L-glutamine

1 INDICATIONS AND USAGE L-glutamine oral powder is indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. L-glutamine oral powder is an amino acid indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION 5 grams to 15 grams orally, twice daily based on body weight. (2) Each dose of L-glutamine oral powder should be mixed in 8 oz. (240 mL) of cold or room temperature beverage or 4 oz. to 6 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 Dosing Weight in kilograms Weight in pounds Per dose in grams Per day in grams Packets per dose Packets per day less than 30 less than 66 5 10 1 2 30 to 65 66 to 143 10 20 2 4 greater than 65 greater than 143 15 30 3 6 2.2 Preparation of Product Mix L-glutamine oral powder immediately before ingestion with 8 oz. (240 mL) of cold or room temperature beverage, such as water, milk or apple juice, or 4 oz. to 6 oz. of food such as applesauce or yogurt. Complete dissolution is not required prior to administration.

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 Dosing Weight in kilograms Weight in pounds Per dose in grams Per day in grams Packets per dose Packets per day less than 30 less than 66 5 10 1 2 30 to 65 66 to 143 10 20 2 4 greater than 65 greater than 143 15 30 3 6

2.2 Preparation of Product Mix L-glutamine oral powder immediately before ingestion with 8 oz. (240 mL) of cold or room temperature beverage, such as water, milk or apple juice, or 4 oz. to 6 oz. of food such as applesauce or yogurt. Complete dissolution is not required prior to administration.

3 DOSAGE FORMS & STRENGTHS Oral Powder: 5 grams of L-glutamine as a white to off-white colored powder filled in foil-plastic laminate packets. Oral Powder: 5 grams of L-glutamine powder per foil-plastic laminate packet. (3)

4 CONTRAINDICATIONS None None ( 4 )

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 a 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 6 months and 109 exposed for ≥1 year. L-glutamine oral powder was studied in 2 placebo-controlled clinical trials (a phase 3 study, n=230 and a phase 2 study, n=70). In these trials, patients with sickle cell anemia or sickle β 0 -thalassemia were randomized to receive L-glutamine oral powder (n=187) or placebo (n=111) orally twice daily for 48 weeks followed by 3 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 a 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 2 below. Table 2. Adverse Reactions Occurring at an Incidence > 10% in Clinical Studies of L-glutamine oral powder Adverse reaction L-glutamine oral powder N = 187 (%) Placebo N = 111 (%) Constipation 21 18 Nausea 19 14 Headache 18 15 Abdominal Pain Abdominal pain = abdominal pain and abdominal pain, upper 17 16 Cough 16 14 Pain in extremity 13 7 Back pain 12 5 Chest pain 12 8

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on L-glutamine oral powder use in pregnant women to inform a 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 Summary There 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 mother’s 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 5 years and older. Use of L-glutamine oral powder is supported by evidence from 2 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 5 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.

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.

11 DESCRIPTION L-glutamine oral powder (L-glutamine) is an amino acid. L-glutamine is designated chemically as (S)-2-aminoglutaramic acid, L-glutamic acid 5-amide, or (S)-2,5-diamino-5-oxopentanoic acid. The molecular formula is C 5 H 10 N 2 O 3 with the molecular weight of 146.15 g/mol and the following structural formula: L-glutamine oral powder is formulated as a white crystalline powder and is packaged as 5 grams in a paper-foil-plastic laminate packet for oral administration. chemstructure

10 OVERDOSAGE Single oral doses of L-glutamine at about 20 g/kg to 22 g/kg, 8 g/kg to 11 g/kg, and 19 g/kg were lethal in mice, rats, and rabbits, respectively. Supportive measures should be undertaken in the event of overdose of L-glutamine oral powder.

16 HOW SUPPLIED/STORAGE AND HANDLING L-glutamine Oral Powder is supplied in foil-plastic laminate packets containing 5 grams of L-glutamine white to off-white colored powder. Carton of 60 packets: NDC 70954-417-20 Store at 20o to 25oC (68o to 77oF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]; away from direct sunlight.