ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere in the labeling:Hypoglycemia [see Warnings and Precautions (5.3)].Hypokalemia [see Warnings and Precautions (5.5)].The following additional adverse reactions have been identified during post-approval use of HUMULIN N. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or to establish causal relationship to drug exposure.. Hypoglycemia [see Warnings and Precautions (5.3)].. Hypokalemia [see Warnings and Precautions (5.5)].. Adverse reactions observed with HUMULIN include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, weight gain, and edema. (6)To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Allergic ReactionsSome patients taking HUMULIN have experienced erythema, local edema, and pruritus at the site of injection. These conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported [see Warnings and Precautions (5.4)].. Peripheral EdemaSome patients taking HUMULIN have experienced sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.. LipodystrophyAdministration of insulin subcutaneously, including HUMULIN N, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration (2.2)] in some patients.. Localized Cutaneous AmyloidosisLocalized 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.. Weight gainWeight gain has occurred with some insulin therapies including HUMULIN and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.. ImmunogenicityDevelopment of antibodies that react with human insulin have been observed with all insulin, including HUMULIN N.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity and fertility studies were not performed in animals. Biosynthetic human insulin was not genotoxic in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. HUMULIN injectable suspension 100 units per mL (U-100) is white and cloudy suspension available as:10 mL multiple-dose vialNDC 0002-8315-01 (HI-310)3 mL multiple-dose vialNDC 0002-8315-17 (HI-313)5 3 mL single-patient-use HUMULIN KwikPenNDC 0002-8805-59 (HP-8805)Each prefilled HUMULIN KwikPen is for use by single patient. HUMULIN KwikPens must never be shared between patients, even if the needle is changed. Patients using HUMULIN vials must never share needles or syringes with another person.The HUMULIN KwikPen dials in unit increments.. 16.2 Storage and Handling. Dispense in the original sealed carton with the enclosed Instructions for Use.Protect from heat and light. Do not freeze. Do not use after the expiration date.. Not In-Use (Unopened) HUMULIN Vials. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen.. Room TemperatureIf stored at room temperature, below 86F (30C) the vial must be discarded after 31days.. In-Use (Opened) HUMULIN Vials. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen. Vials must be used within 31 days or be discarded, even if they still contain HUMULIN N.. Room TemperatureIf stored at room temperature, below 86F (30C) the vial must be discarded after 31 days, even if the vial still contains HUMULIN N.. Not In-Use (Unopened) HUMULIN KwikPen. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen.. Room TemperatureIf stored at room temperature, below 86F (30C) the pen must be discarded after 14 days.. In-Use (Opened) HUMULIN KwikPen. RefrigeratedDo NOT store in refrigerator.. Room TemperatureStore at room temperature, below 86F (30C) and the pen must be discarded after 14 days, even if the pen still contains HUMULIN N. See storage table below:Not In-Use (Unopened)RefrigeratedNot In-Use (Unopened)Room TemperatureIn-Use (Opened)10 mL multiple-dose vial3 mL multiple-dose vialUntil expiration date31 days31 days, refrigerated/room temperature3 mL single-patient-use HUMULIN KwikPenUntil expiration date14 days14 days, room temperature. Do not refrigerate.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. HUMULIN is an intermediate-acting recombinant human insulin indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus.. HUMULIN(R) is an intermediate-acting human insulin indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. (1).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. HUMULIN lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.. 12.2 Pharmacodynamics. HUMULIN is an intermediate-acting insulin with slower onset of action and longer duration of activity than that of regular human insulin. In study in which healthy subjects (n=16) received subcutaneous injections of HUMULIN (0.4 unit/kg) on occasions, the median maximum effect occurred at 6.5 hours (range: 2.8 to 13 hours). In this study, insulin activity was measured by the rate of glucose infusions.The time course of action of insulin, such as HUMULIN may vary in different individuals or within the same individual. The parameters of HUMULIN activity (time of onset, peak time, and duration) as designated in Figure should be considered only as general guidelines. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, physical activity level, and other variables [see Warnings and Precautions (5.3)].Figure 1: Mean Insulin Activity Versus Time Profile After Subcutaneous Injection of HUMULIN (0.4 unit/kg) in Healthy Subjects.. Figure 1. 12.3 Pharmacokinetics. Absorption -- In healthy subjects given subcutaneous doses of HUMULIN (0.4 unit/kg), median peak serum concentration of insulin occurred at approximately hours (range: to 12 hours) after dosing.. Metabolism -- The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the liver being the major organ involved in the clearance of insulin.. Elimination -- Because of the absorption-rate limited kinetics of insulin mixtures, true half-life cannot be accurately estimated from the terminal slope of the concentration versus time curve. In healthy subjects given subcutaneous doses of HUMULIN (0.4 unit/kg), the mean apparent half-life was approximately 4.4 hours (range: 1-84 hours).. Specific PopulationsThe effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of HUMULIN have not been studied.Careful glucose monitoring and dose adjustments of insulin, including HUMULIN N, may be necessary in patients with renal or hepatic dysfunction [see Use in Specific Populations (8.6, 8.7)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. HUMULIN is contraindicated:During episodes of hypoglycemia [see Warnings and Precautions (5.3)], andIn patients who have had hypersensitivity reactions to HUMULIN or any of its excipients [see Warnings and Precautions (5.4)].. During episodes of hypoglycemia [see Warnings and Precautions (5.3)], and. In patients who have had hypersensitivity reactions to HUMULIN or any of its excipients [see Warnings and Precautions (5.4)].. During episodes of hypoglycemia. (4)In patients with hypersensitivity to HUMULIN or any of its excipients. (4). During episodes of hypoglycemia. (4). In patients with hypersensitivity to HUMULIN or any of its excipients. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. HUMULIN (isophane insulin human suspension) is an intermediate-acting human insulin. Human insulin is produced by recombinant DNA technology utilizing non-pathogenic laboratory strain of Escherichia coli. HUMULIN is suspension of crystals produced from combining human insulin and protamine sulfate under appropriate conditions for crystal formation. The amino acid sequence of HUMULIN is identical to human insulin and has the empirical formula C257H383N65O77S6 with molecular weight of 5808.HUMULIN is sterile, white and cloudy suspension that contains isophane insulin human suspension (NPH) for subcutaneous use. Each milliliter of HUMULIN contains 100 units of insulin human, 0.35 mg of protamine sulfate, 16 mg of glycerin, 3.78 mg of dibasic sodium phosphate, 1.6 mg of metacresol, 0.65 mg of phenol, zinc oxide content adjusted to provide 0.025 mg zinc ion, and Water for Injection. The pH is 7.0 to 7.5. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Only administer subcutaneously (in abdominal wall, thigh, upper arm, or buttocks). (2.2)Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (2.2)Individualize and adjust dosage based on metabolic needs, blood glucose monitoring results and glycemic control goal. (2.3)See Full Prescribing Information for dosage adjustments due to drug interactions and patients with renal and hepatic impairment. (2.3, 2.4)May use with meal-time insulin if indicated. (2.4). Only administer subcutaneously (in abdominal wall, thigh, upper arm, or buttocks). (2.2). Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (2.2). Individualize and adjust dosage based on metabolic needs, blood glucose monitoring results and glycemic control goal. (2.3). See Full Prescribing Information for dosage adjustments due to drug interactions and patients with renal and hepatic impairment. (2.3, 2.4). May use with meal-time insulin if indicated. (2.4). 2.1 Important Administration Instructions. Inspect HUMULIN visually before use. It should not contain particulate matter and should appear uniformly cloudy after mixing. Do not use HUMULIN if particulate matter is seen.Use HUMULIN KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose.. 2.2 Route of Administration. HUMULIN should only be administered subcutaneously.Administer in the subcutaneous tissue of the abdominal wall, thigh, upper arm, or buttocks. Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6)]. During changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].The HUMULIN KwikPen dials in unit increments.Do not administer HUMULIN intravenously or intramuscularly and do not use HUMULIN in an insulin infusion pump.. 2.3 Dosage Information. Individualize and adjust the dosage of HUMULIN based on the individuals metabolic needs, blood glucose monitoring results and glycemic control goal.Dosage 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 [see Warnings and Precautions (5.2, 5.3), and Use in Specific Populations (8.6, 8.7)].. 2.4 Dosage Adjustment due to Drug Interactions. Dosage adjustment may be needed when HUMULIN is coadministered with certain drugs [see Drug Interactions (7)]. Dosage adjustment may be needed when switching from another insulin to HUMULIN [see Warnings and Precautions (5.2)].. Instructions for Mixing with Other InsulinsHUMULIN may be used with prandial insulin if indicated. HUMULIN may be mixed with HUMULIN or HUMALOG before injection.If HUMULIN is mixed with HUMULIN R, HUMULIN should be drawn into the syringe first. Injection should occur immediately after mixing.If HUMULIN is mixed with HUMALOG, HUMALOG should be drawn into the syringe first. Injection should occur immediately after mixing.. If HUMULIN is mixed with HUMULIN R, HUMULIN should be drawn into the syringe first. Injection should occur immediately after mixing.. If HUMULIN is mixed with HUMALOG, HUMALOG should be drawn into the syringe first. Injection should occur immediately after mixing.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. HUMULIN injectable suspension: 100 units per mL (U-100) is white and cloudy suspension available as:10 mL multiple-dose vial3 mL multiple-dose vial3 mL single-patient-use HUMULIN KwikPen. 10 mL multiple-dose vial. mL multiple-dose vial. mL single-patient-use HUMULIN KwikPen. Injectable suspension: 100 units per mL (U-100) available as:10 mL multiple-dose vial (3)3 mL multiple-dose vial (3)3 mL single-patient-use HUMULIN(R) KwikPen(R) (3). 10 mL multiple-dose vial (3). mL multiple-dose vial (3). mL single-patient-use HUMULIN(R) KwikPen(R) (3).

DRUG INTERACTIONS SECTION.

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. (5.3, 7.4). 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. (5.3, 7.4). 7.1 Drugs That May Increase the Risk of Hypoglycemia. The risk of hypoglycemia associated with HUMULIN use may be increased when co-administered with antidiabetic agents, salicylates, sulfonamide antibiotics, monoamine oxidase inhibitors, fluoxetine, disopyramide, fibrates, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, and somatostatin analogs (e.g., octreotide). Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN is co-administered with these drugs.. 7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of HUMULIN N. The glucose lowering effect of HUMULIN may be decreased when co-administered with corticosteroids, isoniazid, niacin, estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), somatropin, atypical antipsychotics, glucagon, protease inhibitors, and thyroid hormones. Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN is co-administered with these drugs.. 7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN N. The glucose lowering effect of HUMULIN may be increased or decreased when co-administered with beta-blockers, clonidine, lithium salts, and alcohol. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dose adjustment and increased frequency of glucose monitoring may be required when HUMULIN is co-administered with these drugs.. 7.4 Drugs That May Blunt Signs and Symptoms of Hypoglycemia. The signs and symptoms of hypoglycemia [see Warnings and Precautions (5.3)] may be blunted when beta-blockers, clonidine, guanethidine, and reserpine are co-administered with HUMULIN N.

GERIATRIC USE SECTION.

8.5 Geriatric Use. The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied [see Clinical Pharmacology (12.3)]. Patients with advanced age using any insulin, including HUMULIN N, may be at increased risk of hypoglycemia due to co-morbid disease and polypharmacy [see Warnings and Precautions (5.3)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied [see Clinical Pharmacology (12.3)]. Patients with hepatic impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN dose adjustment and more frequent blood glucose monitoring.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).. Never Share HUMULIN KwikPen or Syringe Between PatientsAdvise patients that they must never share HUMULIN KwikPen with another person, even if the needle is changed. Advise patients using HUMULIN 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)].. Hyperglycemia or HypoglycemiaInstruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia especially at initiation of HUMULIN 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)].Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.2)].Inform patients that accidental mix-ups between HUMULIN and other insulins have been reported. Instruct patients to always carefully check that they are administering the correct insulin (e.g., by checking the insulin label before each injection) to avoid medication errors between HUMULIN and other insulins.. Hypersensitivity ReactionsAdvise patients that hypersensitivity reactions have occurred with HUMULIN N. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.4)].. Visual Inspection Prior to UseInstruct patients to visually inspect HUMULIN before use and to use HUMULIN only if it contains no particulate matter and appears uniformly cloudy after mixing [see Dosage and Administration (2.1)].. HUMULIN(R) and HUMULIN(R) KwikPen(R) are trademarks of Eli Lilly and Company.Literature revised November 2019Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 1997, 2019, Eli Lilly and Company. All rights reserved.LINN-0005-USPI-20191115.

INSTRUCTIONS FOR USE SECTION.

Instructions for UseHUMULIN(R) (HU-mu-lin) N(isophane insulin human suspension)multiple-dose vial (100 Units/mL, U-100)Read the Instructions for Use before you start taking HUMULIN and each time you get new HUMULIN vial. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.Do not share your syringes with other people, even if the needle has been changed. You may give other people serious infection or get serious infection from them.Supplies needed to give your injection:a multiple-dose HUMULIN viala U-100 insulin syringe and needle2 alcohol swabs1 sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.VialSyringePreparing your HUMULIN dose:Wash your hands with soap and water.Check the HUMULIN label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.Do not use HUMULIN past the expiration date printed on the label or 31 days after you first use it.Always use new syringe or needle for each injection to help ensure sterility and prevent blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.Step 1:Gently roll the vial between the palms of your hands at least 10 times.Step 2:Carefully invert the vial at least 10 times.Mixing is important to make sure you get the right dose. Humulin should look white and cloudy after mixing. Do not use it if it looks clear or contains any lumps or particles.Step 3:If you are using new vial, pull off the plastic Protective Cap, but do not remove the Rubber Stopper.Step 4:Wipe the Rubber Stopper with an alcohol swab.Step 5:Hold the syringe with the needle pointing up. Pull down on the Plunger until the tip of the Plunger reaches the line for the number of units for your prescribed dose.(Example Dose: 20 units shown)Step 6:Push the needle through the Rubber Stopper of the vial.Step 7:Push the plunger all the way in. This puts air into the vial.Step 8:Turn the vial and syringe upside down and slowly pull the Plunger down until the tip is few units past the line for your prescribed dose.If there are air bubbles, tap the syringe gently few times to let any air bubbles rise to the top.(Example Dose: 20 units Plunger is shown at 24 units)Step 9:Slowly push the Plunger up until the tip reaches the line for your prescribed dose.Check the syringe to make sure that you have the right dose.(Example Dose: 20 units shown)Step 10:Pull the syringe out of the vials Rubber Stopper.Giving your HUMULIN injection:Inject your insulin exactly as your healthcare provider has shown you.Change (rotate) your injection sites within the area you choose for 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. 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:Choose your injection site.HUMULIN is injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs or upper arms.Wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose.Step 12:Insert the needle into your skin.Step 13:Push down on the Plunger to inject your dose.The needle should stay in your skin for at least seconds to make sure you have injected all of your insulin dose.Step 14:Pull the needle out of your skin.If you see blood after you take the needle out of your skin, press the injection site with piece of gauze or an alcohol swab. Do not rub the area.Do not recap the needle. Recapping the needle can lead to needle stick injury.Disposing of used needles and syringes:Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,-upright and stable during use,-leak-resistant, and-properly labeled to warn of hazardous waste inside the container. When 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. 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/safesharpsdisposalDo 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 HUMULIN NAll unopened HUMULIN vials:Store all unopened vials in the refrigerator.Do not freeze. Do not use if it has been frozen.Keep away from heat and out of direct light.Unopened vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator.Unopened vials should be thrown away after 31 days, if they are stored at room temperature.After HUMULIN vials have been opened:Store opened vials in the refrigerator or at room temperature below 86F (30C) for up to 31 days.Keep away from heat and out of direct light.Throw away all opened vials after 31 days of use, even if there is still insulin left in the vial.General information about the safe and effective use of HUMULIN N.Keep HUMULIN vials, syringes, needles, and all medicines out of the reach of children.Always use new syringe or needle for each injection.Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.If you have any questions or problems with your HUMULIN, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. For more information on HUMULIN and insulin, go to www.humulin.com.Scan this code to launch the humulin.com websiteThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Humulin(R) is trademark of Eli Lilly and Company.Instructions for Use revised: November 2019Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 1992, 2019, Eli Lilly and Company. All rights reserved.LINNVL-0004-IFU-20191115. multiple-dose HUMULIN vial. U-100 insulin syringe and needle. alcohol swabs. sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.. Wash your hands with soap and water.. Check the HUMULIN label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.. Do not use HUMULIN past the expiration date printed on the label or 31 days after you first use it.. Always use new syringe or needle for each injection to help ensure sterility and prevent blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.. Inject your insulin exactly as your healthcare provider has shown you.. Change (rotate) your injection sites within the area you choose for 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. 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.. If you see blood after you take the needle out of your skin, press the injection site with piece of gauze or an alcohol swab. Do not rub the area.. Do not recap the needle. Recapping the needle can lead to needle stick injury.. Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.. If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,-upright and stable during use,-leak-resistant, and-properly labeled to warn of hazardous waste inside the container. -made of heavy-duty plastic,. -can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. -upright and stable during use,. -leak-resistant, and. -properly labeled to warn of hazardous waste inside the container.. When 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. 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. Do 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.. Store all unopened vials in the refrigerator.. Do not freeze. Do not use if it has been frozen.. Keep away from heat and out of direct light.. Unopened vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator.. Unopened vials should be thrown away after 31 days, if they are stored at room temperature.. Store opened vials in the refrigerator or at room temperature below 86F (30C) for up to 31 days.. Keep away from heat and out of direct light.. Throw away all opened vials after 31 days of use, even if there is still insulin left in the vial.. Keep HUMULIN vials, syringes, needles, and all medicines out of the reach of children.. Always use new syringe or needle for each injection.. Do not reuse or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryAvailable data from published literature suggests that exogenous human insulin products, including HUMULIN N, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including HUMULIN on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for HUMULIN and any potential adverse effects on the breastfed child from HUMULIN or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. HUMULIN lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity and fertility studies were not performed in animals. Biosynthetic human insulin was not genotoxic in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.5)]. Mild episodes of hypoglycemia can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or physical activity level may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE CARTON HUMULIN Vial 10 mL 1ct. NDC 0002-8315-0110 mL100 units per mLHumulin(R) NNPHisophane insulin humansuspensionFor subcutaneous use only.U-100www.lilly.comLilly. PACKAGE CARTON HUMULIN Vial 10 mL 1ct.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. HUMULIN has not been studied in pediatric patients. As in adults, the dosage of HUMULIN in pediatric patients must be individualized based on metabolic needs, treatment goal and blood glucose monitoring results.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. HUMULIN is an intermediate-acting insulin with slower onset of action and longer duration of activity than that of regular human insulin. In study in which healthy subjects (n=16) received subcutaneous injections of HUMULIN (0.4 unit/kg) on occasions, the median maximum effect occurred at 6.5 hours (range: 2.8 to 13 hours). In this study, insulin activity was measured by the rate of glucose infusions.The time course of action of insulin, such as HUMULIN may vary in different individuals or within the same individual. The parameters of HUMULIN activity (time of onset, peak time, and duration) as designated in Figure should be considered only as general guidelines. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, physical activity level, and other variables [see Warnings and Precautions (5.3)].Figure 1: Mean Insulin Activity Versus Time Profile After Subcutaneous Injection of HUMULIN (0.4 unit/kg) in Healthy Subjects.. Figure 1.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption -- In healthy subjects given subcutaneous doses of HUMULIN (0.4 unit/kg), median peak serum concentration of insulin occurred at approximately hours (range: to 12 hours) after dosing.. Metabolism -- The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the liver being the major organ involved in the clearance of insulin.. Elimination -- Because of the absorption-rate limited kinetics of insulin mixtures, true half-life cannot be accurately estimated from the terminal slope of the concentration versus time curve. In healthy subjects given subcutaneous doses of HUMULIN (0.4 unit/kg), the mean apparent half-life was approximately 4.4 hours (range: 1-84 hours).. Specific PopulationsThe effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of HUMULIN have not been studied.Careful glucose monitoring and dose adjustments of insulin, including HUMULIN N, may be necessary in patients with renal or hepatic dysfunction [see Use in Specific Populations (8.6, 8.7)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from published studies over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Animal reproduction studies were not performed.The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with HbA1c >7% and has been reported to be as high as 20-25% in women with 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 Considerations. Disease-associated maternal and/or embryo/fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.. Data. Human DataWhile available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. All available studies have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.2)11/2019Warnings and Precautions (5.2)11/2019.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. The effect of renal impairment on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied [see Clinical Pharmacology (12.3)]. Patients with renal impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN dose adjustment and more frequent blood glucose monitoring.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONHUMULIN(R)(HU-mu-lin) N(isophane insulin human suspension)Do not share your HUMULIN KwikPen or syringes 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 HUMULIN NHUMULIN is man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus.Who should not use HUMULIN NDo not use HUMULIN if you:are having an episode of low blood sugar (hypoglycemia).have an allergy to HUMULIN or any of the ingredients in HUMULIN N.Before using HUMULIN N, tell your healthcare provider about all your medical conditions including, if you:have liver or kidney problems.take any other medicines, especially ones commonly called TZDs (thiazolidinediones).have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with HUMULIN N.are pregnant, planning to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.are breast-feeding or plan to breastfeed. HUMULIN may pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while using HUMULIN N.are taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.Before you start using HUMULIN N, talk to your healthcare provider about low blood sugar and how to manage it.How should use HUMULIN NRead the Instructions for Use that come with your HUMULIN N.Use HUMULIN exactly as your healthcare provider tells you to. HUMULIN is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. Change (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. Do not use the exact same spot 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.Know the type and strength of insulin you use. Do not change the type of insulin you use 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 use different types of insulin.Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.Do not share your HUMULIN KwikPen or syringes with other people, even if the needle has been changed. You may give other people serious infection or get serious infection from them.Your HUMULIN dose may need to change because of:change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet.What should avoid while using HUMULIN NWhile using HUMULIN do not:drive or operate heavy machinery, until you know how HUMULIN affects you.drink alcohol or use prescription or over-the-counter medicines that contain alcohol.What are the possible side effects of HUMULIN NHUMULIN 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:dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger. serious allergic reaction (whole body reaction). Get medical help right away, if you have any of these symptoms of an allergic reaction:a rash over your whole body, trouble breathing, fast heartbeat, or sweating.low potassium in your blood (hypokalemia).heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with HUMULIN may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with HUMULIN N. Your healthcare provider should monitor you closely while you are taking TZDs with HUMULIN N. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:shortness of breath, swelling of your ankles or feet, sudden weight gain.Treatment with TZDs and HUMULIN may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure. Get emergency medical help if you have:trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.The most common side effects of HUMULIN include:low blood sugar (hypoglycemia), allergic reactions including reactions at the injection site, skin thickening or pits at the injection site (lipodystrophy), itching, rash, weight gain, and swelling of your hands and feet.These are not all the possible side effects of HUMULIN N. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of HUMULIN N:Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about HUMULIN that is written for health professionals. Do not use HUMULIN for condition for which it was not prescribed. Do not give HUMULIN to other people, even if they have the same symptoms that you have. It may harm them.What are the ingredients in HUMULIN NActive Ingredient: insulin humanInactive Ingredients: protamine sulfate, glycerin, dibasic sodium phosphate, metacresol, phenol, zinc oxide, water for injection, hydrochloric acid or sodium hydroxideFor more information, call 1-800-545-5979 or go to www.humulin.com.This Patient Information has been approved by the U.S. Food and Drug Administration.Patient Information revised November 2019Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright (C) 1997, 2019, Eli Lilly and Company. All rights reserved.LINN-0004-PPI-20191115. HUMULIN is man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus.. are having an episode of low blood sugar (hypoglycemia).. have an allergy to HUMULIN or any of the ingredients in HUMULIN N.. have liver or kidney problems.. take any other medicines, especially ones commonly called TZDs (thiazolidinediones).. have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with HUMULIN N.. are pregnant, planning to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.. are breast-feeding or plan to breastfeed. HUMULIN may pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while using HUMULIN N.. are taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.. Read the Instructions for Use that come with your HUMULIN N.. Use HUMULIN exactly as your healthcare provider tells you to. HUMULIN is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. Change (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. Do not use the exact same spot 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.. Know the type and strength of insulin you use. Do not change the type of insulin you use 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 use different types of insulin.. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.. Do not share your HUMULIN KwikPen or syringes with other people, even if the needle has been changed. You may give other people serious infection or get serious infection from them.. change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet.. drive or operate heavy machinery, until you know how HUMULIN affects you.. drink alcohol or use prescription or over-the-counter medicines that contain alcohol.. low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger. dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger.. serious allergic reaction (whole body reaction). Get medical help right away, if you have any of these symptoms of an allergic reaction:a rash over your whole body, trouble breathing, fast heartbeat, or sweating.. rash over your whole body, trouble breathing, fast heartbeat, or sweating.. low potassium in your blood (hypokalemia).. heart failure. Taking certain diabetes pills called thiazolidinediones or TZDs with HUMULIN may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with HUMULIN N. Your healthcare provider should monitor you closely while you are taking TZDs with HUMULIN N. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:. shortness of breath, swelling of your ankles or feet, sudden weight gain.Treatment with TZDs and HUMULIN may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure. trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.. low blood sugar (hypoglycemia), allergic reactions including reactions at the injection site, skin thickening or pits at the injection site (lipodystrophy), itching, rash, weight gain, and swelling of your hands and feet.

SPL UNCLASSIFIED SECTION.

2.1 Important Administration Instructions. Inspect HUMULIN visually before use. It should not contain particulate matter and should appear uniformly cloudy after mixing. Do not use HUMULIN if particulate matter is seen.Use HUMULIN KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Dispense in the original sealed carton with the enclosed Instructions for Use.Protect from heat and light. Do not freeze. Do not use after the expiration date.. Not In-Use (Unopened) HUMULIN Vials. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen.. Room TemperatureIf stored at room temperature, below 86F (30C) the vial must be discarded after 31days.. In-Use (Opened) HUMULIN Vials. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen. Vials must be used within 31 days or be discarded, even if they still contain HUMULIN N.. Room TemperatureIf stored at room temperature, below 86F (30C) the vial must be discarded after 31 days, even if the vial still contains HUMULIN N.. Not In-Use (Unopened) HUMULIN KwikPen. RefrigeratedStore in refrigerator (36 to 46F [2 to 8C]), but not in the freezer. Do not use if it has been frozen.. Room TemperatureIf stored at room temperature, below 86F (30C) the pen must be discarded after 14 days.. In-Use (Opened) HUMULIN KwikPen. RefrigeratedDo NOT store in refrigerator.. Room TemperatureStore at room temperature, below 86F (30C) and the pen must be discarded after 14 days, even if the pen still contains HUMULIN N. See storage table below:Not In-Use (Unopened)RefrigeratedNot In-Use (Unopened)Room TemperatureIn-Use (Opened)10 mL multiple-dose vial3 mL multiple-dose vialUntil expiration date31 days31 days, refrigerated/room temperature3 mL single-patient-use HUMULIN KwikPenUntil expiration date14 days14 days, room temperature. Do not refrigerate.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from published studies over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Animal reproduction studies were not performed.The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with HbA1c >7% and has been reported to be as high as 20-25% in women with 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 Considerations. Disease-associated maternal and/or embryo/fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.. Data. Human DataWhile available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. All available studies have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size.. 8.2 Lactation. Risk SummaryAvailable data from published literature suggests that exogenous human insulin products, including HUMULIN N, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including HUMULIN on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for HUMULIN and any potential adverse effects on the breastfed child from HUMULIN or from the underlying maternal condition.. 8.4 Pediatric Use. HUMULIN has not been studied in pediatric patients. As in adults, the dosage of HUMULIN in pediatric patients must be individualized based on metabolic needs, treatment goal and blood glucose monitoring results.. 8.5 Geriatric Use. The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied [see Clinical Pharmacology (12.3)]. Patients with advanced age using any insulin, including HUMULIN N, may be at increased risk of hypoglycemia due to co-morbid disease and polypharmacy [see Warnings and Precautions (5.3)].. 8.6 Renal Impairment. The effect of renal impairment on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied [see Clinical Pharmacology (12.3)]. Patients with renal impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN dose adjustment and more frequent blood glucose monitoring.. 8.7 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of HUMULIN has not been studied [see Clinical Pharmacology (12.3)]. Patients with hepatic impairment are at increased risk of hypoglycemia and may require more frequent HUMULIN dose adjustment and more frequent blood glucose monitoring.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Never share HUMULIN KwikPen or syringe between patients, even if the needle is changed. (5.1)Hyperglycemia 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)Hypoglycemia: May be life-threatening. Monitor blood glucose and increase monitoring frequency with changes to insulin dosage, use of glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. (5.3, 7, 8.6, 8.7)Hypersensitivity Reactions: May be life-threatening. Discontinue HUMULIN N, monitor and treat if indicated. (5.4)Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (5.5)Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. (5.6). Never share HUMULIN KwikPen or syringe between patients, even if the needle is changed. (5.1). Hyperglycemia 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). Hypoglycemia: May be life-threatening. Monitor blood glucose and increase monitoring frequency with changes to insulin dosage, use of glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. (5.3, 7, 8.6, 8.7). Hypersensitivity Reactions: May be life-threatening. Discontinue HUMULIN N, monitor and treat if indicated. (5.4). Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (5.5). Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. (5.6). 5.1 Never Share HUMULIN KwikPen or Syringe Between Patients. HUMULIN KwikPens must never be shared between patients, even if the needle is changed. Patients using HUMULIN vials must 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 (5.3)] 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.. 5.3 Hypoglycemia. Hypoglycemia is the most common adverse reaction associated with insulins, including HUMULIN N. 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).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 after an injection is related to the duration of action of the insulin 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 HUMULIN may vary in 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 [see Clinical Pharmacology (12.2)]. 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)]. 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 Hypersensitivity Reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including HUMULIN N. If hypersensitivity reactions occur, discontinue HUMULIN N; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. HUMULIN is contraindicated in patients who have had hypersensitivity reactions to HUMULIN or any of its excipients [see Contraindications (4)].. 5.5 Hypokalemia. All insulin products, including HUMULIN N, 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).. 5.6 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 HUMULIN N, 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.