SEMGLEE Solution for injection Ref.[27592] Active ingredients: Insulin glargine

5.1 Never Share a SEMGLEE Prefilled Pen, Syringe or Needle Between Patients

SEMGLEE prefilled pens must never be shared between patients, even if the needle is changed. Patients using SEMGLEE vials must never re-use or share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.

5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)].

Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant antidiabetic products may be needed.

5.3 Hypoglycemia

Hypoglycemia is the most common adverse reaction associated with insulin, including SEMGLEE [see Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).

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

The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin [see Clinical Pharmacology (12.2)] and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of SEMGLEE may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature.

Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to coadministered 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 and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of 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.

5.4 Medication Errors

Accidental mix-ups between long-acting insulin products and other insulins, particularly rapid-acting insulins, have been reported. To avoid medication errors between SEMGLEE and other insulins, instruct patients to always check the insulin label before each injection [see Adverse Reactions (6.3)].

5.5 Hypersensitivity and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including SEMGLEE. If hypersensitivity reactions occur, discontinue SEMGLEE; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6.1)]. SEMGLEE is contraindicated in patients who have had hypersensitivity reactions to insulin glargine or one of the excipients [see Contraindications (4)].

5.6 Hypokalemia

All insulin products, including SEMGLEE, 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 in patients at risk for hypokalemia, if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists

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 SEMGLEE, 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.

The following adverse reactions are discussed elsewhere:

• Hypoglycemia [see Warnings and Precautions (5.3)]
• Medication Errors [see Warnings and Precautions (5.4)]
• Hypersensitivity and allergic reactions [see Warnings and Precautions (5.5)]
• Hypokalemia [see Warnings and Precautions (5.6)]

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 trial of another drug and may not reflect the rates observed in practice.

The data in Table 1 reflect the exposure of 280 patients with type 1 diabetes to SEMGLEE with mean exposure duration of 50 weeks. The type 1 diabetes study population had the following characteristics: the majority of patients were male, 60.2%, mean age was 42 years, the majority of patients were Caucasian, 94.6%, mean BMI was 26.5 kg/m², mean duration of diabetes prior to entry into the study was 19 years, mean HbA1c at baseline was 7.4%.

The data in Table 2 reflect the exposure of 276 patients with type 2 diabetes to SEMGLEE with mean exposure duration of 22 weeks. The type 2 diabetes study population had the following characteristics: the majority of patients were male, 55.7%, mean age was 55 years, more than half, 52.7%, of the patients were Caucasian, 26.6% were Hispanic, and 9.8% were Black, mean BMI was 31.5 kg/m², the mean duration of diabetes prior to entry into the study was 12 years, mean HbA1c at baseline was 8.1%.

Common adverse reactions (ARs) were defined as those occurring in ≥5% of SEMGLEE treated patients in clinical trials. Common ARs (other than hypoglycemia) from the type 1 diabetes mellitus and type 2 diabetes mellitus trials are listed in Table 1 and Table 2, respectively.

Table 1. Adverse Reactions Occurring in ≥5% of Adult Patients with Type 1 Diabetes Treated with SEMGLEE in a 52-Week Trial:

Table 2. Adverse Reactions Occurring in ≥5% of Adult Patients with Type 2 Diabetes Treated with SEMGLEE in a 24-Week Trial:

The frequencies of adverse reactions during another insulin glargine product clinical trial of 5 years duration in patients with type 2 diabetes mellitus are listed in Table 3.

Table 3. Adverse Reactions Occurring in ≥10% of Adult Patients with Type 2 Diabetes in a 5 Year Trial:

The frequencies of adverse reactions during another insulin glargine product clinical trial of 28 weeks duration in children and adolescents with type 1 diabetes mellitus are listed in Table 4.

Table 4. Adverse Reactions (with Frequency ≥5% and the Same or Higher with Another Insulin Glargine Product, 100 units/mL, than Comparator) in a 28-week Clinical Trial of Pediatric Patients with Type 1 Diabetes:

Severe Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including SEMGLEE [see Warnings and Precautions (5.3)]. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for SEMGLEE with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.

In SEMGLEE trials, an episode of hypoglycemia was classified as severe if it required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions and resulted in neurological recovery, regardless of the availability of a blood glucose measurement. The incidence of severe symptomatic hypoglycemia in patients receiving SEMGLEE with type 1 diabetes mellitus and type 2 diabetes mellitus [see Clinical Studies (14)] was 4% at 52 weeks and 0% at 24 weeks, respectively.

In a clinical trial with another insulin glargine product, severe symptomatic hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose below 50 mg/dL (≤56 mg/dL in the 5-year trial and ≤36 mg/dL in the ORIGIN trial) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. The incidence of severe symptomatic hypoglycemia in children and adolescents age 6 to 15 years with type 1 diabetes [see Clinical Studies (14)] was 23% at 26 weeks. Table 5 displays the proportion of patients experiencing severe symptomatic hypoglycemia in another insulin glargine product and Standard Care groups in the ORIGIN Trial [see Clinical Studies (14)].

Table 5. Severe Symptomatic Hypoglycemia in the ORIGIN Trial:

Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including SEMGLEE and may be life threatening.

Injection Site Reactions

Patients taking SEMGLEE may experience injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult patients, there was a higher incidence of injection site pain in patients treated with another insulin glargine product (2.7%) compared to NPH insulin-treated patients (0.7%). The incidence of injection site reactions in patients receiving SEMGLEE was 0.7% at 24 weeks.

Insulin Initiation and Intensification of Glucose Control

Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Lipodystrophy

Long term use of insulin, including SEMGLEE, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue) and may affect insulin absorption [see Dosage and Administration (2.1)].

Peripheral Edema

Insulin, including SEMGLEE, may cause sodium retention and edema. The incidence of peripheral edema in patients receiving SEMGLEE was 1.4% in the type 1 diabetes mellitus trial and 0.7% in the type 2 diabetes mellitus trial.

Weight Gain

Weight gain can occur with insulin therapy, including SEMGLEE, and has been attributed to the anabolic effects of insulin. The average weight gain in patients receiving SEMGLEE was 1 kg at 52 weeks in the type 1 diabetes mellitus trial and 0.7 kg at 24 weeks in the type 2 diabetes mellitus trial.

As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to SEMGLEE with the incidence of antibodies in other studies or to other products may be misleading. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose.

In a 52 weeks study of type 1 diabetes mellitus patients, changes from baseline in terms of anti-drug antibody (ADA) percentage binding and the incidence of ADA (positive or negative response) for total ADAs and insulin cross-reactive ADAs, were similar in patients who received SEMGLEE compared with another insulin glargine product.

In a 24 weeks study of type 2 diabetes mellitus patients, immunogenicity profiles were comparable between patients who received SEMGLEE or another insulin glargine product, with most patients showing negative responses for total ADAs and insulin cross-reactive ADAs. Immunogenicity profiles were also similar between insulin-naïve and insulin non-naïve patients in the study.

The following adverse reactions have been identified during postapproval use of another insulin glargine product. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported in which other insulin products, particularly rapid-acting insulins, have been accidentally administered instead of insulin glargine.

Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

Table 8 includes clinically significant drug interactions with SEMGLEE.

Table 8. Clinically Significant Drug Interactions with SEMGLEE:

Risk Summary

Published studies with use of insulin glargine during pregnancy have not reported a clear association with insulin glargine and adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).

Rats and rabbits were exposed to insulin glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dose of 0.2 units/kg/day. Overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin (see Data).

The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with an HbA1c >7 and has been reported to be as high as 20% to 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% to 4% and 15% to 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

Published data do not report a clear association with insulin glargine and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups.

Animal Data

Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day), on a mg/kg basis. In rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dose of 0.2 units/kg/day on a mg/kg basis, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal.

Risk Summary

There are either no or only limited data on the presence of insulin glargine in human milk, the effects on breastfed infant, or the effects on milk production. Endogenous insulin is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SEMGLEE, and any potential adverse effects on the breastfed child from SEMGLEE or from the underlying maternal condition.

The safety and effectiveness of SEMGLEE to improve glycemic control in pediatric patients with type 1 diabetes mellitus have been established in pediatric patients. The use of SEMGLEE for this indication is based upon an adequate and well-controlled trial of another insulin glargine product in pediatric patients age 6 to 15 years with type 1 diabetes and additional data in adults with type 1 diabetes [see Clinical Studies (14.2)].

In the pediatric clinical trial, pediatric patients with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in trials with type 1 diabetes [see Adverse Reactions (6.1)].

The safety and effectiveness of SEMGLEE in pediatric patients younger than 6 years of age with type 1 diabetes and pediatric patients with type 2 diabetes have not been established.

In clinical studies of patients with type 1 and type 2 diabetes who were treated with another insulin glargine product, 15% of patients were ≥65 years of age and 2% were ≥75 years of age. The only difference in safety or effectiveness in the subpopulation of patients ≥65 years of age compared to the entire study population was a higher incidence of cardiovascular events typically seen in an older population in the insulin glargine and NPH treatment groups.

Nevertheless, caution should be exercised when SEMGLEE is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in the elderly.

The effect of renal impairment on the pharmacokinetics of SEMGLEE has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Frequent glucose monitoring and dose adjustment may be necessary for SEMGLEE in patients with renal impairment [see Warnings and Precautions (5.3)].

The effect of hepatic impairment on the pharmacokinetics of SEMGLEE has not been studied. Frequent glucose monitoring and dose adjustment may be necessary for SEMGLEE in patients with hepatic impairment [see Warnings and Precautions (5.3)].

8.8 Obesity

In clinical trials, subgroup analyses based on BMI did not show differences in safety and efficacy between SEMGLEE and another insulin glargine product.