ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. oHypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Novolin [ ]. see Warnings and Precautions ) 5.2 oInsulin initiation and glucose control intensificationIntensification or rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. Over the long-term, improved glycemic control decreases the risk of diabetic retinopathy and neuropathy.oLipodystrophyLong-term use of insulin, including Novolin R, 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. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy.oWeight gainWeight gain can occur with insulin therapies, including Novolin R, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.oPeripheral edemaInsulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. These symptoms are usually transitory.oAllergic reactionsAs with other insulins, Novolin can cause injection site reactions. Severe, life-threatening, generalized allergy, including anaphylaxis may occur with any insulin, including Novolin [ ]. see Warnings and Precautions ) 5.6 Clinical Trial ExperienceBecause 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.Adults with type or type diabetesThe incidence of adverse reactions during clinical trials comparing Novolin and insulin aspart in adults with type diabetes mellitus and type diabetes mellitus are listed in the tables below.Table 1: Adverse Reactions in 24-Week Trial Comparing Novolin and Insulin Aspart in Adults with Type Diabetes Mellitus Also Treated with NPH Insulin (adverse reactions with an incidence >= 5% in the Novolin treatment group are listed)Novolin + NPHN= 286Insulin aspart NPHN=596%%Hypoglycemia Hypoglycemia was defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. 7275Table 2: Adverse Reactions in 24-Week Trial Comparing Novolin and Insulin Aspart in Adults with Type Diabetes Mellitus Also Treated with NPH Insulin (adverse reactions with an incidence >= 5% in the Novolin treatment group are listed)Novolin + NPHN= 91Insulin aspart NPHN= 91(%)(%)Hypoglycemia Hypoglycemia was defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. 3627Children and adolescents with type diabetesThe incidence of adverse reactions during 24-week clinical trial comparing Novolin and insulin aspart in children and adolescents with type diabetes mellitus are listed in the table below.Table 3: Adverse Reactions in 24-Week Trial Comparing Novolin and Insulin Aspart in Children and Adolescents with Type Diabetes Mellitus Also Treated with NPH Insulin (adverse reactions with an incidence >=5% in the Novolin treatment group are listed)Novolin + NPHN= 96Insulin aspart NPHN= 187(%)(%)Hypoglycemia Hypoglycemia was defined as an episode of blood glucose concentration <50 mg/dL, with or without symptoms. 8579Injection site hypertrophy88Severe HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Novolin Tables and summarize the incidence of severe hypoglycemia in the Novolin clinical trials. Severe hypoglycemia was defined as hypoglycemia associated with central nervous system symptoms and requiring intervention of another person or hospitalization. The rates of severe hypoglycemia in the Novolin clinical trials (see Section 14 for description of the study designs) were comparable for all treatment regimens (see Tables and 5). [See Warnings and Precautions )]. 5.3 Table 4: Severe Hypoglycemia in Patients with Type DiabetesType DiabetesAdults24 weeks in combination with NPH insulinType DiabetesChildren and Adolescents(age 6-18)24 weeks in combination with NPH insulinType DiabetesChildren(age 2-6)24 weeks in combination with NPH insulinNovolin RInsulin aspartNovolin RInsulin aspartNovolin RInsulin aspartPercent of patients (n/total N)19(55/286)18(105/596)9(9/96)6(11/187)12(3/25)8(2/26)Event/patient/year1.10.90.30.20.50.3Table 5: Severe Hypoglycemia in Patients with Type DiabetesType DiabetesAdults24 weeks in combination withNPH insulinNovolin RInsulin aspartPercent of patients(n/total N)5(5/91)10(9/91)Event/patient/year0.20.3. oHypoglycemia. oInsulin initiation and glucose control intensification. oLipodystrophy. oWeight gain. oPeripheral edema. oAllergic reactions. Adverse reactions observed with Novolin include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, weight gain and edema ). To report SUSPECTED ADVERSE REACTIONS, contactNovo Nordisk Inc. at 1-800-727-6500or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of Novolin R.Novolin is not mutagenic in the following tests: The chromosomal aberration assay in human lymphocytes, the micronucleus assay in mouse polychromatic erythrocytes, and the mutation frequency assay in Chinese hamster cells. in vitro Standard reproduction and teratology studies in animals, including fertility assessments have not been conducted with Novolin R.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Novolin is available in 10 mL vials. The concentration of Novolin is 100 USP units of human insulin (rDNA origin)/mL. . Novolin is available in 10 mL vials. The concentration of Novolin is 100 USP units of human insulin (rDNA origin)/mL. . Novolin R, Regular, Human Insulin Injection (rDNA origin) USP, 100 units/mL (U-100), is supplied in 10 mL vials ).

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The primary activity of Novolin is the regulation of glucose metabolism. Insulins, including Novolin R, bind to insulin receptors on muscle and adipocytes and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.. 12.2 Pharmacodynamics. Novolin is short-acting insulin. When injected subcutaneously, the glucose-lowering effect of Novolin begins approximately 30 minutes post-dose, is maximal between 1.5 and 3.5 hours post-dose and terminates approximately hours post-dose. The onset of action of Novolin R, when administered intravenously, is more rapid in comparison to the subcutaneous administration. When injected subcutaneously, Novolin has slower onset of action and longer duration of action compared to the rapid-acting insulin analogs.. 12.3 Pharmacokinetics. After single subcutaneous administration of 0.1 unit/kg of Novolin to healthy subjects, peak insulin concentrations occurred between 1.5 to 2.5 hours post-dose. On average, insulin concentrations returned to baseline at around hours post-dose.The effects of sex, age, obesity, ethnic origin, renal and hepatic impairment, pregnancy, and smoking, on the pharmacodynamics and pharmacokinetics of Novolin have not been studied.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. Please see for information on the pharmacokinetics and pharmacodynamics of Novolin R. Section 12 CLINICAL PHARMACOLOGY 14.1 Type diabetes mellitus (adults). Two six-month, open-label, active-controlled studies were conducted to compare the safety and efficacy of Novolin and insulin aspart in adults with type diabetes. Insulin aspart was administered by subcutaneous injection immediately prior to meals and Novolin was administered by subcutaneous injection 30 minutes before meals. Both treatment groups also received subcutaneous injections of NPH insulin in either single or divided daily doses. Because the two study designs and results were similar, data are shown for only one study (see Table 6)Table 6: Subcutaneous Novolin Administration in Type Diabetes (24 weeks; N=882)Novolin + NPHN=286Insulin aspart NPH N=596Baseline HbA1c (%) Values are Mean +- SD 8.0 +- 1.27.9 +-1.1Change from Baseline HbA (%) 1c 0.0 +- 0.8-0.1 +- 0.8Treatment Difference in HbA Mean (95% confidence interval) 1c Novolin - insulin aspart group 0.2 [0.1; 0.3]Baseline, total insulin dose (units/kg/day) 0.7 +- 0.20.7 +- 0.2End-of-Study, total insulin dose (units/kg/day) 0.7 +- 0.20.7 +- 0.2Baseline body weight (kg) Weight Change from baseline (kg) 75.9 +- 13.10.9 +- 2.975.3 +- 14.50.5 +- 3.3. 14.2 Type diabetes mellitus (adults). six-month, open-label, active-controlled study was conducted to compare the safety and efficacy of Novolin and insulin aspart in adults with type diabetes (Table 7). Insulin aspart was administered by subcutaneous injection immediately prior to meals and Novolin was administered by subcutaneous injection 30 minutes before meals. Both treatment groups also received subcutaneous injections of NPH insulin in either single or divided daily doses.Table 7: Subcutaneous Novolin Administration in Type Diabetes (24 weeks; N=182)Novolin + NPHN 91Insulin aspart NPHN 91Baseline HbA (%) 1c Values are Mean +- SD 7.8 +- 1.18.1 +- 1.2Change from Baseline HbA (%) 1c -0.1 +- 0.8-0.3 +- 1.0Treatment Difference in HbA Mean (95% confidence interval) 1c, Novolin - insulin aspart group0.1 [-0.1; 0.4]Baseline, total insulin dose (units/kg/day) 0.6 +- 0.30.6 +- 0.3End-of-Study, total insulin dose (units/kg/day) 0.7 +- 0.30.7 +- 0.3Baseline body weight (kg) Weight Change from baseline (kg) 85.8 +- 14.80.4 +- 3.188.4+- 13.31.2+- 3.0. 14.3 Type diabetes mellitus (children and adolescents). six-month, open-label, active-controlled study was conducted to compare the safety and efficacy of Novolin and insulin aspart in children and adolescents aged 6-18 years with type diabetes (Table 8). Insulin aspart was administered by subcutaneous injection immediately prior to meals and Novolin was administered by subcutaneous injection 30 minutes before meals. Both treatment groups also received subcutaneous injections of NPH insulin.Table 8: Subcutaneous Novolin Administration in Children and Adolescents with Type Diabetes (24 weeks; N=283)Novolin + NPHN=96Insulin aspart NPHN=187Baseline HbA (%) 1c Values are Mean +- SD 8.3 +- 1.38.3 +- 1.2Change from Baseline HbA (%) 1c 0.1 +- 1.10.1 +- 1.0Treatment Difference in HbA Mean (95% confidence interval) 1c, Novolin - insulin aspart group The treatment difference and corresponding 95% confidence interval is based on the Analysis of Covariance Model 0.2 [-0.1; 0.5]Baseline, total insulin dose (units/kg/day) 1.0 +- 0.41.0 +- 0.3End-of-Study, total insulin dose (units/kg/day) 1.2 +- 0.41.2 +- 0.4Diabetic ketoacidosis (%)2 (2%)10 (5%)Baseline body weight (kg) Weight Change from baseline (kg) 48.7 +- 15.82.4 +- 2.650.6 +- 19.62.7 +- 3.5Novolin and insulin aspart have also been compared in an open-label, randomized, crossover trial in 26 children with type diabetes aged 2-6 years. Patients received each treatment for 12 weeks. Insulin aspart was administered by subcutaneous injection immediately prior to meals and Novolin was administered by subcutaneous injection 30 minutes before meals. Both treatment groups also received subcutaneous injections of NPH insulin. In this study, the mean baseline HbA was 7.8%. 1c The estimated HbA at end of treatment was 7.6% with Novolin and 7.7% with insulin aspart. 1c.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. Novolin is contraindicated:During episodes of hypoglycemia In patients with hypersensitivity to Novolin or one of its excipients . During episodes of hypoglycemia . In patients with hypersensitivity to Novolin or one of its excipients . Do not use during episodes of hypoglycemia ). 4 Do not use in patients with hypersensitivity to Novolin or one of its excipients ). 4 Do not use during episodes of hypoglycemia ). 4 Do not use in patients with hypersensitivity to Novolin or one of its excipients ). 4.

DESCRIPTION SECTION.


11 DESCRIPTION. Novolin (Regular Human Insulin Injection [Recombinant DNA origin] United States Pharmacopeia) is polypeptide hormone structurally identical to native human insulin and is produced by recombinant DNA technology, utilizing (bakers yeast) as the production organism. Novolin has the empirical formula H O and molecular weight of 5808. Saccharomyces cerevisiae 257 383 65 77 Figure 1: Structural formula of Novolin RNovolin is sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA origin) 100 units/mL, glycerol 16 mg/mL, metacresol mg/mL, zinc chloride approximately mcg/mL and water for injection. The pH is adjusted to 7.4. Hydrochloric acid 2N or sodium hydroxide 2N may be added to adjust pH. Novolin vials are latex-free.. Structural formula of Novolin R.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. The primary activity of Novolin is the regulation of glucose metabolism. Insulins, including Novolin R, bind to insulin receptors on muscle and adipocytes and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of Novolin R.Novolin is not mutagenic in the following tests: The chromosomal aberration assay in human lymphocytes, the micronucleus assay in mouse polychromatic erythrocytes, and the mutation frequency assay in Chinese hamster cells. in vitro Standard reproduction and teratology studies in animals, including fertility assessments have not been conducted with Novolin R.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. The dosage and timing of Novolin must be individualized ). 2.1 Subcutaneous injection: Administer approximately 30 minutes prior to the start of meal ). 2.2 Intravenous use: Use at concentrations from 0.05 to 1.0 Unit/mL in infusion systems using polypropylene infusion bags. Novolin is stable in 0.9% sodium chloride, 5% dextrose, or 10% dextrose with 40 mmol/L potassium chloride ). 2.3 Use in pumps: Not recommended due to risk of precipitation ). 2.4 The dosage and timing of Novolin must be individualized ). 2.1 Subcutaneous injection: Administer approximately 30 minutes prior to the start of meal ). 2.2 Intravenous use: Use at concentrations from 0.05 to 1.0 Unit/mL in infusion systems using polypropylene infusion bags. Novolin is stable in 0.9% sodium chloride, 5% dextrose, or 10% dextrose with 40 mmol/L potassium chloride ). 2.3 Use in pumps: Not recommended due to risk of precipitation ). 2.4 2.1 Dosing. The dosage and timing of Novolin must be individualized. Blood glucose monitoring is essential for all patients receiving insulin therapy.Total daily insulin requirements vary and are usually between 0.5 and 1.0 units/kg/day. Insulin requirements may be altered during stress, major illness, or with changes in exercise, meal patterns, or coadministered medications.. 2.2 Subcutaneous Injection. Novolin should generally be injected approximately 30 minutes prior to the start of meal.Novolin given by subcutaneous injection should generally be used in regimens that include an intermediate or long-acting insulin [see How Supplied/Storage and Handling , )] 16.1 16.2 Novolin should be administered by subcutaneous injection in the abdominal region, buttocks, thigh, or the upper arm. Subcutaneous injection into the abdominal wall is generally associated with faster absorption than other injection sites. Injection sites should be rotated within the same region to reduce the risk of lipodystrophy. Injection into lifted skin fold minimizes the risk of intramuscular injection.. 2.3 Intravenous Use. Novolin can be administered intravenously under medical supervision for glycemic control, with close monitoring of blood glucose and potassium concentrations to avoid hypoglycemia and hypokalemia [see Warnings and Precautions , ), How Supplied/Storage and Handling , )] 5.2 5.3 16.1 16.2 Intravenous administration of insulin is commonly used in the treatment of diabetic ketoacidosis, peri-operative management of diabetes, and maintenance of glycemic control during labor in pregnant diabetic women. For intravenous use, Novolin should be used at concentrations from 0.05 units/mL to 1.0 unit/mL in infusion systems using polypropylene infusion bags. Novolin can be used with the following infusion fluids: 0.9% sodium chloride, 5% dextrose, or 10% dextrose with 40 mmol/L potassium chloride.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Never use Novolin if it has become viscous or cloudy; use Novolin only if it is clear and colorless. Vials should not be used if leakage is observed. Novolin should not be used after the printed expiration date.The onset of action of Novolin R, when administered intravenously, is more rapid in comparison to subcutaneous administration.. 2.4 Use in Insulin Pumps. Use of Novolin in insulin pumps is not recommended because of the risk of precipitation.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. number of medications affect glucose metabolism that may require insulin dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control.The following are examples of medications that may increase the blood glucose-lowering effect of insulin and increase susceptibility to hypoglycemia: oral antidiabetic medications, pramlintide acetate, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. The following are examples of medications that may reduce the blood glucose-lowering effect of insulin, leading to worsening of glycemic control: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), and atypical antipsychotics. Beta-blockers, clonidine, and lithium salts may either potentiate or weaken the blood glucose-lowering effect of insulin. Alcohol can increase susceptibility to hypoglycemia. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic medications such as beta-blockers, clonidine, guanethidine, and reserpine. . The following are examples of medications that may increase the blood glucose-lowering effect of insulin and increase susceptibility to hypoglycemia: oral antidiabetic medications, pramlintide acetate, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. . The following are examples of medications that may reduce the blood glucose-lowering effect of insulin, leading to worsening of glycemic control: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), and atypical antipsychotics. . Beta-blockers, clonidine, and lithium salts may either potentiate or weaken the blood glucose-lowering effect of insulin. . Alcohol can increase susceptibility to hypoglycemia. . Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. . The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic medications such as beta-blockers, clonidine, guanethidine, and reserpine. . Certain medications affect glucose metabolism and may require insulin dose adjustment and close monitoring ). 7 The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic medications (e.g., beta-blockers, clonidine, guanethidine, and reserpine) ). 7 Certain medications affect glucose metabolism and may require insulin dose adjustment and close monitoring ). 7 The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic medications (e.g., beta-blockers, clonidine, guanethidine, and reserpine) ). 7.

GERIATRIC USE SECTION.


8.5 Geriatric Use. In controlled clinical trials 18 of 1285 patients (1.4%) with type diabetes treated with Novolin and insulin aspart were >=65 years of age. In controlled clinical trials 151 of 635 patients (24%) with type diabetes were >=65 years of age. Therefore, conclusions are limited regarding the efficacy and safety of Novolin in patients >=65 years of age, particularly in patients with type diabetes. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on Novolin have not been performed.Use caution in patients with advanced age, due to the potential for decreased renal function in this population [see Warnings and Precautions and )] 5.2 5.5.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. NDC:64725-1833-1 in VIAL of 10 INJECTION, SOLUTIONS. 16.1 How Supplied. Novolin is available in 10 mL vials (NDC 0169-1833-11 and ReliOn brand NDC 0169-1833-02). The concentration of Novolin is 100 USP units of human insulin (rDNA origin)/mL. One vial is provided in each sale pack. (R) 16.2 Recommended Storage. Unopened Novolin vials should be stored in the refrigerator (36 46F [2 8C]). If carried as spare or if refrigeration is not possible, unopened Novolin vials can be kept at room temperature provided they are kept as cool as possible (not above 77 [25 C]). If kept at room temperature, Novolin vials must be discarded after 42 days even if they are unopened. o In addition, unopened Novolin vials should be kept in their cartons so that they will stay clean and protected from light. They should not be exposed to heat or light. Do not freeze and do not use Novolin if it has been frozen. An opened (In use) Novolin vial can be kept at room temperature provided it is kept as cool as possible (not above 77 [25 C]) and away from heat or light. Do not refrigerate after first use. o Unopened and opened (In use) Novolin vials must be discarded 42 days after they are first kept out of the refrigerator, even if they still contain Novolin insulin.Table 9: Storage Conditions for Novolin vialsUnopened(Refrigerated)Unopened(Room Temperature up to 77 [25 C] o Opened (In use)(Room Temperature up to 77 [25 C]) o Until expiration date42 days The total time allowed at room temperature (up to 25 C) is 42 days regardless of whether the product is unopened or opened (In use) 42 days Infusion bags prepared as indicated under are stable at room temperature for 24 hours. certain amount of insulin will be initially adsorbed to the material of the infusion bag. DOSAGE AND ADMINISTRATION ) 2.3 Always remove the needle after each injection. Always use new disposable syringe and needle for each injection to prevent contamination.Never use insulin after the expiry date which is printed on the label and carton.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. Novolin is short-acting recombinant human insulin indicated to improve glycemic control in adults and children with diabetes mellitus ). . 1.1 Treatment of Diabetes Mellitus. Novolin is indicated to improve glycemic control in adults and children with diabetes mellitus.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. See FDA-Approved Patient Labeling (Patient Information and Instructions for Use). 17.1 Instructions for All Patients. Maintenance of normal or near-normal glucose control is treatment goal in diabetes mellitus and has been associated with reduction in some diabetic complications. Patients should be informed about potential risks and benefits of Novolin therapy including possible adverse reactions. Patients should also be offered continued education and advice on insulin therapies, injection technique, life-style management, regular glucose monitoring, periodic glycosylated hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of dose, instruction in the use of injection devices, and proper storage of insulin. Patients should be informed that frequent, patient-performed blood glucose measurements are needed to achieve optimal glycemic control and avoid both hyper- and hypoglycemia.The patients ability to concentrate and react may be impaired as result of hypoglycemia. This may present risk in situations where these abilities are especially important, such as driving or operating other machinery. Patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use caution when driving or operating machinery. Female patients should be advised to tell their physician if they intend to become, or if they become pregnant.Patients should be instructed to always carefully check that they are administering the correct insulin to avoid medication errors between Novolin and other insulins. Patients should check the label for the drug name Novolin R, the enlarged letter, and the blue horizontal bar. If prescription for Novolin is needed, it should be written clearly to avoid confusion with other insulin products.Novolin is registered trademark of Novo Nordisk A/S. (R) ReliOn is registered trademark of Wal-Mart Stores, Inc. and is used under license by Novo Nordisk Inc. (R) (C) 2002-2013 Novo NordiskManufactured by:Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkReliOn brand manufactured by: (R) Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkFor Wal-Mart Stores Inc.For information about Novolin contact:Novo Nordisk Inc.800 Scudders Mill RoadPlainsboro, New Jersey 08536www.novonordisk-us.com1-800-727-6500.

NURSING MOTHERS SECTION.


8.3 Nursing Mothers. It is unknown whether Novolin is excreted in breast milk. Small amounts of human insulin are secreted into breast milk, the significance of which is not known. Use of Novolin is compatible with breastfeeding, but insulin doses may need to be adjusted because lactation can reduce insulin requirements.

OVERDOSAGE SECTION.


10 OVERDOSAGE. Excess insulin administration may cause hypoglycemia and, particularly when given intravenously, hypokalemia. 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 can be treated with intramuscular or subcutaneous glucagon or intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately. see Warnings and Precautions , )] 5.2 5.3.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


NOVOLIN (HUMAN INSULIN) INJECTION, SOLUTION. Label Image.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety and effectiveness of subcutaneous injections of Novolin have been established in pediatric patients (ages to18 years) with type diabetes Novolin has not been studied in pediatric patients younger than years of age. Novolin has not been studied in pediatric patients with type diabetes. [see Clinical Studies )] 14.3 In general, pediatric patients with type diabetes are more susceptible to hypoglycemia than adult patients with type diabetes. As in adults, the dosage of Novolin must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose [see Dosage and Administration ) and Warnings and Precautions )] 2.1 5.2.

PHARMACODYNAMICS SECTION.


12.2 Pharmacodynamics. Novolin is short-acting insulin. When injected subcutaneously, the glucose-lowering effect of Novolin begins approximately 30 minutes post-dose, is maximal between 1.5 and 3.5 hours post-dose and terminates approximately hours post-dose. The onset of action of Novolin R, when administered intravenously, is more rapid in comparison to the subcutaneous administration. When injected subcutaneously, Novolin has slower onset of action and longer duration of action compared to the rapid-acting insulin analogs.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. After single subcutaneous administration of 0.1 unit/kg of Novolin to healthy subjects, peak insulin concentrations occurred between 1.5 to 2.5 hours post-dose. On average, insulin concentrations returned to baseline at around hours post-dose.The effects of sex, age, obesity, ethnic origin, renal and hepatic impairment, pregnancy, and smoking, on the pharmacodynamics and pharmacokinetics of Novolin have not been studied.

PREGNANCY SECTION.


8.1 Pregnancy. Pregnancy Category B: All pregnancies have 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 glycemic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good glycemic 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 important during pregnancy in patients with diabetes. Therefore, women should be advised to tell their healthcare provider if they intend to become, or if they become, pregnant while taking Novolin R.No reproductive toxicity studies have been performed with Novolin R.

RECENT MAJOR CHANGES SECTION.


Warnings and Precautions ) 3/2013 5.9.

SPL UNCLASSIFIED SECTION.


1.1 Treatment of Diabetes Mellitus. Novolin is indicated to improve glycemic control in adults and children with diabetes mellitus.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Category B: All pregnancies have 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 glycemic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good glycemic 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 important during pregnancy in patients with diabetes. Therefore, women should be advised to tell their healthcare provider if they intend to become, or if they become, pregnant while taking Novolin R.No reproductive toxicity studies have been performed with Novolin R.. 8.3 Nursing Mothers. It is unknown whether Novolin is excreted in breast milk. Small amounts of human insulin are secreted into breast milk, the significance of which is not known. Use of Novolin is compatible with breastfeeding, but insulin doses may need to be adjusted because lactation can reduce insulin requirements.. 8.4 Pediatric Use. The safety and effectiveness of subcutaneous injections of Novolin have been established in pediatric patients (ages to18 years) with type diabetes Novolin has not been studied in pediatric patients younger than years of age. Novolin has not been studied in pediatric patients with type diabetes. [see Clinical Studies )] 14.3 In general, pediatric patients with type diabetes are more susceptible to hypoglycemia than adult patients with type diabetes. As in adults, the dosage of Novolin must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose [see Dosage and Administration ) and Warnings and Precautions )] 2.1 5.2 8.5 Geriatric Use. In controlled clinical trials 18 of 1285 patients (1.4%) with type diabetes treated with Novolin and insulin aspart were >=65 years of age. In controlled clinical trials 151 of 635 patients (24%) with type diabetes were >=65 years of age. Therefore, conclusions are limited regarding the efficacy and safety of Novolin in patients >=65 years of age, particularly in patients with type diabetes. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on Novolin have not been performed.Use caution in patients with advanced age, due to the potential for decreased renal function in this population [see Warnings and Precautions and )] 5.2 5.5.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Hypoglycemia: Most common adverse reaction of insulin therapy and may be life-threatening. Closely monitor blood glucose. Changes in insulin or dosage should be made cautiously and only under medical supervision ). 5.2 Hypokalemia: Particularly when insulin is given intravenously or in settings of poor glycemic control. Use caution in patients predisposed to hypokalemia ). 5.3 Renal or hepatic impairment: As with other insulins, the dose requirements for Novolin may be reduced ). 5.5 Allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, may occur ). 5.6 Mixing: Do not mix Novolin with any insulin for intravenous use. Do not mix with insulins other than NPH insulin for subcutaneous use ). 5.7 Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including Novolin ( ). 5.9 Hypoglycemia: Most common adverse reaction of insulin therapy and may be life-threatening. Closely monitor blood glucose. Changes in insulin or dosage should be made cautiously and only under medical supervision ). 5.2 Hypokalemia: Particularly when insulin is given intravenously or in settings of poor glycemic control. Use caution in patients predisposed to hypokalemia ). 5.3 Renal or hepatic impairment: As with other insulins, the dose requirements for Novolin may be reduced ). 5.5 Allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, may occur ). 5.6 Mixing: Do not mix Novolin with any insulin for intravenous use. Do not mix with insulins other than NPH insulin for subcutaneous use ). 5.7 Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including Novolin ( ). 5.9 5.1 Administration. Subcutaneous injection of Novolin should be followed by meal. Patients should wait approximately 30 minutes after injection before starting the meal ]. see Dosage and Administration ) 2.2 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 change in dosage. As with all insulin preparations, the time course of Novolin action may vary in different individuals or at different times in the same individual and is dependent on many conditions, including dosage, 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.. 5.2 Hypoglycemia. Hypoglycemia is the most common adverse reaction of all insulin therapies, including Novolin R. Severe hypoglycemia may lead to unconsciousness, convulsions, temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person, parenteral glucose infusion, and glucagon administration has been observed in clinical trials with insulin, including trials with Novolin R.The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations ]. 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 ]. 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, pediatric patients, and the elderly). The patients ability to concentrate and react may be impaired as result of hypoglycemia. This may present risk in situations where these abilities are especially important, such as driving or operating other machinery. see Clinical Pharmacology , 12.2 12.3 see Drug Interactions ) Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in patients 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 neuropathy, use of medications such as beta-blockers, or intensified glycemic control ]. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patients awareness of hypoglycemia. Intravenously administered insulin has more rapid onset of action than subcutaneously administered insulin, requiring more close monitoring for hypoglycemia. see Drug Interactions ) . 5.3 Hypokalemia. All insulins, including Novolin R, cause 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 and patients taking medications sensitive to serum potassium concentrations). Monitor glucose and potassium frequently when Novolin is administered intravenously.. 5.4 Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar Hyperglycemic Non-Ketotic Syndrome. Hyperglycemia, diabetic ketoacidosis, or hyperosmolar hyperglycemic non-ketotic syndrome may develop in patients who take less insulin than needed to control blood glucose. These conditions can be precipitated by illness, infection, dietary indiscretion, or omission or improper administration of the prescribed insulin dose.. 5.5 Renal or Hepatic Impairment. As with other insulins, the dose requirements for Novolin may be reduced in patients with renal or hepatic impairment.. 5.6 Hypersensitivity and Allergic Reactions. As with other insulins, patients may experience redness, swelling, or itching at the site of injection of Novolin R. These reactions usually resolve in few days to few weeks, but in some occasions, may require discontinuation of Novolin R. In some instances, these reactions may be related to factors other than insulin, such as irritants in skin cleansing agent or poor injection technique. Localized reactions and generalized myalgias have been reported with the use of meta-cresol, which is an excipient in Novolin R. Local Reactions Severe, life-threatening, generalized allergy, including anaphylaxis may occur with any insulin, including Novolin R. Generalized allergy to insulin may manifest as whole body rash (including pruritus), dyspnea, wheezing, hypotension tachycardia, or diaphoresis. Systemic Reactions . 5.7 Mixing of Insulins. If Novolin is mixed with NPH human insulin, Novolin should be drawn into the syringe first and the mixture should be injected immediately after mixing. Insulin mixtures should not be administered intravenously.. 5.8 Antibody Production. Increases in titers of anti-insulin antibodies that react with human insulin have been observed in patients treated with Novolin R. Data from 12-month controlled trial in patients with type diabetes suggest that the increase in these antibodies is transient. The clinical significance of these antibodies is not known but does not appear to cause deterioration in glycemic control or necessitate increases in insulin dose.. 5.9 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 NOVOLIN R, 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.