Admelog

ADMELOG is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.

• See Full Prescribing Information for important preparation and administration instructions. (
  2.1 Important Preparation and Administration Instructions

  • Always check insulin labels before administration
    [see Warnings and Precautions (5.4)]
    .
  • Inspect ADMELOG visually before use. It should appear clear and colorless. Do not use ADMELOG if particulate matter or coloration is seen.
  • Use ADMELOG SoloStar prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  • Do NOT mix ADMELOG with other insulins when administering using a continuous subcutaneous infusion pump.
  ,
  2.2 Preparation and Administration Instructions for the Approved Routes of Administration

  Subcutaneous Injection

  • Administer the dose of ADMELOG subcutaneously within fifteen minutes before a meal or immediately after a meal into the abdominal wall, thigh, upper arm, or buttocks.
  • Rotate injection site 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)]
    .
  • ADMELOG administered by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin.
  • The ADMELOG SoloStar prefilled pen dials in 1-unit increments.
  • Prior to subcutaneous use, ADMELOG may be diluted with sterile 0.9% Sodium Chloride Injection. Dilute one-part ADMELOG to one-part 0.9% Sodium Chloride Injection to yield a concentration one-half that of ADMELOG (equivalent to U-50). If diluted ADMELOG is not used immediately, refrigerate at 2°C to 8°C (36°F to 46°F) for no more than 24 hours or store at room temperature up to 30°C (86°F) for 4 hours. Discard the unused diluted ADEMLOG after 24 hours if refrigerated or after 4 hours if stored at room temperature.

  Continuous Subcutaneous Infusion (Insulin Pump)

  • Refer to the continuous subcutaneous insulin infusion pump user manual to see if ADMELOG can be used with the insulin pump. Use ADMELOG in accordance with the insulin pump system's instructions for use.
  • Administer ADMELOG by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region 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)]
    .
  • Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure
    [see Warnings and Precautions (5.8)].
  • During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions (5.2)]
    .
  • Change ADMELOG in the pump reservoir at least every 7 days or according to the pump user manual, whichever is shorter.
  • Change the infusion sets and the infusion set insertion site according to the manufacturer's user manual.
  • Do NOT dilute or mix ADMELOG when administering by continuous subcutaneous infusion.
  • Do NOT expose ADMELOG in the pump reservoir to temperatures greater than 98.6°F (37°C).

  Intravenous Administration

  • Administer ADMELOG intravenously ONLY under medical supervision
    [see Warnings and Precautions (5.3, 5.6)]
    .
  • Dilute ADMELOG to concentrations from 0.1 unit/mL to 1 unit/mL using 0.9% Sodium Chloride Injection, USP
    [see How Supplied/Storage and Handling (16.2)]
    .
  • Closely monitor of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia
    [see Warnings and Precautions (5.3, 5.6)].
  ,
  2.3 Dosage Recommendations

  • Individualize and adjust the dosage of ADMELOG based on the route of administration, the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal.
  • Dosage modifications 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
    [see Warnings and Precautions (5.2, 5.3)and Use in Specific Populations (8.6, 8.7)]
    .
  • When switching from another insulin lispro product to ADMELOG, the dose of ADMELOG should be the same as the other insulin lispro product
    [see
    Warnings and Precautions (5.2)].
  • When switching from other insulins to ADMELOG, the ADMELOG dosage may need to be adjusted
    [see
    Warnings and Precautions (5.2)]
    .
  ,
  2.4 Dosage Adjustment for Drug Interactions

  • Dosage modification may be needed when ADMELOG is coadministered with certain drugs
    [see Drug Interactions (7)].
  • Do NOT mix ADMELOG with any other insulin.
  )
• Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (
  2.2 Preparation and Administration Instructions for the Approved Routes of Administration

  Subcutaneous Injection

  • Administer the dose of ADMELOG subcutaneously within fifteen minutes before a meal or immediately after a meal into the abdominal wall, thigh, upper arm, or buttocks.
  • Rotate injection site 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)]
    .
  • ADMELOG administered by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin.
  • The ADMELOG SoloStar prefilled pen dials in 1-unit increments.
  • Prior to subcutaneous use, ADMELOG may be diluted with sterile 0.9% Sodium Chloride Injection. Dilute one-part ADMELOG to one-part 0.9% Sodium Chloride Injection to yield a concentration one-half that of ADMELOG (equivalent to U-50). If diluted ADMELOG is not used immediately, refrigerate at 2°C to 8°C (36°F to 46°F) for no more than 24 hours or store at room temperature up to 30°C (86°F) for 4 hours. Discard the unused diluted ADEMLOG after 24 hours if refrigerated or after 4 hours if stored at room temperature.

  Continuous Subcutaneous Infusion (Insulin Pump)

  • Refer to the continuous subcutaneous insulin infusion pump user manual to see if ADMELOG can be used with the insulin pump. Use ADMELOG in accordance with the insulin pump system's instructions for use.
  • Administer ADMELOG by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region 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)]
    .
  • Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure
    [see Warnings and Precautions (5.8)].
  • During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions (5.2)]
    .
  • Change ADMELOG in the pump reservoir at least every 7 days or according to the pump user manual, whichever is shorter.
  • Change the infusion sets and the infusion set insertion site according to the manufacturer's user manual.
  • Do NOT dilute or mix ADMELOG when administering by continuous subcutaneous infusion.
  • Do NOT expose ADMELOG in the pump reservoir to temperatures greater than 98.6°F (37°C).

  Intravenous Administration

  • Administer ADMELOG intravenously ONLY under medical supervision
    [see Warnings and Precautions (5.3, 5.6)]
    .
  • Dilute ADMELOG to concentrations from 0.1 unit/mL to 1 unit/mL using 0.9% Sodium Chloride Injection, USP
    [see How Supplied/Storage and Handling (16.2)]
    .
  • Closely monitor of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia
    [see Warnings and Precautions (5.3, 5.6)].
  )
• Subcutaneous injection (
  2.2 Preparation and Administration Instructions for the Approved Routes of Administration

  Subcutaneous Injection

  • Administer the dose of ADMELOG subcutaneously within fifteen minutes before a meal or immediately after a meal into the abdominal wall, thigh, upper arm, or buttocks.
  • Rotate injection site 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)]
    .
  • ADMELOG administered by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin.
  • The ADMELOG SoloStar prefilled pen dials in 1-unit increments.
  • Prior to subcutaneous use, ADMELOG may be diluted with sterile 0.9% Sodium Chloride Injection. Dilute one-part ADMELOG to one-part 0.9% Sodium Chloride Injection to yield a concentration one-half that of ADMELOG (equivalent to U-50). If diluted ADMELOG is not used immediately, refrigerate at 2°C to 8°C (36°F to 46°F) for no more than 24 hours or store at room temperature up to 30°C (86°F) for 4 hours. Discard the unused diluted ADEMLOG after 24 hours if refrigerated or after 4 hours if stored at room temperature.

  Continuous Subcutaneous Infusion (Insulin Pump)

  • Refer to the continuous subcutaneous insulin infusion pump user manual to see if ADMELOG can be used with the insulin pump. Use ADMELOG in accordance with the insulin pump system's instructions for use.
  • Administer ADMELOG by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region 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)]
    .
  • Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure
    [see Warnings and Precautions (5.8)].
  • During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions (5.2)]
    .
  • Change ADMELOG in the pump reservoir at least every 7 days or according to the pump user manual, whichever is shorter.
  • Change the infusion sets and the infusion set insertion site according to the manufacturer's user manual.
  • Do NOT dilute or mix ADMELOG when administering by continuous subcutaneous infusion.
  • Do NOT expose ADMELOG in the pump reservoir to temperatures greater than 98.6°F (37°C).

  Intravenous Administration

  • Administer ADMELOG intravenously ONLY under medical supervision
    [see Warnings and Precautions (5.3, 5.6)]
    .
  • Dilute ADMELOG to concentrations from 0.1 unit/mL to 1 unit/mL using 0.9% Sodium Chloride Injection, USP
    [see How Supplied/Storage and Handling (16.2)]
    .
  • Closely monitor of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia
    [see Warnings and Precautions (5.3, 5.6)].
  ):
  • Administer ADMELOG by subcutaneous injection into the abdominal wall, thigh, upper arm, or buttocks within 15 minutes before a meal or immediately after a meal.
  • Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis.
• Continuous subcutaneous infusion (Insulin Pump) (
  2.2 Preparation and Administration Instructions for the Approved Routes of Administration

  Subcutaneous Injection

  • Administer the dose of ADMELOG subcutaneously within fifteen minutes before a meal or immediately after a meal into the abdominal wall, thigh, upper arm, or buttocks.
  • Rotate injection site 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)]
    .
  • ADMELOG administered by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin.
  • The ADMELOG SoloStar prefilled pen dials in 1-unit increments.
  • Prior to subcutaneous use, ADMELOG may be diluted with sterile 0.9% Sodium Chloride Injection. Dilute one-part ADMELOG to one-part 0.9% Sodium Chloride Injection to yield a concentration one-half that of ADMELOG (equivalent to U-50). If diluted ADMELOG is not used immediately, refrigerate at 2°C to 8°C (36°F to 46°F) for no more than 24 hours or store at room temperature up to 30°C (86°F) for 4 hours. Discard the unused diluted ADEMLOG after 24 hours if refrigerated or after 4 hours if stored at room temperature.

  Continuous Subcutaneous Infusion (Insulin Pump)

  • Refer to the continuous subcutaneous insulin infusion pump user manual to see if ADMELOG can be used with the insulin pump. Use ADMELOG in accordance with the insulin pump system's instructions for use.
  • Administer ADMELOG by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region 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)]
    .
  • Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure
    [see Warnings and Precautions (5.8)].
  • During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions (5.2)]
    .
  • Change ADMELOG in the pump reservoir at least every 7 days or according to the pump user manual, whichever is shorter.
  • Change the infusion sets and the infusion set insertion site according to the manufacturer's user manual.
  • Do NOT dilute or mix ADMELOG when administering by continuous subcutaneous infusion.
  • Do NOT expose ADMELOG in the pump reservoir to temperatures greater than 98.6°F (37°C).

  Intravenous Administration

  • Administer ADMELOG intravenously ONLY under medical supervision
    [see Warnings and Precautions (5.3, 5.6)]
    .
  • Dilute ADMELOG to concentrations from 0.1 unit/mL to 1 unit/mL using 0.9% Sodium Chloride Injection, USP
    [see How Supplied/Storage and Handling (16.2)]
    .
  • Closely monitor of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia
    [see Warnings and Precautions (5.3, 5.6)].
  ):
  • Refer to the insulin infusion pump user manual to see if ADMELOG can be used. Use in accordance with the insulin pump instructions for use.
  • Administer ADMELOG by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer.
  • Rotate infusion sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis.
  • Do not mix with other insulins or diluents in the pump.
• Intravenous Infusion: Administer ADMELOG by intravenous infusion ONLY after dilution and under medical supervision. (
  2.2 Preparation and Administration Instructions for the Approved Routes of Administration

  Subcutaneous Injection

  • Administer the dose of ADMELOG subcutaneously within fifteen minutes before a meal or immediately after a meal into the abdominal wall, thigh, upper arm, or buttocks.
  • Rotate injection site 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)]
    .
  • ADMELOG administered by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin.
  • The ADMELOG SoloStar prefilled pen dials in 1-unit increments.
  • Prior to subcutaneous use, ADMELOG may be diluted with sterile 0.9% Sodium Chloride Injection. Dilute one-part ADMELOG to one-part 0.9% Sodium Chloride Injection to yield a concentration one-half that of ADMELOG (equivalent to U-50). If diluted ADMELOG is not used immediately, refrigerate at 2°C to 8°C (36°F to 46°F) for no more than 24 hours or store at room temperature up to 30°C (86°F) for 4 hours. Discard the unused diluted ADEMLOG after 24 hours if refrigerated or after 4 hours if stored at room temperature.

  Continuous Subcutaneous Infusion (Insulin Pump)

  • Refer to the continuous subcutaneous insulin infusion pump user manual to see if ADMELOG can be used with the insulin pump. Use ADMELOG in accordance with the insulin pump system's instructions for use.
  • Administer ADMELOG by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region 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)]
    .
  • Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure
    [see Warnings and Precautions (5.8)].
  • During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions (5.2)]
    .
  • Change ADMELOG in the pump reservoir at least every 7 days or according to the pump user manual, whichever is shorter.
  • Change the infusion sets and the infusion set insertion site according to the manufacturer's user manual.
  • Do NOT dilute or mix ADMELOG when administering by continuous subcutaneous infusion.
  • Do NOT expose ADMELOG in the pump reservoir to temperatures greater than 98.6°F (37°C).

  Intravenous Administration

  • Administer ADMELOG intravenously ONLY under medical supervision
    [see Warnings and Precautions (5.3, 5.6)]
    .
  • Dilute ADMELOG to concentrations from 0.1 unit/mL to 1 unit/mL using 0.9% Sodium Chloride Injection, USP
    [see How Supplied/Storage and Handling (16.2)]
    .
  • Closely monitor of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia
    [see Warnings and Precautions (5.3, 5.6)].
  )
• The dosage of ADMELOG must be individualized based on the route of administration and the patient's metabolic needs, blood glucose monitoring results and glycemic control goal. (
  2.3 Dosage Recommendations

  • Individualize and adjust the dosage of ADMELOG based on the route of administration, the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal.
  • Dosage modifications 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
    [see Warnings and Precautions (5.2, 5.3)and Use in Specific Populations (8.6, 8.7)]
    .
  • When switching from another insulin lispro product to ADMELOG, the dose of ADMELOG should be the same as the other insulin lispro product
    [see
    Warnings and Precautions (5.2)].
  • When switching from other insulins to ADMELOG, the ADMELOG dosage may need to be adjusted
    [see
    Warnings and Precautions (5.2)]
    .
  )

Injection: 100 units/mL (U-100) is a clear and colorless solution available as:

• 10 mL multiple-dose vials
• 3 mL multiple-dose vials
• 3 mL single-patient-use SoloStar prefilled pens

Published studies with another insulin lispro product used during pregnancy have not reported an association between insulin lispro and the induction of major birth defects, miscarriage, or adverse maternal or fetal outcomes

Pregnant rats and rabbits were exposed to another insulin lispro product in animal reproduction studies during organogenesis. Fetal growth retardation was observed in offspring of rats exposed to insulin lispro at a dose approximately 3 times the human subcutaneous dose of 1.0 unit/kg/day. No adverse effects on embryo-fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.24 times the human subcutaneous dose of 1.0 unit/kg/day

The estimated background risk of major birth defects is 6%–10% in women with pregestational 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.

• Never share
  an ADMELOG SoloStar disposable prefilled pen or syringe between patients, even if the needle is changed. (
  5.1 Never Share an ADMELOG SoloStar Pen or Syringe Between Patients

  ADMELOG SoloStar prefilled pen must never be shared between patients, even if the needle is changed. Patients using ADMELOG vials must never share needles or syringes with another person. 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 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 anti-diabetic products may be needed.
  )
• Hypoglycemia:
  May be life-threatening. Monitor blood glucose and increase monitoring frequency with changes to insulin dosage, use of glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. (
  5.3 Hypoglycemia

  Hypoglycemia is the most common adverse reaction associated with insulins, including ADMELOG.

  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 after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect time course of ADMELOG 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

  [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 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 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.
  ,
  6 ADVERSE REACTIONS

  The following adverse reactions are discussed elsewhere:

  • Hypoglycemia
    [see Warnings and Precautions (5.3)]
  • Hypoglycemia Due to Medication Errors
    [see Warnings and Precautions (5.4)]
  • Hypersensitivity Reactions
    [see Warnings and Precautions (5.5)]
  • Hypokalemia
    [see Warnings and Precautions (5.6)]

  Adverse reactions associated with ADMELOG include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, and rash.

  
  
  

  To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

  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 observed in practice.

  Adverse Reactions with Subcutaneous Injections of ADMELOG

  Two clinical trials with ADMELOG were conducted: one in patients with type 1 diabetes and one in patients with type 2 diabetes

  [see Clinical Studies (14)]

  .

  • The data in Table 1 reflect the exposure of 252 patients with type 1 diabetes to ADMELOG with mean exposure duration of 49 weeks. The type 1 diabetes population had the following characteristics: Mean age was 43 years and mean duration of diabetes was 20 years. Fifty-nine percent were male, 80% were White, 6% were Black or African American and 7% were Hispanic. At baseline, the mean eGFR was 90 mL/min/1.73 m²and 49% of patients had eGFR ≥90 mL/min/1.73 m². The mean BMI was 26 kg/m². The mean HbA1c at baseline was 8.07%.
  • Two hundred fifty-three patients with type 2 diabetes were exposed to ADMELOG with mean exposure duration of 25 weeks. The type 2 diabetes population had the following characteristics: Mean age was 62 years and mean duration of diabetes was 17 years. Fifty-four percent were male, 90% were White, 6% were Black or African American and 17% were Hispanic. At baseline, the mean eGFR was 77 mL/min/1.73 m²and 27% of patients had eGFR ≥90 mL/min/1.73 m². The mean BMI was 32 kg/m². The mean HbA1c at baseline was 7.99%.

  Common adverse reactions were defined as reactions that occurred in ≥5% of the population studied.

  Common adverse reactions (other than hypoglycemia) during a clinical trial in patients with type 1 diabetes mellitus are listed in Table 1. In a 26-week clinical trial in patients with type 2 diabetes mellitus, no adverse reactions (other than hypoglycemia) occurred in ≥5% of ADMELOG-treated patients (n=253) were observed.

  Table 1: Adverse Reactions that Occurred in ≥5% of ADMELOG-Treated Patients with Type 1 Diabetes in a 52-Week Trial

  	ADMELOG + Insulin Glargine (100 units/mL), % (n=252)
  Nasopharyngitis	13%
  Upper respiratory tract infection	6%

  Severe Hypoglycemia

  Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including ADMELOG

  [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 ADMELOG 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 ADMELOG trials, severe hypoglycemia was defined as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. The incidence of severe hypoglycemia in patients receiving ADMELOG with type 1 diabetes mellitus and type 2 diabetes mellitus was 13.5% at 52 weeks and 2.4% at 26 weeks, respectively

  [see Clinical Studies (14)]

  .

  Adverse Reactions Associated with 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 ADMELOG, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue) and may affect insulin absorption

  [see Dosage and Administration (2.2)]

  .

  Weight Gain

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

  Peripheral Edema

  Insulins, including ADMELOG, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

  Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII) of ADMELOG

  In a randomized, open-label crossover study in adult patients with type 1 diabetes treated over two 4-week periods, the incidence of infusion set occlusions (defined as failure to correct hyperglycemia [plasma glucose ≥300 mg/dL] by insulin bolus via insulin pump) in ADMELOG-treated patients (n=25) was evaluated. Infusion set occlusions were reported by 24% of patients.

  In a randomized, 16-week, open-label, parallel design study of pediatric patients with type 1 diabetes, adverse reactions related to infusion site-related reactions for another insulin lispro product, 100 units/mL, occurred in 21% of patients. The most frequently reported infusion site-related reactions were infusion site erythema and infusion site reaction.

  Allergic Reactions

  Local Allergy

  As with any insulin therapy, patients taking ADMELOG may experience redness, swelling, or itching at the site of the injection. These minor reactions usually resolve in a few days to a few weeks, but in some occasions may require discontinuation of ADMELOG. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique.

  Systemic Allergy

  Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including ADMELOG. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.

  Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in ADMELOG

  [see Contraindications (4)]

  .

  6.2 Immunogenicity

  As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to ADMELOG in the studies described below with the incidence of antibodies in other studies or to other insulin products may be misleading.

  In a 52-week study of ADMELOG in type 1 diabetes patients, 49.4% were positive at baseline and 22.6% had treatment-emergent ADA (i.e., either new ADA, or increase in titer of at least 4-fold).

  In a 26-week study of ADMELOG in type 2 diabetes patients, 26.4% were positive at baseline and 18.8% had treatment-emergent ADA (i.e., either new ADA, or increase in titer of at least 4-fold).

  6.3 Postmarketing Experience

  The following additional adverse reactions have been identified during post approval use of another insulin lispro product, 100 units/mL. 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 in which other insulins have been accidentally substituted for another insulin lispro product, 100 units/mL, have been identified during post approval use.

  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.
  ,
  7 DRUG INTERACTIONS

  Table 2 presents clinically significant drug interactions with ADMELOG.

  Table 2: Clinically Significant Drug Interactions with ADMELOG

  Drugs That May Increase the Risk of Hypoglycemia
  Drugs:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics.
  Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when ADMELOG is concomitantly administered with these drugs.
  Drugs That May Decrease the Blood Glucose Lowering Effect of ADMELOG
  Drugs:	Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
  Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when ADMELOG is concomitantly administered with these drugs.
  Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of ADMELOG
  Drugs:	Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
  Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when ADMELOG is concomitantly administered with these drugs.
  Drugs That May Blunt Signs and Symptoms of Hypoglycemia
  Drugs:	Beta-blockers, clonidine, guanethidine and reserpine.
  Intervention:	Increased frequency of glucose monitoring may be required when ADMELOG is concomitantly administered with these drugs.

  • Drugs that may increase the risk of hypoglycemia:
    antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics .
  • Drugs that may decrease the blood glucose lowering effect:
    atypical antipsychotics, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones .
  • Drugs that may increase or decrease the blood glucose lowering effect:
    alcohol, beta-blockers, clonidine, lithium salts, and pentamidine .
  • Drugs that may blunt the signs and symptoms of hypoglycemia:
    beta-blockers, clonidine, guanethidine, and reserpine .
  ,
  8.6 Renal Impairment

  Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent ADMELOG dose adjustment and more frequent blood glucose monitoring

  [see Clinical Pharmacology (12.3)]

  .
  ,
  8.7 Hepatic Impairment

  Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent ADMELOG dose adjustment and more frequent blood glucose monitoring

  [see Clinical Pharmacology (12.3)]

  .
  )
• 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 ADMELOG and other insulins, instruct patients to always check the insulin label before each injection.
  )
• Hypersensitivity Reactions:
  May be life-threatening. Discontinue ADMELOG, monitor and treat if indicated. (
  5.5 Hypersensitivity Reactions

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

  [see Adverse Reactions (6.1)]

  . ADMELOG is contraindicated in patients who have had hypersensitivity reactions to insulin lispro or any of the excipients in ADMELOG

  [see Contraindications (4)]

  .
  )
• Hypokalemia:
  May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (
  5.6 Hypokalemia

  All insulins, including ADMELOG, 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, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including ADMELOG, 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.
  )
• Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction:
  Monitor glucose and administer ADMELOG by subcutaneous injection if pump malfunction occurs. (
  5.8 Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction

  Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with ADMELOG may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure

  [see How Supplied/Storage and Handling (16.2)and Patient Counseling Information (17)]

  .
  )