INDICATIONS & USAGE SECTION.


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

GERIATRIC USE SECTION.


8.5 Geriatric Use. In clinical trials of LEVEMIR, 64 of 1624 patients (4%) in the type diabetes trials and 309 of 1082 patients (29%) in the type diabetes trials were 65 years or older. total of 52 (7 type 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 elderly patients, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in the elderly.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. Product: 50090-4501NDC: 50090-4501-0 mL in SYRINGE, PLASTIC 5 in CARTON.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere:oHypoglycemia [see Warnings and Precautions (5.3)]oMedication errors [see Warnings and Precautions (5.4)]oHypersensitivity and allergic reactions [see Warnings and Precautions (5.5)]oHypokalemia [see Warnings and Precautions (5.6)]. oHypoglycemia [see Warnings and Precautions (5.3)]. oMedication errors [see Warnings and Precautions (5.4)]. oHypersensitivity and allergic reactions [see Warnings and Precautions (5.5)]. oHypokalemia [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 diabetes mellitus and type diabetes mellitus are listed in Tables 1-4 below. See Tables and for the hypoglycemia findings.In two pooled trials, adults with type 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 Diabetes Mellitus in Two Trials of 16 Weeks and 24 Weeks DurationLEVEMIR, %(n 767)Upper respiratory tract infection26.1Headache22.6Pharyngitis9.5Influenza-like illness7.8Abdominal Pain6.0Adults with type 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 Diabetes Mellitus in 26-week TrialLEVEMIR, %(n 161)Upper respiratory tract infection26.7Headache14.3Back pain8.1Influenza-like illness6.2Gastroenteritis5.6Bronchitis5.0In two pooled trials, adults with type 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 diabetes mellitus; see Table 1.Pediatric patients with type 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 Diabetes Mellitus in 26-week TrialLEVEMIR, %(n 232)Upper respiratory tract infection35.8Headache31.0Pharyngitis17.2Gastroenteritis16.8Influenza-like illness13.8Abdominal pain13.4Pyrexia10.3Cough8.2Viral infection7.3Nausea6.5Rhinitis6.5Vomiting6.5Adverse reactions in pregnant patients occurring at an incidence of >=5% are shown in Table 4. The two most common adverse reactions were nasopharyngitis and headache. These are consistent with findings from other type diabetes trials (see Table 1, Section 6.1.), and are not repeated in Table 4.The incidence of adverse reactions of pre-eclampsia was 10.5% (16 cases) and 7.0% (11 cases) in the LEVEMIR and NPH insulin groups respectively. Out of the total number of cases of pre-eclampsia, eight (8) cases in the LEVEMIR group and case in the NPH insulin group required hospitalization. The rates of pre-eclampsia observed in the study are within expected rates for pregnancy complicated by diabetes. Pre-eclampsia is syndrome defined by symptoms, hypertension and proteinuria; the definition of pre-eclampsia was not standardized in the trial making it difficult to establish link between given treatment and an increased risk of pre-eclampsia. All events were considered unlikely related to trial treatment. In all nine (9) cases requiring hospitalization the women had healthy infants. Events of hypertension, proteinuria and edema were reported less frequently in the LEVEMIR group than in the NPH insulin group as whole. There was no difference between the treatment groups in mean blood pressure during pregnancy and there was no indication of general increase in blood pressure. In the NPH insulin group there were serious adverse reactions in four mothers of the following placental disorders, Placenta previa, Placenta previa hemorrhage, and Premature separation of placenta and serious adverse reaction of Antepartum haemorrhage. There were none reported in the LEVEMIR group.The incidence of early fetal death (abortions) was similar in LEVEMIR and NPH treated patients; 6.6% and 5.1%, respectively. The abortions were reported under the following terms: Abortion spontaneous, Abortion missed, Blighted ovum, Cervical incompetence and Abortion incomplete.In about quarter of infants, LEVEMIR was detected in the infant cord blood at levels above the lower level of quantification (<25 pmol/L).No differences in pregnancy outcomes or the health of the fetus and newborn were seen with LEVEMIR use. Table 4: Adverse Reactions During Pregnancy in Trial Comparing Insulin Aspart LEVEMIR to Insulin Aspart NPH Insulin in Pregnant Women with Type Diabetes (Adverse Reactions with Incidence >= 5%)LEVEMIR, %(n 152)Anemia13.2Diarrhea11.8Pre-eclampsia10.5Urinary tract infection9.9Gastroenteritis8.6Abdominal pain upper5.9Vomiting5.3Abortion spontaneous5.3Abdominal pain5.3Oropharyngeal pain 5.3HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients using insulin, including 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 (type diabetes) and Table (type 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 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 patient who could not assist in the treatment and who may have required glucagon or intravenous glucose. For the adult trials, including the trial in pregnant women (study G), and pediatric 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 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.Table 5: Hypoglycemia in Patients with Type DiabetesSevere HypoglycemiaNon-Severe HypoglycemiaPercent of patients with at least event (n/total N)Event/patient/yearPercent of patients(n/total N)Event/patient/yearStudy AType DiabetesAdults16 weeksIn combination withinsulin aspartTwice-DailyLEVEMIR8.7(24/276)0.5288.0(243/276)26.4Study BType DiabetesAdults26 weeksIn combination withinsulin aspartTwice-DailyLEVEMIR5.0(8/161)0.1382.0(132/161)20.2Study CType DiabetesAdults24 weeksIn combination withregular insulinOnce-Daily LEVEMIR7.5(37/491)0.3588.4(434/491)31.1Study DType DiabetesPediatrics26 weeksIn combination withinsulin aspartOnce- or Twice Daily LEVEMIR15.9(37/232)0.9193.1(216/232)31.6Study IType DiabetesPediatrics52 weeksIn combination with insulin aspartOnce- or Twice Daily LEVEMIR1.7(3/177)0.0294.9(168/177)56.1Study GType Diabetes PregnancyIn combination with insulin aspartOnce- or Twice Daily LEVEMIR16.4(25/152)1.194.7(144/152)114.2Table 6: Hypoglycemia in Patients with Type DiabetesStudy EType DiabetesAdults24 weeksIn combination withoral agentsStudy FType DiabetesAdults22 weeksIn combination withinsulin aspartStudy HType DiabetesAdults26 weeks in combination with Liraglutide and MetforminTwice-Daily LEVEMIROnce- or Twice Daily LEVEMIROnce Daily LEVEMIR Liraglutide +MetforminSevere hypoglycemiaPercent of patients with at least event (n/total N)0.4(1/237)1.5(3/195)0Event/patient/year0.010.040Non-severe hypoglycemiaPercent of patients (n/total N)40.5(96/237)32.3(63/195)9.2 (15/163)Event/patient/year3.51.60.29 Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR, and may be life-threatening.Insulin Initiation and Intensification of Glucose ControlIntensification or rapid improvement in glucose control has been associated with 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.LipodystrophyLong-term use of insulin, including LEVEMIR, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption [see Dosage and Administration (2.1)].Weight GainWeight gain can occur with insulin therapy, including LEVEMIR, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria [see Clinical Studies (14)]. In the clinical program, the mean change in body weight from baseline in adult patients with type diabetes (Study A, B, and C) treated with LEVEMIR ranged from -0.3 kg to 0.5 kg. The mean change in body weight from baseline in adult patients with type diabetes (Study E, F, and H) treated with LEVEMIR ranged from 0.5 kg to 1.2 kg.Peripheral EdemaInsulin, including LEVEMIR, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.Injection Site ReactionsPatients taking LEVEMIR may experience injection site reactions, including localized erythema, pain, pruritus, urticaria, edema, and inflammation. In clinical studies in adults, three patients treated with LEVEMIR reported injection site pain (0.25%).ImmunogenicityAll insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In clinical trials of LEVEMIR, antibody development has been observed with no apparent impact on glycemic control.. Allergic Reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR, and may be life-threatening.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of LEVEMIR. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Medication errors have been reported in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR.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 sudden change to an unaffected injection site.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test.In 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 human dose of 0.5 units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 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.. 12.2 Pharmacodynamics. Insulin detemir is soluble, long-acting basal human insulin analog with up to 24-hour duration of action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak. The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir molecules from the injection site due to self-association of the drug molecules. In addition, the distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin.Figure shows results from study in patients with type diabetes conducted for maximum of 24 hours after the subcutaneous injection of LEVEMIR. The mean time between injection and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to 24 hours (24 hours was the end of the observation period).Figure 2: Activity Profiles in Patients with Type Diabetes in 24-hour Glucose Clamp StudyFor doses in the interval of 0.2 to 0.4 units/kg, insulin detemir exerts more than 50% of its maximum effect from to hours up to approximately 14 hours after dose administration. Figure shows glucose infusion rate results from 16-hour glucose clamp study in patients with type diabetes. The clamp study was terminated at 16 hours according to protocol.Figure 3: Activity Profiles in Patients with Type Diabetes in 16-hour Glucose Clamp Study. Figure 2: Activity Profiles in Patients with Type Diabetes. Figure 3: Activity Profiles in Patients with Type Diabetes. 12.3 Pharmacokinetics. AbsorptionAfter subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin detemir serum concentrations had relatively constant concentration/time profile over 24 hours with the maximum serum concentration (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and AUC0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and abdominal regions. The absolute bioavailability of insulin detemir is approximately 60%.DistributionInsulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein-bound drugs.EliminationAfter subcutaneous administration in patients with type diabetes, insulin detemir has terminal half-life of to hours depending on dose.Specific PopulationsPediatric PatientsThe pharmacokinetic properties of LEVEMIRwere studied in pediatric patients 6-12 years, 13-17 years, and adults with type diabetes. In pediatric patients 6-12 years, the insulin detemir plasma area under the curve (AUC) and Cmax were increased by 10% and 24%, respectively, as compared to adults. There was no difference in pharmacokinetics between pediatric patients 13-17 years and adults.GeriatricsIn clinical trial studying differences in pharmacokinetics of single subcutaneous dose of LEVEMIR in young (20 to 35 years) versus elderly (>=68 years) healthy subjects, the insulin detemir AUC was up to 35% higher among the elderly subjects due to reduced clearance [see Use in Specific Populations (8.5)]. Gender No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed between males and females.RaceIn two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and pharmacodynamics of LEVEMIR were studied in clamp study comparing patients with type diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR were comparable in these three populations.Renal impairmentA single subcutaneous dose of 0.2 units/kg of LEVEMIR was administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate, severe, and hemodialysis-dependent). In this study, there were no differences in the pharmacokinetics of LEVEMIR between healthy subjects and those with renal impairment[see Use in Specific Populations (8.6)].Hepatic impairmentA single subcutaneous dose of 0.2 units/kg of LEVEMIR was administered to healthy subjects and those with varying degrees of hepatic impairment (mild, moderate and severe). LEVEMIR exposure as estimated by AUC decreased with increasing degrees of hepatic impairment with corresponding increase in apparent clearance [see Use in Specific Populations (8.7)].SmokingThe effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied.LiraglutideNo pharmacokinetic interaction was observed between liraglutide and LEVEMIR when separate subcutaneous injections of LEVEMIR 0.5 units/kg (single-dose) and liraglutide 1.8 mg (steady state) were administered in patients with type diabetes.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. The efficacy and safety of LEVEMIR given once-daily at bedtime or twice-daily (before breakfast and at bedtime, before breakfast and with the evening meal, or at 12-hour intervals) was compared to that of once-daily or twice-daily NPH insulin in open-label, randomized, parallel studies of 1155 adults with type diabetes mellitus, 347 pediatric patients with type diabetes mellitus, and 869 adults with type diabetes mellitus. The efficacy and safety of LEVEMIR given twice-daily was compared to once-daily insulin glargine in an open-label, randomized, parallel study of 320 patients with type diabetes. The evening LEVEMIR dose was titrated in all trials according to pre-defined targets for fasting blood glucose. The pre-dinner blood glucose was used to titrate the morning LEVEMIR dose in those trials that also administered LEVEMIR in the morning. In general, the reduction in HbA1c with LEVEMIR was similar to that with NPH insulin or insulin glargine.. 14.1 Type Diabetes Adult In 16-week open-label clinical study (Study A, n=409), adults with type diabetes were randomized to treatment with either LEVEMIR at 12-hour intervals, LEVEMIR administered in the morning and bedtime or NPH insulin administered in the morning and bedtime. Insulin aspart was also administered before each meal. At 16 weeks of treatment, the combined LEVEMIR-treated patients had similar HbA1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 8). Differences in timing of LEVEMIR administration had no effect on HbA1c, fasting plasma glucose (FPG), or body weight. In 26-week, open-label clinical study (Study B, n=320), adults with type diabetes were randomized to twice-daily LEVEMIR (administered in the morning and bedtime) or once-daily insulin glargine (administered at bedtime). Insulin aspart was administered before each meal. LEVEMIR-treated patients had decrease in HbA1c similar to that of insulin glargine-treated patients. In 24-week, open-label clinical study (Study C, n=749), adults with type diabetes were randomized to once-daily LEVEMIR or once-daily NPH insulin, both administered at bedtime and in combination with regular human insulin before each meal. LEVEMIR and NPH insulin had similar effect on HbA1c. Table 8: Type Diabetes Mellitus AdultStudy AStudy BStudy CTreatment duration16 weeks26 weeks24 weeksTreatment in combination withNovoLog(insulin aspart)NovoLog(insulin aspart)Human Soluble Insulin(regular insulin)Twice-dailyLEVEMIRTwice-dailyNPHTwice-daily LEVEMIROnce-daily insulin glargineOnce-daily LEVEMIROnce-daily NPHNumber of patients treated276133161159492257HbA1c (%) Baseline HbA1c 8.68.58.98.88.48.3 Adj. mean change from baseline-0.8-0.7 -0.6 -0.5-0.1 0.0 LEVEMIR NPH 95% CI for Treatment difference-0.2(-0.3, -0.0)-0.0(-0.2, 0.2)-0.1(-0.3, 0.0)Fasting blood glucose (mg/dL) Baseline mean209220153150213206 Adj. mean change from baseline-44-9 -38 -41-30-9 From an ANCOVA model adjusted for baseline value and country.From an ANCOVA model adjusted for baseline value and study site.. 14.2 Type Diabetes Pediatric Two open-label, randomized, controlled clinical studies have been conducted in pediatric patients with type diabetes. One study was 26 weeks in duration and enrolled patients to 17 years of age. The other study was 52 weeks in duration and enrolled patients to 16 years of age. In both studies, LEVEMIR and NPH insulin were administered once- or twice-daily. Bolus insulin aspart was administered before each meal. In the 26-week study, LEVEMIR-treated patients had mean decrease in HbA1c similar to that of NPH insulin (Table 9). In the 52-week study, the randomization was stratified by age (2-5 years, n=82, and 6-16 years, n=265) and the mean HbA1c increased in both treatment arms, with similar findings in the 2-5 year-old age group (n=80) and the 6-16 year-old age group (n=258) (Table 9).Table 9: Type Diabetes Mellitus PediatricStudy DStudy ITreatment duration26 weeks52 weeksTreatment in combination withNovoLog(insulin aspart)NovoLog(insulin aspart)Once- or Twice Daily LEVEMIR Once- or Twice Daily NPH Once- or Twice Daily LEVEMIR Once- or Twice Daily NPH Number of subjects treated232115177170HbA1c (%) Baseline HbA1c 8.88.8 8.48.4 Adj. mean change from baseline-0.7-0.80.30.2 LEVEMIR NPH 95% CI for Treatment difference0.1-0.1; 0.30.1-0.1; 0.4Fasting blood glucose (mg/dL) Baseline mean181181 135141 Adj. mean change from baseline-39-21 -10 From an ANCOVA model adjusted for baseline value, geographical region, gender and age (covariate).From an ANCOVA model adjusted for baseline value, country, pubertal status at baseline and age (stratification factor).. 14.3 Type Diabetes Pregnancy In an open-label clinical study, women with type diabetes who were (between weeks and 12 of gestation) or intended to become pregnant were randomized 1:1 to LEVEMIR (once or twice daily) or NPH insulin (once, twice or thrice daily). Insulin aspart was administered before each meal. total of 152 women in the LEVEMIR arm and 158 women in the NPH arm were or became pregnant during the study (Total pregnant women 310). Approximately one 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 weeks of gestation. In the 310 pregnant women, the mean glycosylated hemoglobin (HbA1c) was <7% at 10, 12, and 24 weeks of gestation in both arms. In the intent-to-treat population, the adjusted mean HbA1c (standard error) at gestational week 36 was 6.27% (0.053) in LEVEMIR-treated patient (n=138) and 6.33% (0.052) in NPH-treated patients (n=145); the difference was not clinically significant.. 14.4 Type Diabetes Adult In 24-week, open-label, randomized, clinical study (Study E, n=476), LEVEMIR administered twice-daily (before breakfast and evening) was compared to NPH insulin administered twice-daily (before breakfast and evening) as part of regimen of stable combination therapy with one or two of the following oral antidiabetic medications: metformin, an insulin secretagogue, or an alpha-glucosidase inhibitor. All patients were insulin-naive at the time of randomization. LEVEMIR and NPH insulin similarly lowered HbA1c from baseline (Table 10).In 22-week, open-label, randomized, clinical study (Study F, n=395) in adults with type diabetes, LEVEMIR and NPH insulin were given once- or twice-daily as part of basal-bolus regimen with insulin aspart. As measured by HbA1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin.Table 10: Type Diabetes Mellitus AdultStudy EStudy FTreatment duration24 weeks22 weeksTreatment in combination withoral agentsinsulin aspartTwice-dailyLEVEMIRTwice-dailyNPHOnce- or Twice Daily LEVEMIR Once- or Twice Daily NPHNumber of subjects treated237239195200HbA1c (%) Baseline HbA1c 8.68.58.28.1 Adj. mean change from baseline-2.0-2.1-0.6-0.6 LEVEMIR NPH 95% CI for Treatment difference0.1(-0.0, 0.3)-0.1(-0.2, 0.1)Fasting blood glucose1 (mg/dL) Baseline mean179173-- Adj. mean change from baseline-69-74--1Study - Fasting blood glucose data not collected From an ANCOVA model adjusted for baseline value, country and oral antidiabetic treatment category.From an ANCOVA model adjusted for baseline value and country.Combination Therapy with Metformin and LiraglutideThis 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA1c 7-10%) on metformin (>=1500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin (>=1500 mg/day) and sulfonylurea. Patients who were on metformin and sulfonylurea discontinued the sulfonylurea then all patients entered 12-week run-in period during which they received add-on therapy with liraglutide titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA1c <7% with liraglutide 1.8 mg and metformin and continued treatment in non-randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in period with approximately one-half of these patients doing so because of gastrointestinal adverse reactions. The remaining 323 patients with HbA1c >=7% (33% of those who entered the run-in period) were randomized to 26 weeks of once-daily LEVEMIR administered in the evening as add-on therapy (N=162) or to continued, unchanged treatment with liraglutide 1.8 mg and metformin (N=161). The starting dose of LEVEMIR was 10 units/day and the mean dose at the end of the 26-week randomized period was 39 units/day. During the 26-week randomized treatment period, the percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment with liraglutide 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with LEVEMIR. Treatment with LEVEMIR as add-on to liraglutide 1.8 mg metformin resulted in statistically significant reductions in HbA1c and FPG compared to continued, unchanged treatment with liraglutide 1.8 mg metformin alone (Table 11). From mean baseline body weight of 96 kg after randomization, there was mean reduction of 0.3 kg in the patients who received LEVEMIR add-on therapy compared to mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide 1.8 mg metformin alone.Table 11: Results of 26-week Open-label Trial of LEVEMIR as Add-on to Liraglutide Metformin Compared to Continued Treatment with Liraglutide Metformin Alone in Patients Not Achieving HbA1c 7% After 12 Weeks of Metformin and LiraglutideStudy HLEVEMIR Liraglutide +Metformin Liraglutide+MetforminIntent-to-Treat Population (N)a 162157HbA1c (%) (Mean) Baseline (week 0)7.67.6 Adjusted mean change from baseline-0.50 Difference from liraglutide metformin arm (LS mean)b 95% Confidence Interval-0.5 (-0.7, -0.4)Percentage of patients achieving A1c <7% 4317Fasting Plasma Glucose (mg/dL) (Mean) Baseline (week 0)166 159 Adjusted mean change from baseline-38-7 Difference from liraglutide metformin arm (LS mean)b 95% Confidence Interval-31(-39, -23)aIntent-to-treat population using last observation on studybLeast squares mean adjusted for baseline value From an ANCOVA model adjusted for baseline value, country and previous oral antidiabetic treatment category. From logistic regression model adjusted for baseline HbA1c. p-value <0.0001.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. LEVEMIR is contraindicated:oDuring episodes of hypoglycemia [see Warnings and Precautions (5.3)]oIn patients with hypersensitivity to LEVEMIR or any of its excipients. Reactions have included anaphylaxis [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].. oDuring episodes of hypoglycemia [see Warnings and Precautions (5.3)]. oIn patients with hypersensitivity to LEVEMIR or any of its excipients. Reactions have included anaphylaxis [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].. oDuring episodes of hypoglycemia (4)oHypersensitivity to LEVEMIR or any of its excipients (4). oDuring episodes of hypoglycemia (4). oHypersensitivity to LEVEMIR or any of its excipients (4).

DESCRIPTION SECTION.


11 DESCRIPTION. LEVEMIR (insulin detemir injection) is solution for subcutaneous use. Insulin detemir is long-acting recombinant human insulin analog. LEVEMIR is produced by 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 C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has molecular formula of C267H402O76N64S6 and molecular weight of 5916.9. It has the following structure:Figure 1: Structural Formula of Insulin DetemirLEVEMIR is clear, colorless, aqueous, neutral sterile solution. Each milliliter of LEVEMIR contains 100 units (14.2 mg/mL) insulin detemir, 65.4 mcg zinc, 2.06 mg m-cresol, 16.0 mg glycerol, 1.80 mg phenol, 0.89 mg disodium phosphate dihydrate, 1.17 mg sodium chloride, and water for injection. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. LEVEMIR has pH of approximately 7.4.. S:\SMART\LABELING\PRODUCTS\Levemir\FIGURES\Chemical Structure.jpg.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. oSee Full Prescribing Information for important administration instructions (2.1).oInject subcutaneously into the thigh, upper arm, or abdomen (2.1).oRotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis (2.1).oIndividualize and titrate the dose of LEVEMIR based on the patients metabolic needs, blood glucose monitoring results, and glycemic control goal (2.2).oAdminister subcutaneously once daily or in divided doses twice daily (2.2).oSee Full Prescribing Information for recommended starting dose in insulin naive patients and patients already on insulin therapy (2.3, 2.4).. oSee Full Prescribing Information for important administration instructions (2.1).. oInject subcutaneously into the thigh, upper arm, or abdomen (2.1).. oRotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis (2.1).. oIndividualize and titrate the dose of LEVEMIR based on the patients metabolic needs, blood glucose monitoring results, and glycemic control goal (2.2).. oAdminister subcutaneously once daily or in divided doses twice daily (2.2).. oSee Full Prescribing Information for recommended starting dose in insulin naive patients and patients already on insulin therapy (2.3, 2.4).. 2.1 Important Administration Instructions. oAlways check insulin labels before administration [see Warnings and Precautions (5.4)].oVisually inspect for particulate matter and discoloration. Only use LEVEMIR if the solution appears clear and colorless.oInject LEVEMIR subcutaneously into the thigh, upper arm, or abdomen.oRotate 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)].oDuring changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)]. oUse LEVEMIR FlexTouch with caution in patients with visual impairment who may rely on audible clicks to dial their dose.oDo not dilute or mix LEVEMIR with any other insulin or solution.oDo not administer LEVEMIR intravenously or in an insulin infusion pump.. oAlways check insulin labels before administration [see Warnings and Precautions (5.4)].. oVisually inspect for particulate matter and discoloration. Only use LEVEMIR if the solution appears clear and colorless.. oInject LEVEMIR subcutaneously into the thigh, upper arm, or abdomen.. oRotate 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)].. oDuring changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)]. oUse LEVEMIR FlexTouch with caution in patients with visual impairment who may rely on audible clicks to dial their dose.. oDo not dilute or mix LEVEMIR with any other insulin or solution.. oDo not administer LEVEMIR intravenously or in an insulin infusion pump.. 2.2 General Dosing Instructions. oLEVEMIR 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.oLEVEMIR FlexTouch dials in 1-unit increments.oIndividualize and titrate the dose of LEVEMIR based on the patients metabolic needs, blood glucose monitoring results, and glycemic control goal.oDose 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)].oIn patients with type diabetes, LEVEMIR must be used in regimen with rapid-acting or short-acting insulin.. oLEVEMIR 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.. oLEVEMIR FlexTouch dials in 1-unit increments.. oIndividualize and titrate the dose of LEVEMIR based on the patients metabolic needs, blood glucose monitoring results, and glycemic control goal.. oDose 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)].. oIn patients with type diabetes, LEVEMIR must be used in regimen with rapid-acting or short-acting insulin.. 2.3 Starting Dose in Insulin Naive Patients oThe recommended starting dose of LEVEMIR in patients with type 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 general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to calculate the initial total daily insulin dose in insulin naive patients with type diabetes.oThe recommended starting dose of LEVEMIR in patients with type diabetes mellitus inadequately controlled on oral antidiabetic medications or 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 twice daily regimen.. oThe recommended starting dose of LEVEMIR in patients with type 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 general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to calculate the initial total daily insulin dose in insulin naive patients with type diabetes.. oThe recommended starting dose of LEVEMIR in patients with type diabetes mellitus inadequately controlled on oral antidiabetic medications or 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 twice daily regimen.. 2.4 Starting Dose in Patients Already on Insulin Therapy. oIf converting from insulin glargine to LEVEMIR, the change can be done on unit-to-unit basis.oIf converting from NPH insulin, the change can be done on unit-to-unit basis. However, some patients with type diabetes mellitus may require more LEVEMIR than NPH insulin, as observed in one trial [see Clinical Studies (14)].. oIf converting from insulin glargine to LEVEMIR, the change can be done on unit-to-unit basis.. oIf converting from NPH insulin, the change can be done on unit-to-unit basis. However, some patients with type diabetes mellitus may require more LEVEMIR than NPH insulin, as observed in one trial [see Clinical Studies (14)].

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Injection: 100 unit per mL (U-100), is clear, colorless, solution available as:o3 mL single-patient-use LEVEMIR FlexTouch prefilled peno10 mL multiple-dose vial. o3 mL single-patient-use LEVEMIR FlexTouch prefilled pen. o10 mL multiple-dose vial. Injection 100 units/mL (U-100) available as:o3 mL single-patient-use LEVEMIR FlexTouch (R) prefilled pen (3)o10 mL multiple-dose vial (3). o3 mL single-patient-use LEVEMIR FlexTouch (R) prefilled pen (3). o10 mL multiple-dose vial (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Table includes clinically significant drug interactions with LEVEMIR.Table 7: 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: Dose 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: Dose 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: Dose 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. oDrugs that Increase Hypoglycemia Risk or Increase or Decrease Blood Glucose Lowering Effect: Adjustment of dosage may be needed; closely monitor blood glucose (7). oDrugs that Blunt Hypoglycemia Signs and Symptoms (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Increased frequency of glucose monitoring may be required (7).. oDrugs that Increase Hypoglycemia Risk or Increase or Decrease Blood Glucose Lowering Effect: Adjustment of dosage may be needed; closely monitor blood glucose (7). oDrugs that Blunt Hypoglycemia Signs and Symptoms (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Increased frequency of glucose monitoring may be required (7).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)Never Share LEVEMIR FlexTouch between PatientsAdvise patients that they must never share LEVEMIR FlexTouch pen with another person, even if the needle is changed. Advise patients using LEVEMIR vials not to share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)]. Hypoglycemia Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of LEVEMIR therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of hypoglycemia.Inform patients that their ability to concentrate and react may be impaired as result of hypoglycemia. 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)]. 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)]. 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(R), Levemir(R), NovoLog(R), FlexTouch(R) NovoFine(R), and NovoTwist(R) are registered trademarks of Novo Nordisk A/S.Patent Information: https://www.novonordisk-us.com/products/product-patents.html(C) 2005-2020 Novo NordiskManufactured by:Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkFor information about LEVEMIR contact:Novo Nordisk Inc.800 Scudders Mill RoadPlainsboro, New Jersey 085361-800-727-6500www.novonordisk-us.com.

LACTATION SECTION.


8.2 Lactation Risk SummaryAvailable 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 mothers clinical need for LEVEMIR and any potential adverse effects on the breastfed infant from LEVEMIR or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.


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.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Standard 2-year carcinogenicity studies in animals have not been performed. Insulin detemir tested negative for genotoxic potential in the in vitro reverse mutation study in bacteria, human peripheral blood lymphocyte chromosome aberration test, and the in vivo mouse micronucleus test.In 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 human dose of 0.5 units/kg/day, based on plasma AUC ratio). There were no effects on fertility in the rat.

OVERDOSAGE SECTION.


10 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. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


insulin detemir. Label Image.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety and effectiveness of LEVEMIR to improve glycemic control in type and type diabetes mellitus have been established in pediatric patients. The use of LEVEMIR for this indication is supported by evidence from an adequate and well-controlled study in 694 pediatric patients aged to 17 years with type 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 (14.4)].

PHARMACODYNAMICS SECTION.


12.2 Pharmacodynamics. Insulin detemir is soluble, long-acting basal human insulin analog with up to 24-hour duration of action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak. The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir molecules from the injection site due to self-association of the drug molecules. In addition, the distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin.Figure shows results from study in patients with type diabetes conducted for maximum of 24 hours after the subcutaneous injection of LEVEMIR. The mean time between injection and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to 24 hours (24 hours was the end of the observation period).Figure 2: Activity Profiles in Patients with Type Diabetes in 24-hour Glucose Clamp StudyFor doses in the interval of 0.2 to 0.4 units/kg, insulin detemir exerts more than 50% of its maximum effect from to hours up to approximately 14 hours after dose administration. Figure shows glucose infusion rate results from 16-hour glucose clamp study in patients with type diabetes. The clamp study was terminated at 16 hours according to protocol.Figure 3: Activity Profiles in Patients with Type Diabetes in 16-hour Glucose Clamp Study. Figure 2: Activity Profiles in Patients with Type Diabetes. Figure 3: Activity Profiles in Patients with Type Diabetes.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. AbsorptionAfter subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin detemir serum concentrations had relatively constant concentration/time profile over 24 hours with the maximum serum concentration (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and AUC0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and abdominal regions. The absolute bioavailability of insulin detemir is approximately 60%.DistributionInsulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein-bound drugs.EliminationAfter subcutaneous administration in patients with type diabetes, insulin detemir has terminal half-life of to hours depending on dose.Specific PopulationsPediatric PatientsThe pharmacokinetic properties of LEVEMIRwere studied in pediatric patients 6-12 years, 13-17 years, and adults with type diabetes. In pediatric patients 6-12 years, the insulin detemir plasma area under the curve (AUC) and Cmax were increased by 10% and 24%, respectively, as compared to adults. There was no difference in pharmacokinetics between pediatric patients 13-17 years and adults.GeriatricsIn clinical trial studying differences in pharmacokinetics of single subcutaneous dose of LEVEMIR in young (20 to 35 years) versus elderly (>=68 years) healthy subjects, the insulin detemir AUC was up to 35% higher among the elderly subjects due to reduced clearance [see Use in Specific Populations (8.5)]. Gender No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed between males and females.RaceIn two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and pharmacodynamics of LEVEMIR were studied in clamp study comparing patients with type diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR were comparable in these three populations.Renal impairmentA single subcutaneous dose of 0.2 units/kg of LEVEMIR was administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate, severe, and hemodialysis-dependent). In this study, there were no differences in the pharmacokinetics of LEVEMIR between healthy subjects and those with renal impairment[see Use in Specific Populations (8.6)].Hepatic impairmentA single subcutaneous dose of 0.2 units/kg of LEVEMIR was administered to healthy subjects and those with varying degrees of hepatic impairment (mild, moderate and severe). LEVEMIR exposure as estimated by AUC decreased with increasing degrees of hepatic impairment with corresponding increase in apparent clearance [see Use in Specific Populations (8.7)].SmokingThe effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied.LiraglutideNo pharmacokinetic interaction was observed between liraglutide and LEVEMIR when separate subcutaneous injections of LEVEMIR 0.5 units/kg (single-dose) and liraglutide 1.8 mg (steady state) were administered in patients with type diabetes.

PREGNANCY SECTION.


8.1 Pregnancy. Risk SummaryAvailable data from published studies and postmarketing case reports with LEVEMIR use in pregnant women have not identified drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In randomized, parallel-group, open-label clinical trial that included 152 pregnant women with type diabetes who were administered LEVEMIR once or twice daily, beginning in gestational weeks to 12 or prior to conception, no clear evidence of maternal or fetal risk attributed to LEVEMIR were observed [see Adverse Reactions (6.1)and Clinical Studies (14)]. 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 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). The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20-25% in women with an 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. Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPoorly 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.DataAnimal DataIn 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 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 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 dose of 900 nmol/kg/day. The rat and rabbit embryofetal 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.

RECENT MAJOR CHANGES SECTION.


Dosage and Administration (2.1) 11/2019Warnings and Precautions (5.2) 11/2019.

SPL PATIENT PACKAGE INSERT SECTION.


Patient Information. Patient InformationLEVEMIR(R) (LEV-uh-mere)(insulin detemir injection)Do not share your Levemir FlexTouch with other people, even if the needle has been changed. You may give other people serious infection, or get serious infection from them.What is LevemiroLevemir is man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus.oLevemir is not meant for use to treat diabetic ketoacidosis.Who should not take LevemirDo not take Levemir if you:ohave an allergy to Levemir or any of the ingredients in Levemir.Before taking Levemir, tell your healthcare provider about all your medical conditions including, if you are:opregnant, planning to become pregnant, or are breastfeeding.otaking new prescription or over-the-counter medicines, vitamins, or herbal supplements.Before you start taking Levemir, talk to your healthcare provider about low blood sugar and how to manage it. How should take LevemiroRead the Instructions for Use that come with your Levemir.oTake Levemir exactly as your healthcare provider tells you to.oKnow the type and strength of insulin you take. Do not change the type of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin.oCheck your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.oDo not reuse or share your needles or syringes with other people. You may give other people serious infection, or get serious infection from them.oLevemir is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).oNever inject Levemir into vein or muscle.oChange (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.oDo not use the exact same spot for each injection.oDo not inject where the skin has pits, is thickened, or has lumps.oDo not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.What should avoid while taking LevemirWhile taking Levemir do not:oDrive or operate heavy machinery, until you know how Levemir affects you.oDrink alcohol or use prescription or over-the-counter medicines that contain alcohol.What are the possible side effects of LevemirLevemir may cause serious side effects that can lead to death, including: Low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:odizziness or light-headednessosweatingoconfusionoheadacheoblurred visionoslurred speechoshakinessofast heart beatoanxiety, irritability, or mood changesohungerYour insulin dose may need to change because of: ochange in level of physical activity or exerciseoweight gain or lossoincreased stressoillnessochange in dietOther common side effects of Levemir may include:oReactions at the injection site, itching, rash, serious allergic reactions (whole body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain, and swelling of your hands and feet. Get emergency medical help if you have:otrouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.These are not all the possible side effects of Levemir. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.What are the ingredients in LevemirActive Ingredient: insulin detemirInactive Ingredients: zinc, m-cresol, glycerol, phenol, disodium phosphate dihydrate, sodium chloride and water for injection. Hydrochloric acid or sodium hydroxide may be added.Manufactured by: Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkFor more information, go to www.novonordisk-us.com or call 1-800-727-6500.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2019Patient Instructions For Use LEVEMIR (R) 10 mL multiple-dose vial Please read the following Instructions for use carefully before using your LEVEMIR(R) 10 mL vial and each time you get refill. You should read the instructions in this manual even if you have used an insulin 10 mL vial before.How should use the LEVEMIR 10 mL vialUsing the 10 mL vial:1. Check to make sure that you have the correct type of insulin. This is especially important if you use different types of insulin.2. Look at the vial and the insulin. The LEVEMIR insulin should be clear and colorless. The tamper-resistant cap should be in place before the first use. If the cap has been removed before your first use of the vial, or if the insulin is cloudy or colored, do not use the insulin and return it to your pharmacy.3. Wash your hands with soap and water.4. If you are using new vial, pull off the tamper-resistant cap. Before each use, wipe the rubber stopper with an alcohol wipe.5. Do not roll or shake the vial. Shaking the vial right before the dose is drawn into the syringe may cause bubbles or foam. This can cause you to draw up the wrong dose of insulin. The insulin should be used only if it is clear and colorless.6. Pull back the plunger on your syringe until the black tip reaches the marking for the number of units you will inject.7. Push the needle through the rubber stopper into the vial.8. Push the plunger all the way in. This inserts air into the vial.9. Turn the vial and syringe upside down and slowly pull the plunger back to few units beyond the correct dose that you need.10. If there are air bubbles, tap the syringe gently with your finger to raise the air bubbles to the top of the needle. Then slowly push the plunger to the correct unit marking for your dose.11. Check to make sure you have the right dose of LEVEMIR in the syringe.12. Pull the syringe out of the vial.13. Inject your LEVEMIR right away as instructed by your healthcare provider. Levemir can be injected under the skin (subcutaneously) of your stomach area (abdomen), upper legs (thighs) or upper arms. For each injection, change (rotate) your injection site within the area of skin that you use to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not use the same injection site for each injection. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.How should inject LEVEMIR with syringeIf you clean your injection site with an alcohol swab, let the injection site dry before you inject. Talk with your healthcare provider about how to rotate injection sites and how to give an injection.1. Pinch your skin between two fingers, push the needle into the skinfold, using dart-like motion and push the plunger to inject the insulin under your skin. The needle will be straight in.2. Keep the needle under your skin for at least seconds to make sure you have injected all the insulin. After you pull the needle from your skin you may see drop of Levemir at the needle tip. This is normal and has no effect on the dose you just received. 3. If blood appears after you pull the needle from your skin, press the injection site lightly with an alcohol swab. Do not rub the area.4. After each injection, remove the needle without recapping and dispose of it in puncture-resistant container. Used vials, syringes, needles, and lancets should be placed in sharps containers (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly.How should store LEVEMIRoDo not freeze LEVEMIR. Do not use LEVEMIR if it has been frozen.oKeep LEVEMIR away from heat or light.oAll unopened vials:oStore unopened LEVEMIR vials in the refrigerator at 36F to 46F (2C to 8C). oUnopened vials may be used until the expiration date printed on the label, if they have been stored in the refrigerator. oUnopened vials should be thrown away after 42 days, if they are stored at room temperature below 86F (30C).oAfter vials have been opened:oOpened LEVEMIRvials can be stored in the refrigerator at 36F to 46F (2C to 8C) or at room temperature below 86F (30C). oThrow away all opened LEVEMIR vials after 42 days, even if they still have insulin left in them. Revised: 11/2019Novo Nordisk(R) and LEVEMIR(R) are registered trademarks of Novo Nordisk A/S.PATENT Information: https://www.novonordisk-us.com/products/product-patents.html(C) 2005-2019 Novo NordiskManufactured by:Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkFor information about LEVEMIR(R) contact:Novo Nordisk Inc.800 Scudders Mill Road Plainsboro, New Jersey 08536Instructions for UseLevemir(R) (LEV-uh-mere) FlexTouch(R) Pen(insulin detemir injection)oDo not share your Levemir FlexTouch Pen with other people, even if the needle has been changed. You may give other people serious infection, or get serious infection from them.oLevemir FlexTouch Pen (Pen) is prefilled disposable, single-patient-use pen containing 300 units of U-100 Levemir (insulin detemir injection) insulin. You can inject from to 80 units in single injection.oPeople who are blind or have vision problems should not use this Pen without help from person trained to use the Pen.Supplies you will need to give your Levemir injection:oLevemir FlexTouch Penoa new NovoFine, NovoFine Plus or NovoTwist needleoalcohol swabo1 sharps container for throwing away used Pens and needles. See Disposing of used Levemir FlexTouch Pens and needles at the end of these instructions.Preparing your Levemir FlexTouch Pen:Wash your hands with soap and water.Before you start to prepare your injection, check the Levemir FlexTouch Pen label to make sure you are taking the right type of insulin. This is especially important if you take more than type of insulin.Levemir should look clear and colorless. Do not use Levemir if it is thick, cloudy, or is colored.Do not use Levemir past the expiration date printed on the label or 42 days after you start using the Pen.Always use new needle for each injection to help ensure sterility and prevent blocked needles. Do not reuse or share your needles with other people. You may give other people serious infection, or get serious infection from them.Step 1:oPull Pen cap straight off (See Figure B).Step 2:oCheck the liquid in the Pen (See Figure C). Levemir should look clear and colorless. Do not use it if it looks cloudy or colored.Step 3:oSelect new needle.oPull off the paper tab from the outer needle cap (See Figure D).Step 4:Push the capped needle straight onto the Pen and twist the needle on until it is tight (See Figure E).Step 5:Pull off the outer needle cap. Do not throw it away (See Figure F).Step 6:Pull off the inner needle cap and throw it away (See Figure G).Priming your Levemir FlexTouch Pen:Step 7:oTurn the dose selector to select units (See Figure H).Step 8:oHold the Pen with the needle pointing up. Tap the top of the Pen gently few times to let any air bubbles rise to the top (See Figure I).Step 9:Hold the Pen with the needle pointing up. Press and hold in the dose button until the dose counter shows 0. The 0 must line up with the dose pointer. drop of insulin should be seen at the needle tip (See Figure J). oIf you do not see drop of insulin, repeat steps to 9, no more than times. oIf you still do not see drop of insulin, change the needle and repeat steps to 9. Selecting your dose:Step 10:oTurn the dose selector to select the number of units you need to inject. The dose pointer should line up with your dose (See Figure K).oIf you select the wrong dose, you can turn the dose selector forwards or backwards to the correct dose.oThe even numbers are printed on the dial.oThe odd numbers are shown as lines. oThe Levemir FlexTouch Pen insulin scale will show you how much insulin is left in your Pen (See Figure L).oTo see how much insulin is left in your Levemir FlexTouch Pen:oTurn the dose selector until it stops. The dose counter will line up with the number of units of insulin that is left in your Pen. If the dose counter shows 80, there are at least 80 units left in your Pen. oIf the dose counter shows less than 80, the number shown in the dose counter is the number of units left in your Pen.Giving your injection:oInject your Levemir exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you need to pinch the skin before injecting. oLevemir can be injected under the skin (subcutaneously) of your stomach area (abdomen), upper legs (thighs) or upper arms.oFor each injection, change (rotate) your injection site within the area of skin that you use to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not use the same injection site for each injection. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Step 11:oChoose your injection site and wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose (See Figure M).Step 12:oInsert the needle into your skin (See Figure N).oMake sure you can see the dose counter. Do not cover it with your fingers; this can stop your injection. Step 13:oPress and hold down the dose button until the dose counter shows 0 (See Figure O). oThe 0 must line up with the dose pointer. You may then hear or feel click.oKeep the needle in your skin after the dose counter has returned to 0 and slowly count to (See Figure P).oWhen the dose counter returns to 0, you will not get your full dose until seconds later. oIf the needle is removed before you count to 6, you may see stream of insulin coming from the needle tip. oIf you see stream of insulin coming from the needle tip you will not get your full dose. If this happens you should check your blood sugar levels more often because you may need more insulin.Step 14:oPull the needle out of your skin (See Figure Q). oIf you see blood after you take the needle out of your skin, press the injection site lightly with piece of gauze or an alcohol swab. Do not rub the area.Step 15:oCarefully remove the needle from the Pen and throw it away (See Figure R). oDo not recap the needle. Recapping the needle can lead to needle stick injury. oIf you do not have sharps container, carefully slip the needle into the outer needle cap (See Figure S). Safely remove the needle and throw it away as soon as you can. oDo not store the Pen with the needle attached. Storing without the needle attached helps prevent leaking, blocking of the needle, and air from entering the Pen.Step 16: oReplace the Pen cap by pushing it straight on (See Figure T).After your injection:oYou can put your used Levemir FlexTouch Pen and needles in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and Pens in your household trash. oIf you do not have FDA-cleared sharps disposal container, you may use household container that is:omade of heavy-duty plasticocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come outoupright and stable during useoleak-resistantoproperly labeled to warn of hazardous waste inside the containeroWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. Do not reuse or share your needles or syringes with other people. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.oDo not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.How should store my Levemir FlexTouch PenoStore unused Levemir FlexTouch Pens in the refrigerator at 36F to 46F (2C to 8C). oStore the Pen you are currently using out of the refrigerator below 86F.oDo not freeze Levemir. Do not use Levemir if it has been frozen.oKeep Levemir away from heat or light.oUnused Pens may be used until the expiration date printed on the label, if kept in the refrigerator.oThe Levemir FlexTouch Pen you are using should be thrown away after 42 days, even if it still has insulin left in it.General Information about the safe and effective use of Levemir:oKeep Levemir FlexTouch Pens and needles out of the reach of children.oAlways use new needle for each injection.oDo not share your Levemir FlexTouch Pen or needles with other people. You may give other people serious infection, or get serious infection from them. This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by:Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkRevised: 11/2019For more information go towww.novotraining.com/levemirflextouch/us02(C) 2005-2019 Novo NordiskLevemir(R) FlexTouch(R) Read before first use. oLevemir is man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus.. oLevemir is not meant for use to treat diabetic ketoacidosis.. ohave an allergy to Levemir or any of the ingredients in Levemir.. opregnant, planning to become pregnant, or are breastfeeding.. otaking new prescription or over-the-counter medicines, vitamins, or herbal supplements.. oRead the Instructions for Use that come with your Levemir.. oTake Levemir exactly as your healthcare provider tells you to.. oKnow the type and strength of insulin you take. Do not change the type of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin.. oCheck your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.. oDo not reuse or share your needles or syringes with other people. You may give other people serious infection, or get serious infection from them.. oLevemir is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).. oNever inject Levemir into vein or muscle.. oChange (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.. oDo not use the exact same spot for each injection.. oDo not inject where the skin has pits, is thickened, or has lumps.. oDo not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. oDrive or operate heavy machinery, until you know how Levemir affects you.. oDrink alcohol or use prescription or over-the-counter medicines that contain alcohol.. odizziness or light-headedness. osweating. oconfusion. oheadache. oblurred vision. oslurred speech. oshakiness. ofast heart beat. oanxiety, irritability, or mood changes. ohunger. ochange in level of physical activity or exercise. oweight gain or loss. oincreased stress. oillness. ochange in diet. oReactions at the injection site, itching, rash, serious allergic reactions (whole body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain, and swelling of your hands and feet. otrouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.. oDo not freeze LEVEMIR. Do not use LEVEMIR if it has been frozen.. oKeep LEVEMIR away from heat or light.. oAll unopened vials:oStore unopened LEVEMIR vials in the refrigerator at 36F to 46F (2C to 8C). oUnopened vials may be used until the expiration date printed on the label, if they have been stored in the refrigerator. oUnopened vials should be thrown away after 42 days, if they are stored at room temperature below 86F (30C).. oStore unopened LEVEMIR vials in the refrigerator at 36F to 46F (2C to 8C). oUnopened vials may be used until the expiration date printed on the label, if they have been stored in the refrigerator. oUnopened vials should be thrown away after 42 days, if they are stored at room temperature below 86F (30C).. oAfter vials have been opened:. oOpened LEVEMIRvials can be stored in the refrigerator at 36F to 46F (2C to 8C) or at room temperature below 86F (30C). oThrow away all opened LEVEMIR vials after 42 days, even if they still have insulin left in them. oDo not share your Levemir FlexTouch Pen with other people, even if the needle has been changed. You may give other people serious infection, or get serious infection from them.. oLevemir FlexTouch Pen (Pen) is prefilled disposable, single-patient-use pen containing 300 units of U-100 Levemir (insulin detemir injection) insulin. You can inject from to 80 units in single injection.. oPeople who are blind or have vision problems should not use this Pen without help from person trained to use the Pen.. oLevemir FlexTouch Pen. oa new NovoFine, NovoFine Plus or NovoTwist needle. oalcohol swab. o1 sharps container for throwing away used Pens and needles. See Disposing of used Levemir FlexTouch Pens and needles at the end of these instructions.. oPull Pen cap straight off (See Figure B).. oCheck the liquid in the Pen (See Figure C). Levemir should look clear and colorless. Do not use it if it looks cloudy or colored.. oSelect new needle.. oPull off the paper tab from the outer needle cap (See Figure D).. oTurn the dose selector to select units (See Figure H).. oHold the Pen with the needle pointing up. Tap the top of the Pen gently few times to let any air bubbles rise to the top (See Figure I).. oIf you do not see drop of insulin, repeat steps to 9, no more than times. oIf you still do not see drop of insulin, change the needle and repeat steps to 9. oIf you do not see drop of insulin, repeat steps to 9, no more than times. oIf you still do not see drop of insulin, change the needle and repeat steps to 9. oTurn the dose selector to select the number of units you need to inject. The dose pointer should line up with your dose (See Figure K).oIf you select the wrong dose, you can turn the dose selector forwards or backwards to the correct dose.oThe even numbers are printed on the dial.oThe odd numbers are shown as lines. oIf you select the wrong dose, you can turn the dose selector forwards or backwards to the correct dose.. oThe even numbers are printed on the dial.. oThe odd numbers are shown as lines.. oThe Levemir FlexTouch Pen insulin scale will show you how much insulin is left in your Pen (See Figure L).. oTo see how much insulin is left in your Levemir FlexTouch Pen:. oTurn the dose selector until it stops. The dose counter will line up with the number of units of insulin that is left in your Pen. If the dose counter shows 80, there are at least 80 units left in your Pen. oIf the dose counter shows less than 80, the number shown in the dose counter is the number of units left in your Pen.. oInject your Levemir exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you need to pinch the skin before injecting. oLevemir can be injected under the skin (subcutaneously) of your stomach area (abdomen), upper legs (thighs) or upper arms.. oFor each injection, change (rotate) your injection site within the area of skin that you use to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not use the same injection site for each injection. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. oChoose your injection site and wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose (See Figure M).. oInsert the needle into your skin (See Figure N).. oMake sure you can see the dose counter. Do not cover it with your fingers; this can stop your injection. oPress and hold down the dose button until the dose counter shows 0 (See Figure O). oThe 0 must line up with the dose pointer. You may then hear or feel click.. oKeep the needle in your skin after the dose counter has returned to 0 and slowly count to (See Figure P).. oWhen the dose counter returns to 0, you will not get your full dose until seconds later. oIf the needle is removed before you count to 6, you may see stream of insulin coming from the needle tip. oIf you see stream of insulin coming from the needle tip you will not get your full dose. If this happens you should check your blood sugar levels more often because you may need more insulin.. oPull the needle out of your skin (See Figure Q). oIf you see blood after you take the needle out of your skin, press the injection site lightly with piece of gauze or an alcohol swab. Do not rub the area.. oCarefully remove the needle from the Pen and throw it away (See Figure R). oDo not recap the needle. Recapping the needle can lead to needle stick injury. oDo not recap the needle. Recapping the needle can lead to needle stick injury.. oIf you do not have sharps container, carefully slip the needle into the outer needle cap (See Figure S). Safely remove the needle and throw it away as soon as you can. oDo not store the Pen with the needle attached. Storing without the needle attached helps prevent leaking, blocking of the needle, and air from entering the Pen.. oDo not store the Pen with the needle attached. Storing without the needle attached helps prevent leaking, blocking of the needle, and air from entering the Pen.. oReplace the Pen cap by pushing it straight on (See Figure T).. oYou can put your used Levemir FlexTouch Pen and needles in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and Pens in your household trash. oIf you do not have FDA-cleared sharps disposal container, you may use household container that is:omade of heavy-duty plasticocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come outoupright and stable during useoleak-resistantoproperly labeled to warn of hazardous waste inside the container. omade of heavy-duty plastic. ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out. oupright and stable during use. oleak-resistant. oproperly labeled to warn of hazardous waste inside the container. oWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. Do not reuse or share your needles or syringes with other people. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.. oDo not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.. oStore unused Levemir FlexTouch Pens in the refrigerator at 36F to 46F (2C to 8C). oStore the Pen you are currently using out of the refrigerator below 86F.. oDo not freeze Levemir. Do not use Levemir if it has been frozen.. oKeep Levemir away from heat or light.. oUnused Pens may be used until the expiration date printed on the label, if kept in the refrigerator.. oThe Levemir FlexTouch Pen you are using should be thrown away after 42 days, even if it still has insulin left in it.. oKeep Levemir FlexTouch Pens and needles out of the reach of children.. oAlways use new needle for each injection.. oDo not share your Levemir FlexTouch Pen or needles with other people. You may give other people serious infection, or get serious infection from them. Figure 4A. Figure 4B. Figure 6. Figure 7. Figure 8. Figure 9. Figure 10. Figure 1. Needle components.. Figure FlexTouch pen components.. Step Fig B.jpg. Step Fig C.jpg. Figure D. Figure E. Figure F. Figure G. Step Fig H.jpg. Step Fig I.jpg. Step Fig J.jpg. Step 10 Fig K.jpg. Step 10 Fig L. Step 11 Fig M. Step 12 Fig N.jpg. Step 13 Fig O.jpg. Step 13 Fig P.jpg. Step 14 Fig Q.jpg. Step 15 Figure R. Step 15 Fig S.jpg. Step 16 Fig T.jpg. FlexTouch QR Code.

SPL UNCLASSIFIED SECTION.


2.1 Important Administration Instructions. oAlways check insulin labels before administration [see Warnings and Precautions (5.4)].oVisually inspect for particulate matter and discoloration. Only use LEVEMIR if the solution appears clear and colorless.oInject LEVEMIR subcutaneously into the thigh, upper arm, or abdomen.oRotate 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)].oDuring changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)]. oUse LEVEMIR FlexTouch with caution in patients with visual impairment who may rely on audible clicks to dial their dose.oDo not dilute or mix LEVEMIR with any other insulin or solution.oDo not administer LEVEMIR intravenously or in an insulin infusion pump.. oAlways check insulin labels before administration [see Warnings and Precautions (5.4)].. oVisually inspect for particulate matter and discoloration. Only use LEVEMIR if the solution appears clear and colorless.. oInject LEVEMIR subcutaneously into the thigh, upper arm, or abdomen.. oRotate 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)].. oDuring changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)]. oUse LEVEMIR FlexTouch with caution in patients with visual impairment who may rely on audible clicks to dial their dose.. oDo not dilute or mix LEVEMIR with any other insulin or solution.. oDo not administer LEVEMIR intravenously or in an insulin infusion pump.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from published studies and postmarketing case reports with LEVEMIR use in pregnant women have not identified drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In randomized, parallel-group, open-label clinical trial that included 152 pregnant women with type diabetes who were administered LEVEMIR once or twice daily, beginning in gestational weeks to 12 or prior to conception, no clear evidence of maternal or fetal risk attributed to LEVEMIR were observed [see Adverse Reactions (6.1)and Clinical Studies (14)]. 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 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). The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20-25% in women with an 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. Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPoorly 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.DataAnimal DataIn 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 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 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 dose of 900 nmol/kg/day. The rat and rabbit embryofetal 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 SummaryAvailable 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 mothers 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 type and type diabetes mellitus have been established in pediatric patients. The use of LEVEMIR for this indication is supported by evidence from an adequate and well-controlled study in 694 pediatric patients aged to 17 years with type 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 (14.4)]. 8.5 Geriatric Use. In clinical trials of LEVEMIR, 64 of 1624 patients (4%) in the type diabetes trials and 309 of 1082 patients (29%) in the type diabetes trials were 65 years or older. total of 52 (7 type 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 elderly patients, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in the elderly.. 8.6 Renal Impairment No difference was observed in the pharmacokinetics of LEVEMIR between non-diabetic individuals with renal impairment and healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with renal impairment. Careful glucose monitoring and dose adjustments of LEVEMIR, may be necessary in patients with renal impairment[see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin detemir compared to healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver impairment. Careful glucose monitoring and dose adjustments of LEVEMIR, may be necessary in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. oNever Share LEVEMIR FlexTouch between patients, even if the needle is changed (5.1).oHyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to patients 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).oHypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness (5.3).oHypoglycemia due to medication errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection (5.4).oHypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue LEVEMIR, monitor and treat if indicated (5.5).oHypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated (5.6).oFluid 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).. oNever Share LEVEMIR FlexTouch between patients, even if the needle is changed (5.1).. oHyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to patients 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).. oHypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness (5.3).. oHypoglycemia due to medication errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection (5.4).. oHypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue LEVEMIR, monitor and treat if indicated (5.5).. oHypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated (5.6).. oFluid 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 LEVEMIR FlexTouch Pen, Needle, or Syringe between Patients LEVEMIR FlexTouch 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 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 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 patients 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 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 an individual 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 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 HypoglycemiaThe 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 insulin preparations, the glucose lowering effect time course of LEVEMIR may vary among 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.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)]. When 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 HypoglycemiaPatients 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 basal insulin products and other insulins, particularly rapid-acting insulins, 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 and Allergic Reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LEVEMIR. 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 [see Contraindications (4)]. 5.6 Hypokalemia. All insulin products, including LEVEMIR, cause shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).. 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists. Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including LEVEMIR, and 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.