Category Filter
- Advanced Imaging
- Autism Spectrum Mandate
- Behavioral Health
- Blue Advantage Policies
- Chronic Condition Management
- Genetic Testing
- HelpScript Program
- Hemophilia Drugs
- Medical Policies
- Pre-Service Review (Predetermination/Precertification)
- Provider-Administered Drug Policies
- Radiation Therapy
- Self-Administered Drug Policies
- Transgender Services
Asset Publisher
Endari (L-glutamine) Prior Authorization Program Summary
Policy Number: PH-1039
This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies.
POLICY REVIEW CYCLE
Effective Date |
Date of Origin |
10-01-2024 |
|
FDA LABELED INDICATIONS AND DOSAGE
Agent(s) |
FDA Indication(s) |
Notes |
Ref# |
Endari® Oral powder* |
To reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older |
* generic available |
1 |
See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm
CLINICAL RATIONALE
Sickle Cell Disease |
Sickle cell disease (SCD) is the name given to a group of lifelong inherited conditions that affect hemoglobin. People with SCD have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle or crescent shape.(2) Signs and symptoms of SCD usually begin in early childhood. Characteristic features of SCD include anemia, repeated infections, and periodic episodes of pain. The severity of symptoms varies from person to person and can range from mild to requiring frequent hospitalizations.(2) SCD affects nearly every system in the body. SCD has both acute and chronic complications. An episode of severe pain [acute vaso-occlusive crisis (VOC)] is the most common acute complication of SCD. In addition to VOCs, other common acute complications of SCD include fever related to infection, acute kidney injury (AKI), hepatobiliary complications, acute anemia, splenic sequestration, acute chest syndrome (ACS), and acute stroke. Chronic complications of SCD can affect almost any organ, and certain acute complications often evolve into chronic phases. The most common chronic complications of SCD include chronic pain, chronic anemia, avascular necrosis, leg ulcers, pulmonary hypertension, renal complications, stuttering/recurrent priapism, and ophthalmologic complications.(2) Pain is the most common complication of SCD for both acute and chronic complications. Pain can be acute, chronic, or an acute episode superimposed on chronic pain. In SCD, pain is considered chronic if it lasts more than 3 months. People with SCD experience both nociceptive and neuropathic pain.(2) Recurrent and unpredictable episodes of vaso-occlusion are the hallmark of sickle cell disease. Discoveries over the past 2 decades have highlighted the important contributions of various cellular and soluble participants in the vaso-occlusive cascade. Although the molecular basis of SCD is well characterized, the complex mechanisms underlying VOC have not been fully elucidated. Based on direct observations in SCD mice, adhesive interactions of SS-RBCs and leukocytes to the endothelium play important roles in the initiation of VOC. It is thought that the activated adherent leukocytes, which are rigid and larger than sickle cell-red blood cells (SS-RBC), likely drive VOC in collecting venules, whereas the SS-RBCs may contribute in smaller vessels or in situations where there is no potent inflammatory trigger.(4) Triggers for VOC vary and can include inflammation, stress, increased viscosity, decreased flow, hemolysis, or a combination of the following factors:(4)
Sickle hemoglobin can cause damage to the RBC membrane from deformation by polymer formation. In addition, the mutated globin can undergo autooxidation and precipitate on the inner surface of the RBC membrane, causing membrane damage via iron-mediated generation of oxidants. Both endothelial selectins, P-selectin and E-selectin, have been suggested to participate in VOC.(4) Nearly all people with SCD have chronic anemia, but individual baseline hemoglobin values vary widely depending upon hemoglobin genotype (HbSS, HbSC, HbSβ+-thalassemia, HbSβ0-thalassemia). It is important for the patient and the primary care provider to know the baseline or “steady state” hemoglobin value to inform ongoing monitoring and management during acute complications.(2) Hydroxyurea, a ribonucleotide reductase inhibitor, was identified as an option to increase fetal hemoglobin (HbF) levels in people with SCD. The initial clinical trial of hydroxyurea for the treatment of sickle cell anemia (SCA) involved two people. The results of this study showed favorable outcomes which lead to two extended studies with larger cohorts of people. Although HbF induction is the most powerful effect of hydroxyurea and provides the biggest direct benefit for people who have SCD, additional mechanisms of actions and benefits exist. Hydroxyurea lowers the number of circulating leukocytes and reticulocytes and alters the expression of adhesion molecules, all of which contribute to vaso-occlusion. Hydroxyurea also raises RBC volume [higher mean corpuscular volume (MCV)] and improves cellular deformability and rheology, which increases blood flow and reduces vaso-occlusion.(3) An expert panel report of evidence-based management of sickle cell disease supports the use of hydroxyurea with strong recommendations in the following:(3)
A clinical response to treatment with hydroxyurea may take 3-6 months. Therefore, the expert panel report of evidence-based management of sickle cell disease recommends a 6 month trial on the maximum tolerated dose is required prior to considering discontinuation due to treatment failure, whether due to lack of adherence or failure to respond to therapy.(3) While hydroxyurea remains the first-line therapy for SCD, L-glutamine, crizanlizumab, and voxelotor have been approved as adjunctive or second-line treatments, and hematopoietic stem cell transplant with a matched sibling donor is now standard care for severe disease. The emergence of gene therapies for SCD now bring the potential for curative therapy without a matched donor.(5) |
Efficacy |
The mechanism of action of the amino acid L-glutamine in treating sickle cell disease (SCD) is not fully understood. Oxidative stress phenomena are involved in the pathophysiology of SCD. Sickle red blood cells (RBCs) are more susceptible to oxidative damage than normal RBCs, which may contribute to the chronic hemolysis and vaso-occlusive events associated with SCD. The pyridine nucleotides, NAD+ (oxidized nicotinamide adenine dinucleotide) and its reduced form NADH (nicotinamide adenine dinucleotide + hydrogen), play roles in regulating and preventing oxidative damage in RBCs. L-glutamine may improve the NAD redox potential in sickle RBCs through increasing the availability of reduced glutathione.(1) The efficacy of L-glutamine was evaluated in a randomized, double-blind, placebo controlled, multi-center clinical trial. The trial evaluated 230 patients with SCD who had 2 or more painful crises within the 12 months prior to enrollment. Eligible patients stabilized on hydroxyurea for at least 3 months continued their therapy throughout the study. Efficacy was demonstrated by a reduction in the number of sickle cell crises through Week 48 and prior to the start of tapering among patients that received L-glutamine compared to patients who received placebo. The recurrent crisis event time analysis yielded an intensity rate ratio (IRR) value of 0.75 with 95% CI= (0.62, 0.90) and (0.55, 1.01) based on unstratified models using the Andersen-Gill and Lin, Wei, Yang and Ying methods, respectively in favor of L-glutamine, suggesting that over the entire 48-week period, the average cumulative crisis count was reduced by 25% from the L-glutamine group over the placebo group.(1) |
Safety |
Endari (L-glutamine) has no FDA labeled contraindications for use.(1) |
REFERENCES
Number |
Reference |
1 |
Endari prescribing information. Emmaus Medical, Inc. October 2020. |
2 |
U.S. National Library of Medicine. Genetics Home Reference. Sickle cell disease. November 2019. |
3 |
U.S. Department of Health and Human Services. National Institute of Health. Evidence-Based Management of Sickle Cell Disease. Expert Panel Report, 2014. |
4 |
Manwani D, Frenette PS, Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood. 2013 Dec 5; 122(24): 3892-3898. |
5 |
Brandow AM, Liem RI. Advances in the diagnosis and treatment of sickle cell disease. Journal of Hematology & Oncology. 2022;15(1). doi:10.1186/s13045-022-01237-z. |
POLICY AGENT SUMMARY PRIOR AUTHORIZATION
Target Brand Agent(s) |
Target Generic Agent(s) |
Strength |
Targeted MSC |
Available MSC |
Final Age Limit |
Preferred Status |
|
||||||
Endari |
glutamine (sickle cell) powd pack |
5 GM |
M ; N ; O ; Y |
O ; Y |
|
|
CLIENT SUMMARY – PRIOR AUTHORIZATION
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
Endari |
glutamine (sickle cell) powd pack |
5 GM |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL
Module |
Clinical Criteria for Approval |
|
Initial Evaluation Target Agent(s) will be approved when ALL of the following are met:
Length of Approval: 12 months *Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.
Renewal Evaluation Target Agent(s) will be approved when ALL of the following are met:
Length of Approval: 12 months |
This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.
Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.
ALBP _ Commercial _ CSReg _ Endari_PA _ProgSum_ 10-01-2024 _
© Copyright Prime Therapeutics LLC. July 2024 All Rights Reserved