Toujeo (Insulin Glargine)

TOUJEO is indicated to improve glycemic control in adults and pediatric patients 6 years of age and older with diabetes mellitus.

• Individualize dose based on type of diabetes, metabolic needs, blood glucose monitoring results and glycemic control goal. (
  2.2 General Dosing Instructions

  • TOUJEO is available in 2 single-patient-use prefilled pens:
    • The TOUJEO SoloStar prefilled pen contains 450 units of insulin glargine. It delivers doses in 1-unit increments and can deliver up to 80 units in a single injection.
    • The TOUJEO Max SoloStar prefilled pen contains 900 units of insulin glargine. It delivers doses in 2-unit increments and can deliver up to 160 units in a single injection. It is recommended for patients requiring at least 20 units per day.
  • When changing between TOUJEO SoloStar and TOUJEO Max SoloStar, if the patient's previous dose was an odd number, the dose should be increased or decreased by 1 unit to match the dose increments dialable on each prefilled pen.
  • The dose counter of the TOUJEO SoloStar or TOUJEO Max SoloStar prefilled pen shows the number of units of TOUJEO to be injected and no conversion is required.
  • Inject TOUJEO subcutaneously once a day at the same time of day.
  • During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions (5.2)]
    .
  • Individualize and titrate the dosage of TOUJEO based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal.
  • Titrate the dose of TOUJEO no more frequently than every 3 to 4 days.
  • Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness to minimize the risk of hypoglycemia or hyperglycemia
    [see Warnings and Precautions (5.2)and Use in Specific Populations (8.6, 8.7)]
    .
  )
• Administer subcutaneously into the abdominal area, thigh, or deltoid once daily at any time during the day, at the same time every day. (
  2.1 Important Administration Instructions

  • Always check insulin labels before administration
    [see Warnings and Precautions (5.4)]
    .
  • Visually inspect the TOUJEO solution for particulate matter and discoloration prior to administration and only use if the solution is clear and colorless with no visible particles.
  • Inject TOUJEO subcutaneously into the abdominal area, thigh, or deltoid.
  • 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)]
    .
  • Use TOUJEO with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  • Do not administer TOUJEO intravenously or in an insulin pump.
  • Do not dilute or mix TOUJEO with any other insulin products or solutions.
  • Never transfer TOUJEO from the cartridges of the TOUJEO SoloStar or TOUJEO Max SoloStar prefilled pen into a syringe for administration
    [see Warnings and Precautions (5.4)]
    .
  )
• Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (
  2.1 Important Administration Instructions

  • Always check insulin labels before administration
    [see Warnings and Precautions (5.4)]
    .
  • Visually inspect the TOUJEO solution for particulate matter and discoloration prior to administration and only use if the solution is clear and colorless with no visible particles.
  • Inject TOUJEO subcutaneously into the abdominal area, thigh, or deltoid.
  • 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)]
    .
  • Use TOUJEO with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  • Do not administer TOUJEO intravenously or in an insulin pump.
  • Do not dilute or mix TOUJEO with any other insulin products or solutions.
  • Never transfer TOUJEO from the cartridges of the TOUJEO SoloStar or TOUJEO Max SoloStar prefilled pen into a syringe for administration
    [see Warnings and Precautions (5.4)]
    .
  )
• Do not dilute or mix with any other insulin or solution. (
  2.1 Important Administration Instructions

  • Always check insulin labels before administration
    [see Warnings and Precautions (5.4)]
    .
  • Visually inspect the TOUJEO solution for particulate matter and discoloration prior to administration and only use if the solution is clear and colorless with no visible particles.
  • Inject TOUJEO subcutaneously into the abdominal area, thigh, or deltoid.
  • 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)]
    .
  • Use TOUJEO with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  • Do not administer TOUJEO intravenously or in an insulin pump.
  • Do not dilute or mix TOUJEO with any other insulin products or solutions.
  • Never transfer TOUJEO from the cartridges of the TOUJEO SoloStar or TOUJEO Max SoloStar prefilled pen into a syringe for administration
    [see Warnings and Precautions (5.4)]
    .
  )
• See Full Prescribing Information for the recommended starting dosage in patients with type 2 diabetes and how to switch to TOUJEO from other insulins (
  2.3 Starting Dose in Insulin-Naive Pediatric and Adult Patients

  Recommended Starting Dosage in Patients with Type 1 Diabetes

  • The recommended starting dose of TOUJEO in insulin-naive patients with type 1 diabetes is approximately one-third to one-half of the total daily insulin dose. The remainder of the total daily insulin dose should be given as a short-acting insulin and divided between each daily meal. As a general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to calculate the initial total daily insulin dose in insulin-naive patients with type 1 diabetes.
  • The maximum glucose lowering effect of a dose of TOUJEO may take five days to fully manifest and the first dose may be insufficient to cover metabolic needs in the first 24 hours of use
    [see Clinical Pharmacology (12.2)]
    . When initiating TOUJEO, monitor glucose daily.

  Recommended Starting Dosage in Patients with Type 2 Diabetes

  • The recommended starting dose of TOUJEO in insulin-naive patients with type 2 diabetes is 0.2 units per kilogram of body weight once daily.
  ,
  2.4 Starting Dose in Pediatric and Adult Patients with Either Type 1 or Type 2 Diabetes Already on Insulin Therapy

  Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to TOUJEO from another insulin therapy

  [see Warnings and Precautions (5.3)].

  • For patients currently on once-daily long or intermediate-acting insulin, start TOUJEO at the same unit dose as the once-daily long-acting insulin dose. For patients controlled on LANTUS (insulin glargine, 100 units/mL), expect that a higher daily dose of TOUJEO will be needed to maintain the same level of glycemic control
    [see Clinical Pharmacology (12.2)and Clinical Studies (14.1)]
    .
  • For patients currently on twice-daily long or intermediate-acting insulin, start TOUJEO at 80% of the total daily NPH or insulin detemir twice-daily dosage.
  • When switching patients to TOUJEO, monitor glucose frequently in the first weeks of therapy
    [see Warnings and Precautions (5.2)and Clinical Pharmacology (12.2)]
    .
  )
• Closely monitor glucose when switching to TOUJEO and during initial weeks thereafter. (
  2.4 Starting Dose in Pediatric and Adult Patients with Either Type 1 or Type 2 Diabetes Already on Insulin Therapy

  Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to TOUJEO from another insulin therapy

  [see Warnings and Precautions (5.3)].

  • For patients currently on once-daily long or intermediate-acting insulin, start TOUJEO at the same unit dose as the once-daily long-acting insulin dose. For patients controlled on LANTUS (insulin glargine, 100 units/mL), expect that a higher daily dose of TOUJEO will be needed to maintain the same level of glycemic control
    [see Clinical Pharmacology (12.2)and Clinical Studies (14.1)]
    .
  • For patients currently on twice-daily long or intermediate-acting insulin, start TOUJEO at 80% of the total daily NPH or insulin detemir twice-daily dosage.
  • When switching patients to TOUJEO, monitor glucose frequently in the first weeks of therapy
    [see Warnings and Precautions (5.2)and Clinical Pharmacology (12.2)]
    .
  )

Injection: 300 units/mL (U-300) of insulin glargine in a clear, colorless, solution available as:

• 1.5 mL SoloStar single-patient-use prefilled pen (450 units per 1.5 mL pen)
• 3 mL Max SoloStar single-patient-use prefilled pen (900 units per 3 mL pen)

Published studies with use of insulin glargine during pregnancy have not reported a clear association with insulin glargine and adverse developmental outcomes

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 unit/kg/day. Overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin

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. The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown.

• Never share
  a TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pen between patients, even if the needle is changed. (
  5.1 Never Share a TOUJEO SoloStar or TOUJEO Max SoloStar Pen Between Patients

  TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pens must never be shared between patients, even if the needle is changed. Pen sharing poses a risk for transmission of blood-borne pathogens.
  )
• Hyperglycemia or hypoglycemia with changes in insulin regimen:
  Make changes to a patient's insulin regimen (e.g., insulin strength, manufacturer, type, injection site, or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. (
  5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

  Changes in Insulin Regimen Including Changes to Administration Site

  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 antidiabetic products may be needed.

  Changing to TOUJEO from other Insulin Therapies

  On a unit-to-unit basis, TOUJEO has a lower glucose lowering effect than LANTUS

  [see Clinical Pharmacology (12.2)]

  . In clinical trials, patients who changed to TOUJEO from other basal insulins experienced higher average fasting plasma glucose levels in the first weeks of therapy compared to patients who were changed to LANTUS. Higher doses of TOUJEO were required to achieve similar levels of glucose control compared to LANTUS in clinical trials

  [see Clinical Studies (14.1)]

  .

  The onset of action of TOUJEO develops over 6 hours following an injection. In type 1 diabetes patients treated with IV insulin, consider the longer onset of action of TOUJEO before stopping IV insulin. The full glucose lowering effect may not be apparent for at least 5 days

  [see Dosage and Administration (2.2)and Clinical Pharmacology (12.2)]

  .

  To minimize the risk of hyperglycemia when initiating TOUJEO monitor glucose daily, titrate TOUJEO as described in this prescribing information, and adjust coadministered glucose-lowering therapies per standard of care

  [see Dosage and Administration (2.2, 2.3)]

  .
  )
• Hypoglycemia:
  May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, concomitant drugs, meal pattern, physical activity, and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. (
  5.3 Hypoglycemia

  Hypoglycemia is the most common adverse reaction associated with insulin, including TOUJEO. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient 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 patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, in patients using drugs that block the sympathetic nervous system (e.g., beta-blockers)

  [see Drug Interactions (7)]

  , or who experience recurrent hypoglycemia.

  The long-acting effect of TOUJEO may delay recovery from hypoglycemia compared to shorter-acting insulins.

  Risk Factors for Hypoglycemia

  The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. As with all insulins, the glucose lowering effect time course of TOUJEO may vary in different patients or at different times in the same patient and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature

  [see Clinical Pharmacology (12.2)]

  . 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 concomitant drugs

  [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. To minimize the risk of hypoglycemia, do not administer TOUJEO intravenously, intramuscularly or in an insulin pump, or dilute or mix TOUJEO with any other insulin products or solutions.
  ,
  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 actually observed in clinical practice.

  The data in Table 1 reflect the exposure of 304 patients with type 1 diabetes to TOUJEO with mean exposure duration of 23 weeks. The type 1 diabetes population had the following characteristics: Mean age was 46 years and mean duration of diabetes was 21 years. Fifty-five percent were male, 86% were White, 5% were Black or African American, and 5% were Hispanic or Latino. At baseline, the mean eGFR was 82 mL/min/1.73 m²and 35% of patients had eGFR ≥90 mL/min/1.73 m². The mean body mass index (BMI) was 28 kg/m². HbA1c at baseline was greater than or equal to 8% in 58% of patients.

  The data in Table 2 reflect the exposure of 1242 patients with type 2 diabetes to TOUJEO with mean exposure duration of 25 weeks. The type 2 diabetes population had the following characteristics: Mean age was 59 years and mean duration of diabetes was 13 years. Fifty-three percent were male, 88% were White, 7% were Black or African American, and 17% were Hispanic or Latino. At baseline, mean eGFR was 79 mL/min/1.73 m²and 27% of patients had an eGFR ≥90 mL/min/1.73 m². The mean BMI was 35 kg/m². HbA1c at baseline was greater than or equal to 8% in 66% of patients.

  TOUJEO was studied in 233 pediatric patients (6–17 years of age) with type 1 diabetes for a mean duration of 26 weeks

  [see Clinical Studies (14.1)]

  .

  Common adverse reactions (occurring ≥5%) in TOUJEO-treated subjects during clinical trials in adult patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively. Common adverse reactions for TOUJEO-treated pediatric subjects with type 1 diabetes mellitus were similar to the adverse reactions listed in Table 1. Hypoglycemia is discussed in a dedicated subsection below.

  Table 1: Adverse Reactions Occurring ≥5% in Two Pooled Clinical Trials of 26 Weeks and 16 Weeks Duration in Adults with Type 1 Diabetes

  	TOUJEO + Mealtime Insulin"mealtime insulin" refers to insulin glulisine, insulin lispro, or insulin aspart., % (n=304)
  Nasopharyngitis	12.8
  Upper respiratory tract infection	9.5

  Table 2: Adverse Reactions Occurring ≥5% in Three Pooled Clinical Trials of 26 Weeks Duration in Adults with Type 2 Diabetes

  	TOUJEOone of the trials in type 2 diabetes included mealtime insulin., % (n=1242)
  Nasopharyngitis	7.1
  Upper respiratory tract infection	5.7

  Hypoglycemia

  Hypoglycemia is the most commonly observed adverse reaction in patients treated with TOUJEO. 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 TOUJEO 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 the TOUJEO adult program, severe hypoglycemia was defined as an event requiring assistance of another person to administer a resuscitative action. In the pediatric program, severe hypoglycemia was defined as an event with semiconsciousness, unconsciousness, coma and/or convulsions in a patient who had altered mental status and could not assist in his own care, and who may have required glucagon or intravenous glucose.

  The incidence of severe hypoglycemia in adult patients with type 1 diabetes receiving TOUJEO as part of a multiple daily injection regimen was 6.6% at 26 weeks. The incidence of hypoglycemia with a glucose level less than 54 mg/dL with or without symptoms was 77.7% at 26 weeks.

  The incidence of severe hypoglycemia in pediatric patients with type 1 diabetes receiving TOUJEO as part of a multiple daily injection regimen was 6% at 26 weeks and the incidence of hypoglycemia accompanied by a self-monitored or plasma glucose value less than 54 mg/dL regardless of symptoms was 80.3%.

  The incidence of severe hypoglycemia in adult patients with type 2 diabetes was 5% at 26 weeks in patients receiving TOUJEO as part of a multiple daily injection regimen, and 1.0% and 0.9% respectively at 26 weeks in the two studies where patients received TOUJEO as part of a basal-insulin only regimen. The incidence of hypoglycemia accompanied by a self-monitored or plasma glucose value less than 54 mg/dL regardless of symptoms in patients with type 2 diabetes receiving TOUJEO ranged from 9% to 44.6% at 26 weeks and the highest risk was again seen in patients receiving TOUJEO as part of a multiple daily injection regimen.

  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.

  Peripheral Edema

  Insulin, including TOUJEO, may cause sodium retention and edema, particularly if previously poor metabolic control was improved by intensified insulin therapy.

  Lipodystrophy

  Long-term use of insulin, including TOUJEO, can cause lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients and may affect insulin absorption

  [see Dosage and Administration (2.1)]

  .

  Weight Gain

  Weight gain has occurred with insulins, including TOUJEO and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

  Hypersensitivity Reactions

  Patients taking TOUJEO experienced erythema, local edema, and pruritus at the site of injection. These conditions were usually self-limiting.

  Severe cases of generalized allergy (anaphylaxis) have been reported.
  )
• Hypoglycemia Due to Medication errors:
  Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (
  5.4 Hypoglycemia Due to Medication Errors

  Accidental mix-ups between insulin products have been reported. To avoid medication errors between TOUJEO and other insulins, instruct patients to always check the insulin label before each injection.

  To avoid dosing errors and potential overdose, never use a syringe to remove TOUJEO from the TOUJEO SoloStar or TOUJEO Max SoloStar prefilled pen into a syringe

  [see Dosage and Administration (2.4)and Warnings and Precautions (5.3)]

  .
  )
• Hypersensitivity reactions:
  Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue TOUJEO, monitor and treat if indicated. (
  5.5 Hypersensitivity Reactions

  Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including TOUJEO. If hypersensitivity reactions occur, discontinue TOUJEO; treat per standard of care and monitor until symptoms and signs resolve

  [see Adverse Reactions (6)]

  . TOUJEO is contraindicated in patients who have had hypersensitivity reactions to insulin glargine or any of the excipients in TOUJEO.
  ,
  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 actually observed in clinical practice.

  The data in Table 1 reflect the exposure of 304 patients with type 1 diabetes to TOUJEO with mean exposure duration of 23 weeks. The type 1 diabetes population had the following characteristics: Mean age was 46 years and mean duration of diabetes was 21 years. Fifty-five percent were male, 86% were White, 5% were Black or African American, and 5% were Hispanic or Latino. At baseline, the mean eGFR was 82 mL/min/1.73 m²and 35% of patients had eGFR ≥90 mL/min/1.73 m². The mean body mass index (BMI) was 28 kg/m². HbA1c at baseline was greater than or equal to 8% in 58% of patients.

  The data in Table 2 reflect the exposure of 1242 patients with type 2 diabetes to TOUJEO with mean exposure duration of 25 weeks. The type 2 diabetes population had the following characteristics: Mean age was 59 years and mean duration of diabetes was 13 years. Fifty-three percent were male, 88% were White, 7% were Black or African American, and 17% were Hispanic or Latino. At baseline, mean eGFR was 79 mL/min/1.73 m²and 27% of patients had an eGFR ≥90 mL/min/1.73 m². The mean BMI was 35 kg/m². HbA1c at baseline was greater than or equal to 8% in 66% of patients.

  TOUJEO was studied in 233 pediatric patients (6–17 years of age) with type 1 diabetes for a mean duration of 26 weeks

  [see Clinical Studies (14.1)]

  .

  Common adverse reactions (occurring ≥5%) in TOUJEO-treated subjects during clinical trials in adult patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively. Common adverse reactions for TOUJEO-treated pediatric subjects with type 1 diabetes mellitus were similar to the adverse reactions listed in Table 1. Hypoglycemia is discussed in a dedicated subsection below.

  Table 1: Adverse Reactions Occurring ≥5% in Two Pooled Clinical Trials of 26 Weeks and 16 Weeks Duration in Adults with Type 1 Diabetes

  	TOUJEO + Mealtime Insulin"mealtime insulin" refers to insulin glulisine, insulin lispro, or insulin aspart., % (n=304)
  Nasopharyngitis	12.8
  Upper respiratory tract infection	9.5

  Table 2: Adverse Reactions Occurring ≥5% in Three Pooled Clinical Trials of 26 Weeks Duration in Adults with Type 2 Diabetes

  	TOUJEOone of the trials in type 2 diabetes included mealtime insulin., % (n=1242)
  Nasopharyngitis	7.1
  Upper respiratory tract infection	5.7

  Hypoglycemia

  Hypoglycemia is the most commonly observed adverse reaction in patients treated with TOUJEO. 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 TOUJEO 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 the TOUJEO adult program, severe hypoglycemia was defined as an event requiring assistance of another person to administer a resuscitative action. In the pediatric program, severe hypoglycemia was defined as an event with semiconsciousness, unconsciousness, coma and/or convulsions in a patient who had altered mental status and could not assist in his own care, and who may have required glucagon or intravenous glucose.

  The incidence of severe hypoglycemia in adult patients with type 1 diabetes receiving TOUJEO as part of a multiple daily injection regimen was 6.6% at 26 weeks. The incidence of hypoglycemia with a glucose level less than 54 mg/dL with or without symptoms was 77.7% at 26 weeks.

  The incidence of severe hypoglycemia in pediatric patients with type 1 diabetes receiving TOUJEO as part of a multiple daily injection regimen was 6% at 26 weeks and the incidence of hypoglycemia accompanied by a self-monitored or plasma glucose value less than 54 mg/dL regardless of symptoms was 80.3%.

  The incidence of severe hypoglycemia in adult patients with type 2 diabetes was 5% at 26 weeks in patients receiving TOUJEO as part of a multiple daily injection regimen, and 1.0% and 0.9% respectively at 26 weeks in the two studies where patients received TOUJEO as part of a basal-insulin only regimen. The incidence of hypoglycemia accompanied by a self-monitored or plasma glucose value less than 54 mg/dL regardless of symptoms in patients with type 2 diabetes receiving TOUJEO ranged from 9% to 44.6% at 26 weeks and the highest risk was again seen in patients receiving TOUJEO as part of a multiple daily injection regimen.

  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.

  Peripheral Edema

  Insulin, including TOUJEO, may cause sodium retention and edema, particularly if previously poor metabolic control was improved by intensified insulin therapy.

  Lipodystrophy

  Long-term use of insulin, including TOUJEO, can cause lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients and may affect insulin absorption

  [see Dosage and Administration (2.1)]

  .

  Weight Gain

  Weight gain has occurred with insulins, including TOUJEO and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

  Hypersensitivity Reactions

  Patients taking TOUJEO experienced erythema, local edema, and pruritus at the site of injection. These conditions were usually self-limiting.

  Severe cases of generalized allergy (anaphylaxis) have been reported.
  )
• Hypokalemia:
  May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (
  5.6 Hypokalemia

  All insulins, including TOUJEO, 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).
  )
• Fluid retention and heart failure with concomitant use of Thiazolidinediones (TZDs):
  Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. (
  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, when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including TOUJEO, 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.
  )