L-glutamine oral powder (Endari)

L-glutamine oral powder (Endari)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand

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Overview

L-glutamine oral powder (Endari) is a amino acid that is FDA approved for the reduction of the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older. Common adverse reactions include constipation, nausea, headache, abdominal pain, cough, pain in extremity, back pain, and chest pain.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indication

• 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.

Dosage

• Administer L-glutamine oral powder orally, twice per day at the dose based on body weight according to Table 1.

This image is provided by the National Library of Medicine.

Dosage Forms and Strengths

• Oral powder: 5 grams of L–glutamine as a white crystalline powder in paper-foil-plastic laminate packets.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding L-glutamine oral powder Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding L-glutamine oral powder Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Indication

• 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.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding L-glutamine oral powder Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding L-glutamine oral powder Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Contraindications

• None.

Warnings

There is limited information regarding L-glutamine oral powder (Endari) Warnings' in the drug label.

Adverse Reactions

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 β0-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.

This image is provided by the National Library of Medicine.

Postmarketing Experience

There is limited information regarding L-glutamine oral powder (Endari) Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding L-glutamine oral powder (Endari) Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

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.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of L-glutamine oral powder (Endari) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of L-glutamine oral powder (Endari) during labor and delivery.

Nursing Mothers

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.

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.

Geriatic 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.

Gender

There is no FDA guidance on the use of L-glutamine oral powder (Endari) with respect to specific gender populations.

Race

There is no FDA guidance on the use of L-glutamine oral powder (Endari) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of L-glutamine oral powder (Endari) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of L-glutamine oral powder (Endari) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of L-glutamine oral powder (Endari) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of L-glutamine oral powder (Endari) in patients who are immunocompromised.

Administration and Monitoring

Administration

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.

Monitoring

• (Oral powder) Reduction in acute complications of sickle cell disease may be indicative of efficacy.
• (Oral powder for solution) Clinical signs of improvement in short bowel syndrome may be indicative of efficacy.
• (Oral powder for solution) Hepatic and renal function: During treatment, especially in patients with renal or hepatic impairment.

IV Compatibility

There is limited information regarding the compatibility of L-glutamine oral powder (Endari) and IV administrations.

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.

Pharmacology

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.

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

• In vivo analyses demonstrated that L-glutamine supplementation improved NAD redox potential.

Pharmacokinetics

• The pharmacokinetics of L-glutamine has been studied in healthy subjects and a variety of disease states. Relevant results from published literature are summarized below.

Absorption

• Following single-dose oral administration of L-glutamine at 0.1 g/kg, mean peak L-glutamine concentration was 1028 µM (or 150 mcg/mL) occurring approximately 30 minutes after administration. The pharmacokinetics following multiple oral doses has not been characterized.

Distribution

• After an intravenous (IV) bolus dose, the volume of distribution was estimated to be approximately 200 mL/kg.

Elimination

• After an intravenous bolus dose, the terminal half-life of L-glutamine was approximately one hour.

Metabolism

• Endogenous 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.

Excretion

• Metabolism 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 Populations

• The safety of L-glutamine oral powder has not been established in patients with renal or hepatic impairment.

Drug Interactions

• No drug interaction studies have been conducted.

Nonclinical Toxicology

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 a bacterial mutagenicity (Ames) assay, nor clastogenic in a 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 a pregnant woman or whether it can affect reproductive capacity.

Clinical Studies

• The efficacy of L-glutamine oral powder in sickle cell disease was evaluated in a randomized, double-blind, placebo-controlled, multi-center clinical trial entitled "A Phase III Safety and Efficacy Study of L-Glutamine to Treat Sickle Cell Disease or Sickle βo-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 β0-thalassemia who had 2 or more painful crises within 12 months prior to enrollment. Eligible patients stabilized on hydroxyurea for at least 3 months continued their therapy throughout the study. The trial excluded patients who had received blood products within 3 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 a treatment duration of 48 weeks followed by 3 weeks of tapering.
• 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 oral powder compared to patients who received placebo. A sickle cell crisis was defined as a visit to an emergency room/medical facility for sickle cell disease-related pain which was treated with a 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 a lower incidence of acute chest syndrome.

This image is provided by the National Library of Medicine.

• 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.

This image is provided by the National Library of Medicine.

How Supplied

• L-glutamine oral powder is supplied in paper-foil-plastic laminate packets containing 5 grams of L-glutamine white crystalline powder.

• Carton of 60 packets: NDC 42457-420-60

Storage

• Store at 20°C to 25°C (68°F to 77°F) away from direct sunlight.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

Dosage and Administration

• Advise patient to take a missed dose as soon as they remember. Patient should not double the dose that they take.
• Instruct patient to mix each dose in 8 oz. (240 mL) of cold or room temperature beverage or 4 to 6 oz. of food.
• Advise patient that complete dissolution is not required prior to administration.

Precautions with Alcohol

Alcohol-L-glutamine oral powder (Endari) interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

• Endari

Look-Alike Drug Names

There is limited information regarding L-glutamine oral powder (Endari) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.