1 INDICATIONS AND USAGE •NovoLog is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus (1.1). 1.1 Treatment of Diabetes Mellitus NovoLog is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus.
3 DOSAGE FORMS AND STRENGTHS NovoLog is available in the following package sizes: each presentation contains 100 units of insulin aspart per mL (U-100). •10 mL vials •3 mL PenFill cartridges for the 3 mL PenFill cartridge delivery device (with or without the addition of a NovoPen® 3 PenMate®) with NovoFine® disposable needles •3 mL NovoLog FlexPen •3 mL NovoLog FlexTouch Each presentation contains 100 Units of insulin aspart per mL (U-100) •10 mL vials (3) •3 mL PenFill® cartridges for the 3 mL PenFill cartridge device (3) •3 mL NovoLog FlexPen® (3) •3 mL NovoLog FlexTouch® (3)
4 CONTRAINDICATIONS NovoLog is contraindicated •during episodes of hypoglycemia •in patients with hypersensitivity to NovoLog or one of its excipients. •Do not use during episodes of hypoglycemia (4). •Do not use in patients with hypersensitivity to NovoLog or one of its excipients.
5 WARNINGS AND PRECAUTIONS •Never share a NovoLog FlexPen, NovoLog FlexTouch, PenFill cartridge, or Penfill cartridge compatible insulin delivery device between patients, even if the needle is changed (5.1). •Hypoglycemia is the most common adverse effect of insulin therapy. Glucose monitoring is recommended for all patients with diabetes. Any change of insulin dose should be made cautiously and only under medical supervision (5.2, 5.3). •Insulin, particularly when given intravenously or in settings of poor glycemic control, can cause hypokalemia. Use caution in patients predisposed to hypokalemia (5.4). •Like all insulins, NovoLog requirements may be reduced in patients with renal impairment or hepatic impairment (5.5, 5.6). •Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with insulin products, including NovoLog (5.7). •Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including NovoLog (5.11). 5.1 Never Share a NovoLog FlexPen, NovoLog FlexTouch, PenFill Cartridge, or PenFill Cartridge Compatible Insulin Delivery Device Between Patients NovoLog FlexPen, NovoLog FlexTouch, PenFill cartridge, and PenFill cartridge compatible insulin delivery devices must never be shared between patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 Administration NovoLog has a more rapid onset of action and a shorter duration of activity than regular human insulin. An injection of NovoLog should immediately be followed by a meal within 5-10 minutes. Because of NovoLog’s short duration of action, a longer acting insulin should also be used in patients with type 1 diabetes and may also be needed in patients with type 2 diabetes. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using external pump infusion therapy. Any change of insulin dose should be made cautiously and only under medical supervision. Changing from one insulin product to another or changing the insulin strength may result in the need for a change in dosage. As with all insulin preparations, the time course of NovoLog action may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the site of injection, local blood supply, temperature, and physical activity. Patients who change their level of physical activity or meal plan may require adjustment of insulin dosages. Insulin requirements may be altered during illness, emotional disturbances, or other stresses. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure. 5.3 Hypoglycemia Hypoglycemia is the most common adverse effect of all insulin therapies, including NovoLog. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with NovoLog. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations [see Clinical Pharmacology (12) ]. Other factors such as changes in food intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions (7) ]. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., patients who are fasting or have erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control [see Drug Interactions (7) ]. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia. Intravenously administered insulin has a more rapid onset of action than subcutaneously administered insulin, requiring more close monitoring for hypoglycemia. 5.4 Hypokalemia All insulin products, including NovoLog, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations, and patients receiving intravenously administered insulin). 5.5 Renal Impairment As with other insulins, the dose requirements for NovoLog may be reduced in patients with renal impairment [see Use in Specific Populations (8.7) ]. 5.6 Hepatic Impairment As with other insulins, the dose requirements for NovoLog may be reduced in patients with hepatic impairment [see Use in Specific Populations (8.8) ]. 5.7 Hypersensitivity and Allergic Reactions Local Reactions - As with other insulin therapy, patients may experience redness, swelling, or itching at the site of NovoLog injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of NovoLog. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in NovoLog. Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin product, including NovoLog. Anaphylactic reactions with NovoLog have been reported post-approval. Generalized allergy to insulin may also cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled clinical trials, allergic reactions were reported in 3 of 735 patients (0.4%) treated with regular human insulin and 10 of 1394 patients (0.7%) treated with NovoLog. In controlled and uncontrolled clinical trials, 3 of 2341 (0.1%) NovoLog-treated patients discontinued due to allergic reactions. 5.8 Antibody Production Increases in anti-insulin antibody titers that react with both human insulin and insulin aspart have been observed in patients treated with NovoLog. Increases in anti-insulin antibodies are observed more frequently with NovoLog than with regular human insulin. Data from a 12-month controlled trial in patients with type 1 diabetes suggest that the increase in these antibodies is transient, and the differences in antibody levels between the regular human insulin and insulin aspart treatment groups observed at 3 and 6 months were no longer evident at 12 months. In this study these antibodies did not appear to cause deterioration in glycemic control or necessitate increases in insulin dose. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency towards hyperglycemia or hypoglycemia. 5.9 Mixing of Insulins •Mixing NovoLog with NPH human insulin immediately before injection attenuates the peak concentration of NovoLog, without significantly affecting the time to peak concentration or total bioavailability of NovoLog. If NovoLog is mixed with NPH human insulin, NovoLog should be drawn into the syringe first, and the mixture should be injected immediately after mixing. •The efficacy and safety of mixing NovoLog with insulin preparations produced by other manufacturers have not been studied. •Insulin mixtures should not be administered intravenously. 5.10 Continuous Subcutaneous Insulin Infusion by External Pump When used in an external subcutaneous insulin infusion pump, NovoLog should not be mixed with any other insulin or diluent. When using NovoLog in an external insulin pump, the NovoLog-specific information should be followed (e.g., in-use time, frequency of changing infusion sets) because NovoLog-specific information may differ from general pump manual instructions. Pump or infusion set malfunctions or insulin degradation can lead to a rapid onset of hyperglycemia and ketosis because of the small subcutaneous depot of insulin. This is especially pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have a shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim therapy with subcutaneous injection may be required [see Dosage and Administration (2.3), Warnings and Precautions (5.9 , 5.10), How Supplied/Storage and Handling (16.2), and Patient Counseling Information (17.3) ]. NovoLog should not be exposed to temperatures greater than 37°C (98.6°F). NovoLog that will be used in a pump should not be mixed with other insulin or with a diluent [see Dosage and Administration (2.3), Warnings and Precautions (5.9, 5.10), How Supplied/Storage and Handling (16.2), and Patient Counseling Information (17.3) ]. 5.11 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 NovoLog, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
6 ADVERSE REACTIONS 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. • Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including NovoLog [see Warnings and Precautions (5) ]. • Insulin initiation and glucose control intensification Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. • Lipodystrophy Long-term use of insulin, including NovoLog, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy. • Weight gain Weight gain can occur with some insulin therapies, including NovoLog, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. • Peripheral Edema Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. • Frequencies of adverse drug reactions The frequencies of adverse drug reactions during NovoLog clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below. Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus (Adverse events with frequency ≥ 5% and occurring more frequently with NovoLog compared to human regular insulin are listed) NovoLog + NPH N= 596 Human Regular Insulin + NPH N= 286 Preferred Term N (%) N (%) HypoglycemiaHypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See Section 14 for the incidence of serious hypoglycemia in the individual clinical trials. 448 75% 205 72% Headache 70 12% 28 10% Injury accidental 65 11% 29 10% Nausea 43 7% 13 5% Diarrhea 28 5% 9 3% Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus (except for hypoglycemia, adverse events with frequency ≥ 5% and occurring more frequently with NovoLog compared to human regular insulin are listed) NovoLog + NPH N= 91 Human Regular Insulin + NPH N= 91 N (%) N (%) HypoglycemiaHypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See Section 14 for the incidence of serious hypoglycemia in the individual clinical trials. 25 27% 33 36% Hyporeflexia 10 11% 6 7% Onychomycosis 9 10% 5 5% Sensory disturbance 8 9% 6 7% Urinary tract infection 7 8% 6 7% Chest pain 5 5% 3 3% Headache 5 5% 3 3% Skin disorder 5 5% 2 2% Abdominal pain 5 5% 1 1% Sinusitis 5 5% 1 1% Postmarketing Data The following additional adverse reactions have been identified during post-approval use of NovoLog. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency. Medication errors in which other insulins have been accidentally substituted for NovoLog have been identified during post-approval use [see Patient Counseling Information (17) ]. Adverse reactions observed with NovoLog include hypoglycemia, allergic reactions, local 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.
7 DRUG INTERACTIONS •Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed (7.1, 7.2, 7.3). •Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent (7.3, 7.4). 7.1 Drugs That May Increase the Risk of Hypoglycemia The risk of hypoglycemia associated with NovoLog use may be increased with antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Dose adjustment and increased frequency of glucose monitoring may be required when NovoLog is co-administered with these drugs. 7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of NovoLog The glucose lowering effect of NovoLog may be decreased when co-administered with 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. Dose adjustment and increased frequency of glucose monitoring may be required when NovoLog is co-administered with these drugs. 7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of NovoLog The glucose lowering effect of NovoLog may be increased or decreased when co-administered with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dose adjustment and increased frequency of glucose monitoring may be required when NovoLog is co-administered with these drugs. 7.4 Drugs That May Affect Hypoglycemia Signs and Symptoms The signs and symptoms of hypoglycemia may be blunted when beta-blockers, clonidine, guanethidine, and reserpine are co-administered with NovoLog.
8 USE IN SPECIFIC POPULATIONS •Pediatric: Has not been studied in children with type 2 diabetes. Has not been studied in children with type 1 diabetes <2 years of age (8.4). 8.1 Pregnancy Pregnancy Category B. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients. Therefore, female patients should be advised to tell their physician if they intend to become, or if they become pregnant while taking NovoLog. An open-label, randomized study compared the safety and efficacy of NovoLog (n=157) versus regular human insulin (n=165) in 322 pregnant women with type 1 diabetes. Two-thirds of the enrolled patients were already pregnant when they entered the study. Because only one-third of the patients enrolled before conception, the study was not large enough to evaluate the risk of congenital malformations. Both groups achieved a mean HbA1c of ~ 6% during pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia. Subcutaneous reproduction and teratology studies have been performed with NovoLog and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis. The effects of NovoLog did not differ from those observed with subcutaneous regular human insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at a dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and in rabbits at a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits, based on U/body surface area. 8.3 Nursing Mothers It is unknown whether insulin aspart is excreted in human milk. Use of NovoLog is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses. 8.4 Pediatric Use NovoLog is approved for use in children for subcutaneous daily injections and for subcutaneous continuous infusion by external insulin pump. NovoLog has not been studied in pediatric patients younger than 2 years of age. NovoLog has not been studied in pediatric patients with type 2 diabetes. Please see Section 14 CLINICAL STUDIES for summaries of clinical studies. 8.5 Geriatric Use Of the total number of patients (n= 1,375) treated with NovoLog in 3 controlled clinical studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type 1 diabetes (18/1285) and the other half had type 2 diabetes (18/90). The HbA1c response to NovoLog, as compared to human insulin, did not differ by age. 8.6 Gender There was no significant difference in efficacy noted (as assessed by HbA1c) between genders in a trial in patients with type 1 diabetes. 8.7 Renal Impairment Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be necessary in patients with renal impairment [see Warnings and Precautions (5.5) ]. 8.8 Hepatic Impairment Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be necessary in patients with hepatic impairment [see Warnings and Precautions (5.6) ].