Levemir (insulin detemir): Uses, Dosage, Side Effects & Warnings

Q: Who makes Levemir?

Levemir is listed by 1 labeler in the FDA NDC directory, including A-S Medication Solutions.

Uses

1 INDICATIONS AND USAGE LEVEMIR is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. Limitations of Use LEVEMIR is not recommended for the treatment of diabetic ketoacidosis. LEVEMIR is a long-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus ( 1 ). Limitations of Use: Not recommended for the treatment of diabetic ketoacidosis.

Dosage and administration

• See Full Prescribing Information for important administration instructions ( 2.1 ).
• Inject subcutaneously into the thigh, upper arm, or abdomen ( 2.1 ).
• Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis ( 2.1 ).
• Individualize and titrate the dose of LEVEMIR based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal ( 2.2 ).
• Administer subcutaneously once daily or in divided doses twice daily ( 2.2 ).
• See Full Prescribing Information for recommended starting dose in insulin naïve patients and patients already on insulin therapy ( 2.3 , 2.4 ). 2.1 Important Administration Instructions
• Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )].
• 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 ( 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 )].
• 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. 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 ( 5.3 )].
• In patients with type 1 diabetes, LEVEMIR must be used in a regimen with rapid-acting or short-acting insulin. 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 ( 5.3 )].
• 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 ( 14 )] .

Dosage forms and strengths

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 Injection: 100 units/mL (U-100) of insulin detemir available as:
• 3 mL single-patient-use FlexPen ® prefilled pen ( 3 )
• 10 mL multiple-dose vial ( 3 )

Contraindications

4 CONTRAINDICATIONS LEVEMIR is contraindicated:
• During episodes of hypoglycemia [see Warnings and Precautions (5.3)]
• In patients with hypersensitivity to insulin detemir or any of the excipients in LEVEMIR. Reactions have included anaphylaxis [ see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] .
• During episodes of hypoglycemia ( 4 )
• Hypersensitivity to insulin detemir or any of the excipients in LEVEMIR ( 4 )

Warnings and precautions

• Never Share a LEVEMIR FlexPen, insulin syringe, or needle between patients, even if the needle is changed ( 5.1 ).
• 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 ).
• 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 due to medication errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection ( 5.4 ).
• Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue LEVEMIR, monitor and treat if indicated ( 5.5 ).
• Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated ( 5.6 ).
• 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 ). 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. 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 ( 5.4 )] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions ( 6 )]. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant antidiabetic products may be needed [see Dosage and Administration ( 2.4 )]. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction of insulin, including LEVEMIR [see Adverse Reactions ( 6.1 )]. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place 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 ( 4 )]. 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 ( 7 )], 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 ( 12.2 )] 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 ( 7 )]. 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 ( 6.1 )] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations ( 8.6 , 8.7 )]. Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. 5.4 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. 5.5 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including LEVEMIR [see Adverse Reactions ( 6.1 )] . 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 .

Side effects

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 LEVEMIR include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, rash and pruritus ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Tables 1-4 below. See Tables 5 and 6 for the hypoglycemia findings. In two pooled trials, adults with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=767) or NPH (n=388). The mean duration of exposure to LEVEMIR was 153 days, and the total exposure to LEVEMIR was 321 patient-years. The most common adverse reactions are summarized in Table 1. Table 1: Adverse Reactions Occurring in ≥ 5% of LEVEMIR-Treated Adult Patients with Type 1 Diabetes Mellitus in Two Trials of 16 Weeks and 24 Weeks Duration LEVEMIR, % (n = 767) Upper respiratory tract infection 26.1 Headache 22.6 Pharyngitis 9.5 Influenza-like illness 7.8 Abdominal Pain 6.0 Adults with type 1 diabetes were exposed to LEVEMIR (n=161) or insulin glargine (n=159). The mean duration of exposure to LEVEMIR was 176 days, and the total exposure to LEVEMIR was 78 patient-years. The most common adverse reactions are summarized in Table 2. Table 2: Adverse Reactions Occurring in ≥ 5% of LEVEMIR-Treated Adult Patients with Type 1 Diabetes Mellitus in a 26-week Trial LEVEMIR, % (n = 161) Upper respiratory tract infection 26.7 Headache 14.3 Back pain 8.1 Influenza-like illness 6.2 Gastroenteritis 5.6 Bronchitis 5.0 In two pooled trials, adults with type 2 diabetes were exposed to LEVEMIR (n=432) or NPH (n=437). The mean duration of exposure to LEVEMIR was 157 days, and the total exposure to LEVEMIR was 186 patient-years. The most common adverse reactions were comparable to that observed in adult patients with type 1 diabetes mellitus; see Table 1. Pediatric patients with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=232) or NPH (n=115). The mean duration of exposure to LEVEMIR was 180 days, and the total exposure to LEVEMIR was 114 patient-years. The most common adverse reactions are summarized in Table 3. Table 3: Adverse Reactions Occurring in ≥ 5% of LEVEMIR-Treated Pediatric Patients with Type 1 Diabetes Mellitus in a 26-week Trial LEVEMIR, % (n = 232) Upper respiratory tract infection 35.8 Headache 31.0 Pharyngitis 17.2 Gastroenteritis 16.8 Influenza-like illness 13.8 Abdominal pain 13.4 Pyrexia 10.3 Cough 8.2 Viral infection 7.3 Nausea 6.5 Rhinitis 6.5 Vomiting 6.5 Hypoglycemia Hypoglycemia was the most commonly observed adverse reaction in patients treated with LEVEMIR. 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 LEVEMIR 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. Table 4 (type 1 diabetes) and Table 5 (type 2 diabetes) summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR clinical trials. For the adult trials and one of the pediatric trials (Study D), severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring assistance of another person and associated with either a plasma glucose value below 56 mg/dL (blood glucose below 50 mg/dL) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. For the other pediatric trial (Study I), severe hypoglycemia was defined as an event with semi-consciousness, unconsciousness, coma and/or convulsions in a patient who could not assist in the treatment and who may have required glucagon or intravenous glucose. For the adult trials and pediatric trial (Study D), non-severe hypoglycemia was defined as an asymptomatic or symptomatic plasma glucose <56 mg/dL (or equivalently blood glucose <50 mg/dL as used in Study A and C) that was self-treated by the patient. For pediatric Study I, non-severe hypoglycemia included asymptomatic events with plasma glucose <65 mg/dL as well as symptomatic events that the patient could self-treat or treat by taking oral therapy provided by the caregiver.

Drug interactions

Table 6 includes clinically significant drug interactions with LEVEMIR. Table 6: Clinically Significant Drug Interactions with LEVEMIR 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, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors. Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when LEVEMIR is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of LEVEMIR 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: Dosage increases and increased frequency of glucose monitoring may be required when LEVEMIR is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of LEVEMIR Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dosage adjustment and increased frequency of glucose monitoring may be required when LEVEMIR is co-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 LEVEMIR is co-administered with these drugs.
• Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. ( 7 )
• Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. ( 5.3 , 7 )

Use in specific populations

8.1 Pregnancy Risk Summary 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 (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). 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 (see Data) . 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. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk 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. Data Human Data 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 [see Adverse Reactions ( 6.1 )]. 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). Animal Data 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. 8.2 Lactation Risk Summary Available data from published literature demonstrate that exogenous human insulin products, including biosynthetic insulins such as insulin detemir, are transferred into human milk. There are no published reports of adverse reactions, including hypoglycemia, in breastfed infants exposed to exogenous human insulin products, including insulin detemir, in breastmilk. There are no data on the effects of exogenous human insulin products, including insulin detemir, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LEVEMIR and any potential adverse effects on the breastfed infant from LEVEMIR or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of LEVEMIR to improve glycemic control in pediatric patients with diabetes mellitus have been established. The use of LEVEMIR for this indication is supported by evidence from adequate and well-controlled trials (Studies D and I) in 694 pediatric patients aged 2 to 17 years with type 1 diabetes mellitus [see Clinical Studies ( 14.2 )] and from other studies in pediatric patients and adults with diabetes mellitus [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.3 )]. 8.5 Geriatric Use In clinical trials of LEVEMIR, 64 of 1624 patients (4%) in the type 1 diabetes trials and 309 of 1082 patients (29%) in the type 2 diabetes trials were 65 years or older. A total of 52 (7 type 1 and 45 type 2) patients (2%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but small sample sizes limits conclusions. Greater sensitivity of some older individuals cannot be ruled out.

Pregnancy

8.1 Pregnancy Risk Summary 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 (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). 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 (see Data) . 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. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk 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. Data Human Data 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 [see Adverse Reactions ( 6.1 )]. 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). Animal Data 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.

Pediatric use

8.4 Pediatric Use The safety and effectiveness of LEVEMIR to improve glycemic control in pediatric patients with diabetes mellitus have been established. The use of LEVEMIR for this indication is supported by evidence from adequate and well-controlled trials (Studies D and I) in 694 pediatric patients aged 2 to 17 years with type 1 diabetes mellitus [see Clinical Studies ( 14.2 )] and from other studies in pediatric patients and adults with diabetes mellitus [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.3 )].

Geriatric use

8.5 Geriatric Use In clinical trials of LEVEMIR, 64 of 1624 patients (4%) in the type 1 diabetes trials and 309 of 1082 patients (29%) in the type 2 diabetes trials were 65 years or older. A total of 52 (7 type 1 and 45 type 2) patients (2%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but small sample sizes limits conclusions. Greater sensitivity of some older individuals cannot be ruled out. In geriatric patients, the initial dosing, dosage increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in the geriatric patients.

Overdosage

An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.6 )] . Mild episodes of hypoglycemia usually can be treated with oral glucose. Lowering the insulin dosage, and adjustments in meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia must be corrected appropriately.

Description

Insulin detemir is a long-acting recombinant human insulin analog produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification. Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been omitted, and a C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has a molecular formula of C 267 H 402 O 76 N 64 S 6 and a molecular weight of 5.917 kDa. It has the following structure: Figure 1: Structural Formula of Insulin Detemir LEVEMIR (insulin detemir) injection is a clear, colorless, aqueous, neutral sterile solution for subcutaneous use. Each milliliter of LEVEMIR contains 100 units insulin detemir, dibasic sodium phosphate (0.71 mg), glycerin (16 mg), metacresol (2.06 mg), phenol (1.8 mg), sodium chloride (1.17 mg), zinc (65.4 mcg), and Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. LEVEMIR has a pH of approximately 7.4. Levemir Chemical Structure.jpg

Mechanism of action

12.1 Mechanism of Action The primary activity of insulin, including LEVEMIR, is regulation of glucose metabolism. Insulins and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin also inhibits lipolysis and proteolysis, and enhances protein synthesis.

How supplied

Product: 50090-1276 NDC: 50090-1276-0 10 mL in a VIAL, GLASS / 1 in a CARTON Product: 50090-1475

Patient information

See FDA-Approved Patient Labeling (Patient Information and Instructions for Use). There are separate Instructions for Use for the Vials and LEVEMIR FlexPen Prefilled Pen. Never Share a LEVEMIR FlexPen or Insulin Syringe Between Patients Advise patients that they must never share a LEVEMIR FlexPen with another person, even if the needle is changed. Advise patients using LEVEMIR vials not to share needles or insulin syringes with another person. Sharing poses 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 (e.g., impaired ability to concentrate and react). 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 )] . Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with LEVEMIR. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions ( 5.5 )]. Hypoglycemia Due to Medication Errors Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.4)] . Novo Nordisk ® , Levemir ® , NovoLog ® , FlexPen ® , and NovoFine ® are registered trademarks of Novo Nordisk A/S. Patent Information: https://www.novonordisk-us.com/products/product-patents.html © 2005-2022 Novo Nordisk Manufactured by: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 U.S. License Number 1261 For information about LEVEMIR contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, New Jersey 08536 1-800-727-6500 www.novonordisk-us.com

Active ingredients

Insulin Detemir in 1 product

Levemir NDC products (1)

NDC	Strength & form	Labeler	Type
50090-1276	Insulin Detemir 100 [iU]/mL Injection, Solution	A-S Medication Solutions	BLA

Frequently asked questions

What is Levemir used for?

1 INDICATIONS AND USAGE LEVEMIR is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. Limitations of Use LEVEMIR is not recommended for the treatment of diabetic ketoacidosis. LEVEMIR is a long-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus ( 1 ). Limitations of Use: Not…

What are the side effects of Levemir?

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 LEVEMIR include hypoglycemia, allergic reactions,… See the full label for the complete list.

Who makes Levemir?

Levemir is listed by 1 labeler in the FDA NDC directory, including A-S Medication Solutions.