Limitations of Use

Insulin glargine is not recommended for the treatment of diabetic ketoacidosis.

2.1 Important Administration Instructions

• Administer Insulin glargine subcutaneously once daily at any time of day but at the same time every day.
• Prior to initiation of Insulin glargine, train patients on proper use and injection technique.
• Patient should follow the Instructions for Use to correctly administer Insulin glargine.
• Administer Insulin glargine subcutaneously into the abdominal area, thigh, or deltoid, and rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2), Adverse Reactions (6)].
• During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].
• Visually inspect Insulin glargine vials and SoloStar prefilled pens for particulate matter and discoloration prior to administration. Only use if the solution is clear and colorless with no visible particles.
• The Insulin glargine SoloStar prefilled pen dials in 1-unit increments.
• Use Insulin glargine SoloStar prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
• Refrigerate unused (unopened) Insulin glargine vials and SoloStar® prefilled pens.
• Do not administer intravenously or via an insulin pump.
• Do not dilute or mix Insulin glargine with any other insulin or solution.
• The SoloStar prefilled pen is for single patient use only [see Warnings and Precautions (5.1)].

2.2 General Dosing Instructions

• Individualize and adjust the dosage of Insulin glargine based on the individual's metabolic needs, blood glucose monitoring results and glycemic control goal.
• Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), during acute illness, or changes in renal or hepatic function. Dosage adjustments should only be made under medical supervision with appropriate glucose monitoring [see Warnings and Precautions (5.2)].

2.3 Initiation of Insulin Glargine Therapy

2.4 Changing to Insulin Glargine from Other Insulin Therapies

• If changing patients from once-daily TOUJEO (insulin glargine) 300 units/mL to once-daily Insulin glargine, the recommended initial Insulin glargine dose is 80% of the TOUJEO dose that is being discontinued. This dose reduction will lower the likelihood of hypoglycemia [see Warnings and Precautions (5.3)].
• If changing from a treatment regimen with an intermediate or long-acting insulin to a regimen with Insulin glargine, a change in the dose of the basal insulin may be required and the amount and timing of the shorter-acting insulins and doses of any oral antidiabetic drugs may need to be adjusted.
• If changing patients from once-daily NPH insulin to once-daily Insulin glargine, the recommended initial Insulin glargine dose is the same as the dose of NPH that is being discontinued.
• If changing patients from twice-daily NPH insulin to once-daily Insulin glargine, the recommended initial Insulin glargine dosage is 80% of the total NPH dose that is being discontinued. This dosage reduction will lower the likelihood of hypoglycemia [see Warnings and Precautions (5.3)].

5.1 Never Share an Insulin Glargine SoloStar Prefilled Pen, Syringe, or Needle Between Patients

Insulin glargine SoloStar prefilled pens must never be shared between patients, even if the needle is changed. Patients using Insulin glargine 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 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 oral and antidiabetic products may be needed.

5.3 Hypoglycemia

Hypoglycemia is the most common adverse reaction associated with insulin, including Insulin glargine. 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.

5.4 Medication Errors

Accidental mix-ups among insulin products, particularly between long-acting insulins and rapid-acting insulins, have been reported. To avoid medication errors between Insulin glargine 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 Insulin glargine. If hypersensitivity reactions occur, discontinue Insulin glargine; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6.1)]. Insulin glargine 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 Insulin glargine, 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 Insulin glargine, 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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 2327 patients with type 1 diabetes to Insulin glargine or NPH. The type 1 diabetes population had the following characteristics: Mean age was 38.5 years. Fifty-four percent were male, 96.9% were Caucasian, 1.8% were Black or African American and 2.7% were Hispanic. The mean BMI was 25.1 kg/m2.

The data in Table 2 reflect the exposure of 1563 patients with type 2 diabetes to Insulin glargine or NPH. The type 2 diabetes population had the following characteristics: Mean age was 59.3 years. Fifty-eight percent were male, 86.7% were Caucasian, 7.8% were Black or African American and 9% were Hispanic. The mean BMI was 29.2 kg/m2.

The frequencies of adverse events during Insulin glargine clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. All insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical trials of Insulin glargine, increases in titers of antibodies to insulin were observed in NPH insulin and Insulin glargine treatment groups with similar incidences.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Insulin glargine. 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 insulins, particularly rapid-acting insulins, have been accidentally administered instead of Insulin glargine [see Patient Counseling Information (17)]. To avoid medication errors between Insulin glargine and other insulins, patients should be instructed to always verify the insulin label before each injection.

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of Insulin glargine have been established in pediatric patients (age 6 to 15 years) with type 1 diabetes [see Clinical Studies (14.2)]. The safety and effectiveness of Insulin glargine in pediatric patients younger than 6 years of age with type 1 diabetes and pediatric patients with type 2 diabetes have not been established.

The dosage recommendation when changing to Insulin glargine in pediatric patients (age 6 to 15 years) with type 1 diabetes is the same as that described for adults [see Dosage and Administration (2.2, 2.4), Clinical Studies (14)]. As in adults, the dosage of Insulin glargine must be individualized in pediatric patients (age 6 to 15 years) with type 1 diabetes based on metabolic needs and frequent monitoring of blood glucose.

In the pediatric clinical trial, pediatric patients (age 6 to 15 years) 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)].

8.5 Geriatric Use

Of the total number of subjects in controlled clinical studies of patients with type 1 and type 2 diabetes who were treated with Insulin glargine, 15% 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 Insulin glargine is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly.

8.6 Hepatic Impairment

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

8.7 Renal Impairment

The effect of renal impairment on the pharmacokinetics of Insulin glargine 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 Insulin glargine in patients with renal impairment [see Warnings and Precautions (5.3)].

8.8 Obesity

In controlled clinical trials, subgroup analyses based on BMI did not show differences in safety and efficacy between Insulin glargine and NPH.

12.1 Mechanism of Action

The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogs 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.

12.2 Pharmacodynamics

In clinical studies, the glucose-lowering effect on a molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as that for human insulin. Figure 1 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 hours after the injection. The median time between injection and the end of pharmacological effect was 14.5 hours (range: 9.5 to 19.3 hours) for NPH insulin, and 24 hours (range: 10.8 to >24.0 hours) (24 hours was the end of the observation period) for insulin glargine.

The duration of action after abdominal, deltoid, or thigh subcutaneous administration was similar. The time course of action of insulins, including Insulin glargine, may vary between individuals and within the same individual.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which was for the rat approximately 65 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day) on a mg/kg basis. Histiocytomas were found at injection sites in male rats and mice in acid vehicle containing groups and are considered a response to chronic tissue irritation and inflammation in rodents. These tumors were not found in female animals, in saline control, or insulin comparator groups using a different vehicle.

Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters).

In a combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day) maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.

14.1 Overview of Clinical Studies

The safety and effectiveness of Insulin glargine given once-daily at bedtime was compared to that of once-daily and twice-daily NPH insulin in open-label, randomized, active-controlled, parallel studies of 2,327 adult patients and 349 pediatric patients with type 1 diabetes mellitus and 1,563 adult patients with type 2 diabetes mellitus (see Tables 9–11). In general, the reduction in glycated hemoglobin (HbA1c) with Insulin glargine was similar to that with NPH insulin.

14.2 Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes

In two clinical studies (Studies A and B), patients with type 1 diabetes (Study A n=585, Study B n=534) were randomized to 28 weeks of basal-bolus treatment with Insulin glargine or NPH insulin. Regular human insulin was administered before each meal. Insulin glargine was administered at bedtime. NPH insulin was administered either as once daily at bedtime or in the morning and at bedtime when used twice daily.

In Study A, the average age was 39.2 years. The majority of patients were White (99%) and 55.7% were male. The mean BMI was approximately 24.9 kg/m2. The mean duration of diabetes was 15.5 years.

In Study B, the average age was 38.5 years. The majority of patients were White (95.3%) and 50.6% were male. The mean BMI was approximately 25.8 kg/m2. The mean duration of diabetes was 17.4 years.

In another clinical study (Study C), patients with type 1 diabetes (n=619) were randomized to 16 weeks of basal-bolus treatment with Insulin glargine or NPH insulin. Insulin lispro was used before each meal. Insulin glargine was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 39.2 years. The majority of patients were White (96.9%) and 50.6% were male. The mean BMI was approximately 25.6 kg/m2. The mean duration of diabetes was 18.5 years.

In these 3 studies, Insulin glargine and NPH insulin had similar effects on HbA1c (Table 9) with a similar overall rate of severe symptomatic hypoglycemia [see Adverse Reactions (6.1)].

14.3 Clinical Studies in Adults with Type 2 Diabetes

In a randomized, controlled clinical study (Study E) (n=570), Insulin glargine was evaluated for 52 weeks in combination with oral antidiabetic medications (a sulfonylurea, metformin, acarbose, or combinations of these drugs). The average age was 59.5 years. The majority of patients were White (92.8%) and 53.7% were male. The mean BMI was approximately 29.1 kg/m2. The mean duration of diabetes was 10.3 years. Insulin glargine administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA1c and fasting glucose (Table 11). The rate of severe symptomatic hypoglycemia was similar in Insulin glargine and NPH insulin treated patients [see Adverse Reactions (6.1)].

In a randomized, controlled clinical study (Study F), in patients with type 2 diabetes not using oral antidiabetic medications (n=518), a basal-bolus regimen of Insulin glargine once daily at bedtime or NPH insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals, as needed. The average age was 59.3 years. The majority of patients were White (80.7%) and 60% were male. The mean BMI was approximately 30.5 kg/m2. The mean duration of diabetes was 13.7 years. Insulin glargine had similar effectiveness as either once- or twice-daily NPH insulin in reducing HbA1c and fasting glucose (Table 11) with a similar incidence of hypoglycemia [see Adverse Reactions (6.1)].

In a randomized, controlled clinical study (Study G), patients with type 2 diabetes were randomized to 5 years of treatment with once-daily Insulin glargine or twice-daily NPH insulin. For patients not previously treated with insulin, the starting dose of Insulin glargine or NPH insulin was 10 units daily. Patients who were already treated with NPH insulin either continued on the same total daily NPH insulin dose or started Insulin glargine at a dose that was 80% of the total previous NPH insulin dose. The primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. HbA1c change from baseline was a secondary endpoint. Similar glycemic control in the 2 treatment groups was desired in order to not confound the interpretation of the retinal data. Patients or study personnel used an algorithm to adjust the Insulin glargine and NPH insulin doses to a target fasting plasma glucose ≤100 mg/dL. After the Insulin glargine or NPH insulin dose was adjusted, other antidiabetic agents, including premeal insulin were to be adjusted or added. The average age was 55.1 years. The majority of patients were White (85.3%) and 53.9% were male. The mean BMI was approximately 34.3 kg/m2. The mean duration of diabetes was 10.8 years. The Insulin glargine group had a smaller mean reduction from baseline in HbA1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in the Insulin glargine group (Table 11). The incidences of severe symptomatic hypoglycemia were similar between groups [see Adverse Reactions (6.1)].

16.1 How Supplied

Insulin glargine injection is supplied as a clear solution containing 100 units per mL (U-100) available in:

The insulin glargine SoloStar prefilled pen dials in 1-unit increments.

Needles are not included in the packs.

BD Ultra-Fine® needles1 to be used in conjunction with SoloStar prefilled pens are sold separately and are manufactured by BD.

1

Other brands listed are the trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC

16.2 Storage

Dispense in the original sealed carton with the enclosed Instructions for Use.

Insulin glargine should not be stored in the freezer and should not be allowed to freeze. Discard Insulin glargine if it has been frozen. Protect Insulin glargine from direct heat and light.

Storage conditions are summarized in the following table.

Never Share an Insulin Glargine SoloStar Prefilled Pen or Syringe Between Patients

Advise patients that they must never share an Insulin glargine SoloStar prefilled pen with another person, even if the needle is changed. Advise patients using Insulin glargine vials not to re-use or share needles or syringes with another person. Sharing carries a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia. Inform patients that the ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions (5.3)].

Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.2)].

Medications Errors

Instruct patients to always check the insulin label before each injection [see Warnings and Precautions (5.4)].

Administration

Advise patients that Insulin glargine must NOT be diluted or mixed with any other insulin or solution and that Insulin glargine must only be used if the solution is clear and colorless with no particles visible [see Dosage and Administration (2)].