GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of L-glutamine oral powder 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Instructions for Use). Dosage and AdministrationAdvise patient to take missed dose as soon as they remember. Patient should not double the dose that they take.Instruct patient to mix each dose in oz. (240 mL) of cold or room temperature beverage or to oz. of food.Advise patient that complete dissolution is not required prior to administration.Distributed by: Renova Pharma LLC 161 Dwight Pl, Fairfield, NJ 07004Rev. 05/2026.

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 Renova Pharmaceuticals LLC. at 1-888-211-5593 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 L-glutamine oral powder in 187 patients, including 136 exposed for months and 109 exposed for >=1 year. L-glutamine oral powder 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 L-glutamine oral powder (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 L-glutamine oral powder. 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 L-glutamine oral powder treatment group as compared to none in the placebo treatment group. None of the deaths were considered to be related to L-glutamine oral powder treatment. Adverse reactions occurring in greater than 10% of patients treated with L-glutamine oral powder are shown in Table below.Table 2. Adverse Reactions Occurring at an Incidence 10% in Clinical Studies of L-glutamine oral powderAdverse reactionL-glutamine oral powderN 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 at 0.1 g/kg, 0.3 g/kg, and 0.6 g/kg found peak concentrations increasing with each dose, but maximum concentration did not increase proportionally to the dose, suggesting saturable absorption process. The peak concentration was seen occurring approximately one hour after administration. There was no accumulation of L-glutamine levels upon multiple oral doses administered twice-daily.Effect of FoodNo significant change in L-glutamine concentration was associated with food, suggesting that L-glutamine can be taken with or without food.DistributionAfter multiple oral doses, the apparent volume of distribution was estimated to be approximately 750 mL/kg.EliminationAfter an intravenous bolus dose, the terminal elimination 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 disappearance for L-glutamine from the plasma. Urinary excretion of L-glutamine was less than 0.3% of the administered dose in intravenous infusion studies.Specific PopulationsIn population pharmacokinetic analysis, body weight was found to be significant covariate of L-glutamine exposures supporting the tiered body weight based dosing of L-glutamine oral powder. The pharmacokinetics of L-glutamine oral powder has not been studied in subjects with renal or hepatic impairment.Drug InteractionsNo drug interaction studies have been conducted.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of L-glutamine oral powder 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 0-thalassemia [NCT01179217] (see Table 3).The clinical trial evaluated the efficacy and safety of L-glutamine oral powder 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 L-glutamine oral powder 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 L-glutamine oral powder 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 L-glutamine oral powder 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 L-glutamine oral powder Clinical Trial in Sickle Cell DiseaseEventL-glutamine oral powder(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 L-glutamine oral powder, suggesting that over the entire 48-week period, the average cumulative crisis count was reduced by 25% from the L-glutamine oral powder 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). figure1.

CLINICAL TRIALS EXPERIENCE SECTION.

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 L-glutamine oral powder in 187 patients, including 136 exposed for months and 109 exposed for >=1 year. L-glutamine oral powder 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 L-glutamine oral powder (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 L-glutamine oral powder. 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 L-glutamine oral powder treatment group as compared to none in the placebo treatment group. None of the deaths were considered to be related to L-glutamine oral powder treatment. Adverse reactions occurring in greater than 10% of patients treated with L-glutamine oral powder are shown in Table below.Table 2. Adverse Reactions Occurring at an Incidence 10% in Clinical Studies of L-glutamine oral powderAdverse reactionL-glutamine oral powderN 187(%)PlaceboN 111(%)Constipation2118Nausea1914Headache1815Abdominal PainAbdominal pain abdominal pain and abdominal pain, upper 1716Cough1614Pain in extremity137Back pain125Chest pain128.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. grams to 15 grams orally, twice daily based on body weight. (2) Each dose of L-glutamine oral powder should be mixed in oz. (240 mL) of cold or room temperature beverage or oz. to oz. of food before ingestion. (2) 5 grams to 15 grams orally, twice daily based on body weight. (2) Each dose of L-glutamine oral powder 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 L-glutamine oral powder 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 65greater than 143153036. 2.2 Preparation of Product. Mix L-glutamine oral powder 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.

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.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of L-glutamine oral powder have been established in pediatric patients years and older. Use of L-glutamine oral powder 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 L-glutamine oral powder 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 at 0.1 g/kg, 0.3 g/kg, and 0.6 g/kg found peak concentrations increasing with each dose, but maximum concentration did not increase proportionally to the dose, suggesting saturable absorption process. The peak concentration was seen occurring approximately one hour after administration. There was no accumulation of L-glutamine levels upon multiple oral doses administered twice-daily.Effect of FoodNo significant change in L-glutamine concentration was associated with food, suggesting that L-glutamine can be taken with or without food.DistributionAfter multiple oral doses, the apparent volume of distribution was estimated to be approximately 750 mL/kg.EliminationAfter an intravenous bolus dose, the terminal elimination 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 disappearance for L-glutamine from the plasma. Urinary excretion of L-glutamine was less than 0.3% of the administered dose in intravenous infusion studies.Specific PopulationsIn population pharmacokinetic analysis, body weight was found to be significant covariate of L-glutamine exposures supporting the tiered body weight based dosing of L-glutamine oral powder. The pharmacokinetics of L-glutamine oral powder has not been studied in subjects 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 L-glutamine oral powder use in pregnant women to inform drug-associated risk of major birth defects and miscarriage. Animal reproduction studies were not conducted with L-glutamine oral powder.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. L-glutamine oral powderRead this Instructions for Use before you start taking L-glutamine oral powder 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 L-glutamine oral powder before you start taking it and at regular checkups. L-glutamine oral powder is usually taken times day. Take L-glutamine oral powder as prescribed by your healthcare provider.You will need the following supplies to mix and take L-glutamine oral powder:Your prescribed dose of L-glutamine oral powder (1, 2, or packets as directed by your healthcare provider).a clean cup or small bowla spoon You can mix L-glutamine oral powder:with liquid, such as water, milk, or apple juice Or with food, such as applesauce or yogurtHow to mix and take dose of L-glutamine oral powder.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 L-glutamine oral powder packet.Use the perforations to fully tear open each L-glutamine oral powder packet.Step 3:Pour the contents of the L-glutamine oral powder 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 dose of L-glutamine oral powder.Step 4:Use the spoon to mix the prescribed dose of L-glutamine oral powder with the liquid or food.L-glutamine oral powder may not fully dissolve. You can take your dose of L-glutamine oral powder even if it does not fully dissolve.Step 5:Drink or eat the prescribed dose of L-glutamine oral powder right away after mixing it.Do not store the L-glutamine oral powder mixture for later use.If you miss dose of L-glutamine oral powder, take the missed dose as soon as you remember. Do not double the dose to make up for missed dose.How should store L-glutamine oral powderStore L-glutamine oral powder at room temperature between 68F to 77F (20C to 25C).Keep L-glutamine oral powder away from direct sunlight.Keep L-glutamine oral powder and all medicines out of the reach of children.Distributed by: Renova Pharma LLC 161 Dwight Pl, Fairfield, NJ 07004Rev. 05/2026. Your prescribed dose of L-glutamine oral powder (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 L-glutamine oral powder at room temperature between 68F to 77F (20C to 25C).. Keep L-glutamine oral powder away from direct sunlight.. 1. figure-3. figure-4. figure-5. figure-6. figure-7. figure-8. figure-9. figure-10. figure-11. figure-12.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on L-glutamine oral powder use in pregnant women to inform drug-associated risk of major birth defects and miscarriage. Animal reproduction studies were not conducted with L-glutamine oral powder.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 L-glutamine oral powder 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 L-glutamine oral powder and any potential adverse effects on the breastfed child from L-glutamine oral powder or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of L-glutamine oral powder have been established in pediatric patients years and older. Use of L-glutamine oral powder 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 L-glutamine oral powder in pediatric patients with sickle cell disease younger than years old has not been established.. 8.5 Geriatric Use. Clinical studies of L-glutamine oral powder 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.