ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (incidence 10%) are constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain. (6)To report SUSPECTED ADVERSE REACTIONS, contact Emmaus Medical, Inc. at 1-877-420-6493 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described below reflect exposure to Endari in 187 patients, including 136 exposed for months and 109 exposed for >=1 year. Endari was studied in placebo-controlled clinical trials (a phase study, n=230 and phase study, n=70). In these trials, patients with sickle cell anemia or sickle 0-thalassemia were randomized to receive Endari (n=187) or placebo (n=111) orally twice daily for 48 weeks followed by weeks of tapering. Both studies included pediatric and adult patients (5-58 years of age) and 54% were female. The majority of patients were black (97.3%), had diagnosis of sickle cell anemia (89.9%) and were receiving hydroxyurea at baseline (63.4%).Treatment discontinuation due to adverse reactions was reported in 2.7% (n=5) of patients receiving Endari. These adverse reactions included one case each of hypersplenism, abdominal pain, dyspepsia, burning sensation, and hot flash.Serious adverse reactions were reported in both treatment groups, more frequently in the placebo group, and were consistent with the underlying disease.Three deaths (3/187=1.6%) occurred during the study in the Endari treatment group as compared to none in the placebo treatment group. None of the deaths were considered to be related to Endari treatment. Adverse reactions occurring in greater than 10% of patients treated with Endari are shown in Table below.Table 2. Adverse Reactions Occurring at an Incidence 10% in Clinical Studies of EndariAdverse reactionEndariN 187(%)PlaceboN 111(%)Constipation2118Nausea1914Headache1815Abdominal PainAbdominal pain abdominal pain and abdominal pain, upper 1716Cough1614Pain in extremity137Back pain125Chest pain128.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been performed to evaluate the carcinogenic potential of L-glutamine.L-glutamine was not mutagenic in bacterial mutagenicity (Ames) assay, nor clastogenic in chromosome aberration assay in mammalian (Chinese Hamster Lung CHL/IU) cells.Animal reproduction studies and its potential for impairment of fertility have not been conducted with L-glutamine It is also not known whether L-glutamine can cause fetal harm when administered to pregnant woman or whether it can affect reproductive capacity.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. 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+ and its reduced form NADH, 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.. 12.2 Pharmacodynamics. In vivo analyses demonstrated that L-glutamine supplementation improved NAD redox potential. 12.3 Pharmacokinetics. The pharmacokinetics of L-glutamine has been studied in healthy subjects and variety of disease states. Relevant results from published literature are summarized below.. AbsorptionFollowing single-dose oral administration of L-glutamine at 0.1 g/kg, mean peak L-glutamine concentration was 1028 uM (or 150 mcg/mL) occurring approximately 30 minutes after administration. The pharmacokinetics following multiple oral doses has not been characterized.. DistributionAfter an intravenous (IV) bolus dose, the volume of distribution was estimated to be approximately 200 mL/kg.. EliminationAfter an intravenous bolus dose, the terminal half-life of L-glutamine was approximately one hour.. MetabolismEndogenous L-glutamine participates in various metabolic activities, including the formation of glutamate, and synthesis of proteins, nucleotides, and amino sugars. Exogenous L-glutamine is anticipated to undergo similar metabolism.. ExcretionMetabolism is the major route of elimination for L-glutamine. Although L-glutamine is eliminated by glomerular filtration, it is almost completely reabsorbed by the renal tubules.. Specific PopulationsThe safety of Endari has not been established in patients with renal or hepatic impairment. Drug InteractionsNo drug interaction studies have been conducted.

CLINICAL STUDIES SECTION.

14 Clinical Studies. The efficacy of Endari in sickle cell disease was evaluated in randomized, double-blind, placebo-controlled, multi-center clinical trial entextd A Phase III Safety and Efficacy Study of L-Glutamine to Treat Sickle Cell Disease or Sickle o-thalassemia [NCT01179217] (see Table 3).The clinical trial evaluated the efficacy and safety of Endari in 230 patients (5 to 58 years of age) with sickle cell anemia or sickle 0-thalassemia who had or more painful crises within 12 months prior to enrollment. Eligible patients stabilized on hydroxyurea for at least months continued their therapy throughout the study. The trial excluded patients who had received blood products within weeks, had renal insufficiency or uncontrolled liver disease, or were pregnant (or planning pregnancy) or lactating. Study patients received Endari or placebo for treatment duration of 48 weeks followed by weeks of tapering.Efficacy was demonstrated by reduction in the number of sickle cell crises through Week 48 and prior to the start of tapering among patients that received Endari compared to patients who received placebo. This clinical benefit was observed irrespective of hydroxyurea use. sickle cell crisis was defined as visit to an emergency room/medical facility for sickle cell disease-related pain which was treated with parenterally administered narcotic or parenterally administered ketorolac. In addition, the occurrence of chest syndrome, priapism, and splenic sequestration were considered sickle cell crises. Treatment with Endari also resulted in fewer hospitalizations due to sickle cell pain at Week 48, fewer cumulative days in hospital and lower incidence of acute chest syndrome. Table 3. Results from the Endari Clinical Trial in Sickle Cell DiseaseEventEndari(n 152)Placebo(n 78)Median number of sickle cell crises (min,max)Measured through 48 weeks of treatment (0, 15)4 (0, 15)Median number of hospitalizations for sickle cell pain (min, max) (0, 14)3 (0, 13)Median cumulative days hospitalized (min, max) 6.5 (0, 94)11 (0, 187)Median time (days) to first sickle cell crisis (95% CI) Hazard Ratio=0.69 (95% CI=0.52, 0.93), estimated based on unstratified Coxs proportional model. Median time and 95% CI were estimated based on the Kaplan Meier method. 84 (62, 109)54 (31, 73)Patients with occurrences of acute chest syndrome (%) 13 (8.6%)18 (23.1%)The recurrent crisis event time analysis (Figure 1) 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 Endari, suggesting that over the entire 48-week period, the average cumulative crisis count was reduced by 25% from the Endari group over the placebo group.Figure 1. Recurrent Event Time for Sickle Cell Crises by Treatment GroupAndersen-Gill: 95% CI (0.62, 0.90); Lin-Wei-Yang-Ying: 95% CI (0.55, 1.01). Figure 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. grams to 15 grams orally, twice daily based on body weight. (2)Each dose of Endari should be mixed in oz. (240 mL) of cold or room temperature beverage or oz. to oz. of food before ingestion. (2). grams to 15 grams orally, twice daily based on body weight. (2). Each dose of Endari should be mixed in oz. (240 mL) of cold or room temperature beverage or oz. to oz. of food before ingestion. (2). 2.1 Dosage. Administer Endari orally, twice per day at the dose based on body weight according to Table 1.Table 1. Recommended DosingWeight in kilogramsWeight in poundsPer dose in gramsPer day in gramsPackets per dosePackets per dayless than 30less than 665101230 to 6566 to 143102024greater than 65 greater than 143153036. 2.2 Preparation of Product. Mix Endari immediately before ingestion with oz. (240 mL) of cold or room temperature beverage, such as water, milk or apple juice, or oz. to oz. of food such as applesauce or yogurt. Complete dissolution is not required prior to administration.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of Endari did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. 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+ and its reduced form NADH, 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been performed to evaluate the carcinogenic potential of L-glutamine.L-glutamine was not mutagenic in bacterial mutagenicity (Ames) assay, nor clastogenic in chromosome aberration assay in mammalian (Chinese Hamster Lung CHL/IU) cells.Animal reproduction studies and its potential for impairment of fertility have not been conducted with L-glutamine It is also not known whether L-glutamine can cause fetal harm when administered to pregnant woman or whether it can affect reproductive capacity.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 5 gram Packet Carton. NDC: 42457-420-60ENDARI(TM)(L-glutamine oral powder)Contents: 60 Packets (5 grams/packet)Directions: Mix the contents of each packet with cold or room temperature beverage or foodimmediately before dosing.Administer the prescribed amount orally, twice daily, taking no more than packets per day.Package is not child resistant. Keep this and all drugs out of reach of children.Store at 20C to 25C (68F to 77F) away from direct sunlight.Rx OnlyLOT XX XXX XX XXEXP. MM/YYYYManufactured for Emmaus Medical, Inc.. PRINCIPAL DISPLAY PANEL 5 gram Packet Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Endari have been established in pediatric patients years and older. Use of Endari is supported by evidence from placebo-controlled studies in adult and pediatric patients with sickle cell disease. The clinical studies enrolled 110 pediatric patients in the following age groups: 46 children (5 years up to less than 12 years) and 64 adolescents (12 years to less than 17 years).The safety and effectiveness of Endari in pediatric patients with sickle cell disease younger than years old has not been established.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of L-glutamine has been studied in healthy subjects and variety of disease states. Relevant results from published literature are summarized below.. AbsorptionFollowing single-dose oral administration of L-glutamine at 0.1 g/kg, mean peak L-glutamine concentration was 1028 uM (or 150 mcg/mL) occurring approximately 30 minutes after administration. The pharmacokinetics following multiple oral doses has not been characterized.. DistributionAfter an intravenous (IV) bolus dose, the volume of distribution was estimated to be approximately 200 mL/kg.. EliminationAfter an intravenous bolus dose, the terminal half-life of L-glutamine was approximately one hour.. MetabolismEndogenous L-glutamine participates in various metabolic activities, including the formation of glutamate, and synthesis of proteins, nucleotides, and amino sugars. Exogenous L-glutamine is anticipated to undergo similar metabolism.. ExcretionMetabolism is the major route of elimination for L-glutamine. Although L-glutamine is eliminated by glomerular filtration, it is almost completely reabsorbed by the renal tubules.. Specific PopulationsThe safety of Endari has not been established in patients with renal or hepatic impairment. Drug InteractionsNo drug interaction studies have been conducted.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on Endari use in pregnant women to inform drug-associated risk of major birth defects and miscarriage. Animal reproduction studies were not conducted with Endari. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

SPL PATIENT PACKAGE INSERT SECTION.

INSTRUCTIONS FOR USE. ENDARI(R) (en-dar-ee) (L-glutamine oral powder)Read this Instructions for Use before you start taking Endari and each time you get refill. There may be new information. This Instructions for Use does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about Endari before you start taking it and at regular checkups.Endari is usually taken times day. Take Endari as prescribed by your healthcare provider.You will need the following supplies to mix and take Endari:Your prescribed dose of Endari (1, 2, or packets as directed by your healthcare provider) .a clean cup or small bowla spoonYou can mix Endari:with liquid, such as water, milk, or apple juice Or with food, such as applesauce or yogurtHow to mix and take dose of Endari.Mixing with LiquidMixing with FoodStep 1: Fill cup with ounces (240 mL) of liquid or small bowl with to ounces of food. The food or liquid should be cold or room temperature. Do not use hot food or liquid.Step 2: Find the perforations at the top of each side of the Endari packet. Use the perforations to fully tear open each Endari packet.Step 3: Pour the contents of the Endari packet into the cup or bowl. If more than packet is needed, repeat steps and above for all of the packets needed to prepare your prescribed does of Endari.Step 4:Use the spoon to mix the prescribed dose of Endari with the liquid or food.Endari may not fully dissolve. You can take your dose of Endari even if it does not fully dissolve.Step 5: Drink or eat the prescribed dose of Endari right away after mixing it. Do not store the Endari mixture for later use.If you miss dose of Endari, take the missed dose as soon as you remember. Do not double the dose to make up for missed dose.How should store EndariStore Endari at room temperature between 68F to 77F (20C to 25C).Keep Endari away from direct sunlight.Keep Endari and all medicines out of the reach of children.Manufactured for:Emmaus Medical, Inc.Torrance, CA 90503For more information got to www.EnadriRx.com or call 1-877-420-6493.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: 04/2020. Your prescribed dose of Endari (1, 2, or packets as directed by your healthcare provider) .. clean cup or small bowl. spoon. with liquid, such as water, milk, or apple juice Or with food, such as applesauce or yogurt. Store Endari at room temperature between 68F to 77F (20C to 25C).. Keep Endari away from direct sunlight.. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on Endari use in pregnant women to inform drug-associated risk of major birth defects and miscarriage. Animal reproduction studies were not conducted with Endari. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. 8.2 Lactation. Risk SummaryThere are no data on the presence of Endari in human milk, the effect on the breastfed infant or the effect on milk production. The developmental and health benefits from breastfeeding should be considered along with the mothers clinical need for Endari and any potential adverse effects on the breastfed child from Endari or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of Endari have been established in pediatric patients years and older. Use of Endari is supported by evidence from placebo-controlled studies in adult and pediatric patients with sickle cell disease. The clinical studies enrolled 110 pediatric patients in the following age groups: 46 children (5 years up to less than 12 years) and 64 adolescents (12 years to less than 17 years).The safety and effectiveness of Endari in pediatric patients with sickle cell disease younger than years old has not been established.. 8.5 Geriatric Use. Clinical studies of Endari did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.