July 7, 2017
On July 7, 2017, the U.S. Food and Drug Administration approved L-glutamine oral powder (Endari™, Emmaus Medical, Inc.) for oral administration to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years and older.
Approval was based on data from a randomized, double-blind, placebo-controlled, multi-center clinical trial (NCT01179217) enrolling 230 patients (5 to 58 years old) with sickle cell anemia or sickle β0-thalassemia who had two 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. Patients were randomized to receive either L-glutamine or placebo for 48 weeks followed by three weeks of drug tapering.
Efficacy was demonstrated by a reduction in the number of sickle cell crises through Week 48 among patients who received L-glutamine compared to those receiving placebo. A sickle cell crisis was defined as an emergency room/medical facility visit for sickle cell disease-related pain treated with a parenteral narcotic or parenteral ketorolac. The occurrence of chest syndrome, priapism, and splenic sequestration were considered sickle cell crises. Over the 48-week period, patients receiving L-glutamine had a median of 3 sickle cell crises compared with a median of 4 crises for those receiving placebo. Treatment with L-glutamine also resulted in fewer hospitalizations due to sickle cell pain, fewer cumulative hospital days, and a lower incidence of acute chest syndrome.
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.
The recommended dose of L-glutamine is 10 grams to 30 grams per day (based on body weight) taken orally, twice daily. See recommended dosing based on weight listed in the product label. Each dose should be mixed in 8 oz. (240 mL) of cold or room temperature beverage or 4 to 6 oz. of food before ingestion.
Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208587s000lbl.pdf.
FDA previously granted Orphan Drug Designation to L-glutamine for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Pharmacist’s Applications to Practice
L-glutamine for Sickle Cell Disease
Author: Cady Noda, PharmD BCPS
Clinical Pharmacy Specialist, Pediatric Hematology and Oncology
Virginia Commonwealth University Health System
What is the potential role for L-glutamine in the treatment of sickle cell disease?1-5
- L-glutamine is the second medication for sickle cell disease (alongside hydroxyurea) approved by the U.S. Food and Drug Administration (FDA).
- L-glutamine should not replace hydroxyurea therapy at this time, but it may be considered as add-on therapy for sickle cell patients on hydroxyurea.
- L-glutamine is an amino acid that is synthesized by the body during metabolic stress or severe illness. In sickle cell disease, L-glutamine is proposed to decrease oxidative stress of sickle red blood cells by increasing red blood cell uptake of glutamine, leading to increased levels of an intrinsic antioxidant, nicotinamide adenine dinucleotide.
- L-glutamine was approved on July 7, 2017, for sickle cell patients aged 5 years and older for the reduction in acute complications related to sickle cell.
- The phase 3 randomized, double-blind, placebo-controlled, multicenter clinical trial found that L-glutamine reduced the number of sickle cell crises by one compared to placebo over a 48-week period (median of 3 vs. 4; p = .0052).
- As compared to placebo, other benefits may include these:
- longer median onset to first sickle cell crisis (84 vs. 54 days; p = .0152)
- lower occurrences of acute chest syndrome (9% vs. 23%)
- lower median number of hospitalizations for sickle cell pain (2.3 vs. 3)
- The benefits are combined with a highly tolerable adverse-effect profile, which includes constipation, nausea, headache, cough, and pain.
- 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.
- No head-to-head trials have compared L-glutamine and hydroxyurea. However, 63% of patients on the phase 3 trial were also taking hydroxyurea.
- 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.
What role can the pharmacist play in the management of patients on L-glutamine?1-2
- L-glutamine is a white crystalline powder that comes in 5-gram packets
- The powder may be mixed in 8 oz. of a cold or room-temperature liquid or mixed into 4–6 oz. of food.
- The powder does not need to be completely dissolved before ingestion.
- Dosing is based on weight:
- less than 30 kg: 1 packet twice daily
- 30-65 kg: 2 packets twice daily
- greater than 65 kg: 3 packets twice daily
- Drug interaction studies have not been conducted by the manufacturer.
- Medication adherence education should be provided because of the preventative effects of the medication and the inconvenient dosage formulation.
- Published literature is lacking on the use of L-glutamine in patients with hemoglobin SC or sickle β+-thalassemia as well as in sickle cell patients with liver disease or renal insufficiency.
- L-glutamine is intended for long-term use for the prevention of the acute complications of sickle cell in patients with homologous hemoglobin SS and sickle β0-thalassemia.
- L-glutamine has shown modest benefits in the reduction of sickle cell acute crisis with a minimal toxicity profile.
- Additional laboratory monitoring is not required for L-glutamine therapy.
- Endari (L-glutamine oral powder) [package insert]. Torrance, CA: Emmaus Medical, Inc.; July 2017.
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Oral L-glutamine powder NDA 208587, May 24, 2017. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM559736.pdf. Accessed August 2, 2017.
- ClinicalTrials.gov Registry. National Institutes of Health. Available at: www.Clinicaltrials.gov. Accessed August 2, 2017.
- Niihara Y, Macan H, Eckman JR, Koh H, Cooper ML, et al. L-glutamine therapy reduces hospitalization for sickle cell anemia and sickle β°-thalassemia patients at six months—a phase II randomized trial. Clin Pharmacol Biopharm. 2014;3:116.
- Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995;May 18;332(20):1317-1322.