Levemir

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

LEVEMIR is not recommended for the treatment of diabetic ketoacidosis.

• •See Full Prescribing Information for important administration instructions (
  2.1 Important Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions ].
  • •Visually inspect for particulate matter and discoloration. Only use LEVEMIR if the solution appears clear and colorless.
  • •Inject LEVEMIR subcutaneously into the thigh, upper arm, or abdomen.
  • •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 , Adverse Reactions ]
    .
  • •During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions ].
  • •Do not dilute or mix LEVEMIR with any other insulin or solution.
  • •Do not administer LEVEMIR intravenously or in an insulin infusion pump.
  • •LEVEMIR FlexPen dials in 1-unit increments.
  • •Use the LEVEMIR FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  ).
• •Inject subcutaneously into the thigh, upper arm, or abdomen (
  2.1 Important Administration Instructions

  • •Always check insulin labels before administration
    [see Warnings and Precautions ].
  • •Visually inspect for particulate matter and discoloration. Only use LEVEMIR if the solution appears clear and colorless.
  • •Inject LEVEMIR subcutaneously into the thigh, upper arm, or abdomen.
  • •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 , Adverse Reactions ]
    .
  • •During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions ].
  • •Do not dilute or mix LEVEMIR with any other insulin or solution.
  • •Do not administer LEVEMIR intravenously or in an insulin infusion pump.
  • •LEVEMIR FlexPen dials in 1-unit increments.
  • •Use the LEVEMIR FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  ).
• •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 ].
  • •Visually inspect for particulate matter and discoloration. Only use LEVEMIR if the solution appears clear and colorless.
  • •Inject LEVEMIR subcutaneously into the thigh, upper arm, or abdomen.
  • •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 , Adverse Reactions ]
    .
  • •During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring
    [see Warnings and Precautions ].
  • •Do not dilute or mix LEVEMIR with any other insulin or solution.
  • •Do not administer LEVEMIR intravenously or in an insulin infusion pump.
  • •LEVEMIR FlexPen dials in 1-unit increments.
  • •Use the LEVEMIR FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
  ).
• •Individualize and titrate the dose of LEVEMIR based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal (
  2.2 General Dosing Instructions

  • •LEVEMIR can be administered by subcutaneous injection once or twice daily. Administer once daily doses with the evening meal or at bedtime. For twice daily dosing, administer the evening dose with the evening meal, at bedtime, or 12 hours after the morning dose.
  • •Individualize and titrate the dose of LEVEMIR based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal.
  • •Dose 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 ].
  • •In patients with type 1 diabetes, LEVEMIR must be used in a regimen with rapid-acting or short-acting insulin.
  ).
• •Administer subcutaneously once daily or in divided doses twice daily (
  2.2 General Dosing Instructions

  • •LEVEMIR can be administered by subcutaneous injection once or twice daily. Administer once daily doses with the evening meal or at bedtime. For twice daily dosing, administer the evening dose with the evening meal, at bedtime, or 12 hours after the morning dose.
  • •Individualize and titrate the dose of LEVEMIR based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal.
  • •Dose 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 ].
  • •In patients with type 1 diabetes, LEVEMIR must be used in a regimen with rapid-acting or short-acting insulin.
  ).
• •See Full Prescribing Information for recommended starting dose in insulin naïve patients and patients already on insulin therapy (
  2.3 Starting Dose in Insulin Naïve Patients

  Recommended Starting Dosage in Patients with Type 1 Diabetes

  The recommended starting dose of LEVEMIR in patients with type 1 diabetes mellitus is approximately one-third to one-half of the total daily insulin dose. The remainder of the total daily insulin dose should be administered as short-acting pre-meal insulin. 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 naïve patients with type 1 diabetes.

  Recommended Starting Dosage in Patients with Type 2 Diabetes

  The recommended starting dose of LEVEMIR in patients with type 2 diabetes mellitus inadequately controlled on oral antidiabetic medications or a GLP-1 receptor agonist is 10 units (or 0.1 units/kg to 0.2 units/kg) given once daily in the evening or divided into a twice daily regimen.
  ,
  2.4 Switching to LEVEMIR from Other Insulin Therapies

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

  [see Warnings and Precautions ].

  • •If converting from insulin glargine to LEVEMIR, the change can be done on a unit-to-unit basis.
  • •If converting from NPH insulin, the change can be done on a unit-to-unit basis. However, some patients with type 2 diabetes mellitus may require more LEVEMIR than NPH insulin, as observed in one trial
    [see Clinical Studies ]
    .
  ).

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

• •3 mL single-patient-use FlexPen prefilled pen
• •10 mL multiple-dose vial

Available data from published studies and postmarketing case reports with LEVEMIR use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In a randomized, parallel-group, open-label clinical trial that included 152 pregnant women with type 1 diabetes who were administered LEVEMIR once or twice daily, beginning in gestational weeks 8 to 12 or prior to conception, no clear evidence of maternal or fetal risk associated with LEVEMIR was observed

Animal reproduction studies were conducted in non-diabetic pregnant rats and rabbits with insulin detemir administration at 3 and 135 times the human dose of 0.5 units/kg/day, respectively, throughout pregnancy. Overall, the effects of insulin detemir 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 pre-gestational diabetes with a peri-conceptional HbA_1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA_1c >10. The estimated background risk of miscarriage for the indicated population is unknown.

Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

In an open-label clinical trial, pregnant females with type 1 diabetes (n=310) were treated with LEVEMIR (once or twice daily) or NPH insulin (once, twice, or thrice daily); both groups also received preprandial insulin aspart. Approximately half of the study participants in each arm were randomized as pregnant and were exposed to NPH or to other insulins prior to conception and in the first 8 weeks of gestation. The rates of preeclampsia observed in the study were within expected rates for pregnancy complicated by diabetes. No differences in pregnancy outcomes or the health of the fetus and newborn were seen between the two groups. In this study, the proportion of subjects with severe hypoglycemia and non-severe hypoglycemia was similar between the two treatment arms; for the definitions of severe hypoglycemia and non-severe hypoglycemia

In about a quarter of infants, LEVEMIR was detected in the infant cord blood at levels above the lower level of quantification (<25 pmol/L).

In a fertility and embryonic development study, insulin detemir was administered to female rats before mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose of 0.5 units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300 nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day (approximately 135 times a human dose of 0.5 units/kg/day based on AUC ratio) were given to rabbits during organogenesis. Drug and dose related increases in the incidence of fetuses with gallbladder abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at a dose of 900 nmol/kg/day. The rat and rabbit embryo-fetal development studies that included concurrent human insulin control groups indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and teratogenicity suggesting that the effects seen were the result of hypoglycemia resulting from insulin exposure in normal animals.

• •
  Never Share
  a LEVEMIR FlexPen, insulin syringe, or needle between patients, even if the needle is changed (
  5.1 Never Share a LEVEMIR FlexPen, Needle, or Insulin Syringe between Patients

  LEVEMIR FlexPen prefilled pens must never be shared between patients, even if the needle is changed. Patients using LEVEMIR vials should 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 ]

  or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia

  [see Adverse Reactions ].

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

  [see Dosage and Administration ].
  ).
• •
  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 of insulin, including LEVEMIR

  [see Adverse Reactions ].

  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). LEVEMIR, or any insulin, should not be used during episodes of hypoglycemia

  [see Contraindications ].

  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, using drugs that block the sympathetic nervous system (e.g., beta-blockers)

  [see Drug Interactions ],

  or who experience recurrent hypoglycemia.

  Risk Factors for Hypoglycemia

  The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin

  [see Clinical Pharmacology ]

  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 LEVEMIR may vary among 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.

  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 ].

  When a GLP-1 receptor agonist is used in combination with LEVEMIR, the LEVEMIR dose may need to be lowered or more conservatively titrated to minimize the risk of hypoglycemia

  [see Adverse Reactions ]

  . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia

  [see Use in Specific Populations ].

  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.
  ).
• •
  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 LEVEMIR and other insulins, instruct patients to always check the insulin label before each injection.
  ).
• •
  Hypersensitivity reactions:
  Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue LEVEMIR, monitor and treat if indicated (
  5.5 Hypersensitivity Reactions

  Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including LEVEMIR

  [see Adverse Reactions ]

  . If hypersensitivity reactions occur, discontinue LEVEMIR; treat per standard of care and monitor until symptoms and signs resolve. LEVEMIR is contraindicated in patients who have had hypersensitivity reactions to insulin detemir or any of the excipients

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

  All insulins, including LEVEMIR, 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 LEVEMIR, 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.
  ).