MYXREDLIN

• Inspect MYXREDLIN visually before use. It should appear clear and colorless. Do not use MYXREDLIN if particulate matter or coloration is seen.
• Administer MYXREDLIN intravenously ONLY under medical supervision with close monitoring of blood glucose and potassium levels [see Warnings and Precautions (5.2, 5.4)].
• Do not add supplementary medication or additives.
• Do not use in series connections.
• Do not shake. Do not freeze. Discard any unused portion.

• Individualize and adjust the dosage of MYXREDLIN based on the individual's metabolic needs, blood glucose monitoring results, and glycemic control goal.
• Dosage adjustments may be needed with changes in nutrition, changes in renal or hepatic function or during acute illness [see Warnings and Precautions (5.1, 5.2) and Use in Specific Populations (8.6, 8.7)].

• Dosage adjustment may be needed when MYXREDLIN is used concomitantly with certain drugs [see Drug Interactions (7)].

Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.2)] or hyperglycemia. These changes should be made cautiously and under close medical supervision and the frequency of blood glucose monitoring should be increased.

Hypoglycemia is the most common adverse reaction of all insulins, including MYXREDLIN. Severe hypoglycemia can cause seizures, may lead to unconsciousness, may be life threatening or cause death. Hypoglycemia can impair concentration ability and reaction time.

Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.

Risk Factors for Hypoglycemia
Factors which may increase the risk of hypoglycemia include changes in nutrition and co-administered medication [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].

Risk Mitigation Strategies for Hypoglycemia
Patients and caregivers must be educated to recognize hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with MYXREDLIN. Generalized allergy to insulin may manifest as a whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. If hypersensitivity reactions occur, discontinue MYXREDLIN; treat per standard of care and monitor until symptoms and signs resolve. MYXREDLIN is contraindicated in patients who have had hypersensitivity reactions to insulin human or any of the excipients in MYXREDLIN [see Contraindications (4)].

All insulins, including MYXREDLIN, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels and treat if indicated.

Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including MYXREDLIN, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

Risk Summary
Available data from published studies over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Animal reproduction studies were not performed.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

Data
Human Data

While available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. All available studies have methodological limitations including lack of blinding, unclear methods of randomization, and small sample size.

Risk Summary
Available data from published literature suggest that exogenous human insulin products, including insulin human injection, are transferred into human milk. There are no adverse reactions reported in the breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including MYXREDLIN, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MYXREDLIN and any potential adverse effects on the breastfed infant from MYXREDLIN or from the underlying maternal condition.

MYXREDLIN is indicated to improve glycemic control in pediatric patients with diabetes mellitus.

The dosage of MYXREDLIN must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose to reduce the risk of hypoglycemia [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

The effect of age on the pharmacokinetics and pharmacodynamics of insulin human injection has not been studied.

Elderly patients using MYXREDLIN, may be at increased risk of hypoglycemia due to co-morbid disease [see Warnings and Precautions (5.2)].

The effect of renal impairment on the pharmacokinetics and pharmacodynamics of MYXREDLIN has not been studied. Patients with renal impairment are at increased risk of hypoglycemia and may require more frequent MYXREDLIN dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.2) ].

The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of MYXREDLIN has not been studied. Patients with hepatic impairment are at increased risk of hypoglycemia and may require more frequent MYXREDLIN dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.2)].

The primary activity of insulin, including MYXREDLIN is the regulation of glucose metabolism. Insulins lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.

MYXREDLIN is a short-acting insulin. The time course of insulin action (i.e., glucose lowering) may vary considerably in different individuals, within the same individual, and different doses. In a double-blind, randomized, crossover, euglycemic glucose clamp study described below, the average onset of action, defined as start of intravenous glucose infusion during the clamp, was approximately 21 minutes after starting of the intravenous infusion administration. The glucose infusion rate gradually increased to a maximum response of 13.7 mg/kg/min after 5 hours of human insulin infusion.

In a double-blind, randomized, crossover, euglycemic glucose clamp study, fifty eight healthy male subjects between 19 and 50 years of age received an intravenous infusion of either MYXREDLIN or another human insulin at 1 milliUnit/kg/min for 6 hours (0.36 units/kg total dose). On average, insulin concentrations of about 300 pM were attained approximately from 1.5 hours to 6 hours after starting intravenous infusion of MYXREDLIN, followed by a return to the baseline level 1.5 hours after stopping intravenous infusion.

Metabolism and Elimination

The mean terminal half-life from concentration data after stopping the intravenous infusion was estimated to be 23.4 minutes in healthy volunteers.

Specific Population

The effects of gender, age, obesity, renal and hepatic impairment on the pharmacodynamics and pharmacokinetics of insulin human injection have not been studied.

Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of insulin human injection.

Human insulin is not mutagenic in the following in vitro tests: The chromosomal aberration assay in human lymphocytes, the micronucleus assay in mouse polychromatic erythrocytes, and the mutation frequency assay in Chinese hamster cells.

Standard reproduction and teratology studies in animals, including fertility assessments have not been conducted with insulin human injection.

MYXREDLIN (insulin human) in 0.9% sodium chloride injection contains 100 units/100 mL (1 unit/mL) of insulin human in 0.9% sodium chloride and is a clear, colorless solution available as:

1. 100 mL single-dose GALAXY container, package of 12, NDC 0338-0126-12

Store MYXREDLIN in the refrigerator (36°F to 46°F [2°C to 8°C]) in the original carton to protect from light. Do not use after the expiration date printed on the carton and container label.

If needed, MYXREDLIN may be removed from the original carton and stored at room temperature up to 77°F (25°C) for up to 30 days. Once stored at room temperature, do not place back in the refrigerator. Discard MYXREDLIN after 30 days if stored at room temperature.

Do not freeze and do not use MYXREDLIN if it has been frozen. Do not shake.