11

11 CLINICAL TRIALS, DEFINITIONS, PEER-REVIEWED PUBLICATIONS Minniti CP, Lu K, Groninger H. Pain in sickle cell disease. J Palliat Med 2013;16: Kanter J, Kruse-Jarres R. Management of sickle cell disease from childhood through adulthood. Blood Rev 2013:27: Niihara Y, Koh HA, Tran L, et al. A Phase III Safety and Efficacy Study of L-Glutamine to Treat Sickle Cell Disease or Sickle βo-thalassemia [abstract]. Blood. 2014;124(21):86. Rodgers G.P, George A. (Sep 2017). Hydroxyurea use in sickle cell disease. In S.L. Schrier, D.H. Mahoney & J.S. Tirnauer. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Available at: Accessed January [via subscription only] Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312: Available at: Accessed January GOVERNMENT AGENCIES, PROFESSIONAL SOCIETIES, OTHER AUTHORITATIVE PUBLICATIONS National Heart, Lung, and Blood Institute. Evidence-based management of sickle cell disease: expert panel report, Available at: Published Accessed January Section on Hematology/Oncology Committee on Genetics, American Academy of Pediatrics. Health supervision for children with sickle cell disease. Pediatrics Mar;109(3):526-35, reaffirmed 2011 Jan Policy History Policy Developed AMR Peer Review Network. 1/11/2018. Practicing physician. Board certified in Internal Medicine, Oncology, Hematology MCPC 3/8/18 Page 11 of 11