Insulin Lispro Protamine and Insulin Lispro Injectable Suspension

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

Insulin Lispro Protamine and Insulin Lispro Mix75/25 is indicated to improve glycemic control in adults with diabetes mellitus.

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

Injectable Suspension: 100 units/mL (U-100) of Insulin Lispro Protamine and Insulin Lispro, 75% insulin lispro protamine and 25% insulin lispro is a white and cloudy suspension available as: 3 mL single-patient-use KwikPen prefilled pen

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

Insulin Lispro Protamine and Insulin Lispro Mix75/25 is contraindicated: during episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] in patients who have had hypersensitivity reactions to Insulin Lispro Protamine and Insulin Lispro Mix75/25 or to any of its excipients. [see Warnings and Precautions ( 5.5 )]

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

The following adverse reactions are discussed elsewhere in the labeling: Hypoglycemia [see Warnings and Precautions ( 5.3 )] Hypoglycemia Due to Medication Errors [see Warnings and Precautions ( 5.4 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] Hypokalemia [see Warnings and Precautions ( 5.6 )]

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

Table 1 below presents clinically significant drug interactions with Insulin Lispro Protamine and Insulin Lispro Mix75/25. Table 1: Clinically Significant Drug Interactions with Insulin Lispro Protamine and Insulin Lispro Mix75/25 Drugs that May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when Insulin Lispro Protamine and Insulin Lispro Mix75/25 is co-administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of Insulin Lispro Protamine and Insulin Lispro Mix75/25 Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when Insulin Lispro Protamine and Insulin Lispro Mix75/25 is co-administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Lispro Protamine and Insulin Lispro Mix75/25 Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when Insulin Lispro Protamine and Insulin Lispro Mix75/25 is co-administered with these drugs. Drugs that May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine. Intervention: Increased frequency of glucose monitoring may be required when Insulin Lispro Protamine and Insulin Lispro Mix75/25 is co-administered with these drugs.

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

Excess insulin administration may cause hypoglycemia and 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 may be treated with a glucagon product for emergency use 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 [see Warnings and Precautions ( 5.3 , 5.6 )].

11 DESCRIPTION

DESCRIPTION SECTION

Insulin lispro is a rapid-acting insulin analog produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli . Insulin lispro differs from human insulin in that the amino acid proline at position B28 is replaced by lysine and the lysine in position B29 is replaced by proline. Chemically, it is Lys(B28), Pro(B29) human insulin analog and has the empirical formula C 257 H 383 N 65 O 77 S 6 and a molecular weight of 5.808 kDa, both identical to that of human insulin. Insulin Lispro Protamine and Insulin Lispro Mix75/25 is a mixture of 75% insulin lispro protamine, an intermediate-acting human insulin analog, and 25% insulin lispro, a rapid-acting human insulin analog. Insulin lispro protamine suspension is a suspension of crystals produced from combining insulin lispro and protamine sulfate under appropriate conditions for crystal formation. Insulin lispro has the following primary structure: Insulin Lispro Protamine and Insulin Lispro Mix75/25 injectable suspension is a white and cloudy, sterile suspension for subcutaneous use. Each mL of Insulin Lispro Protamine and Insulin Lispro Mix75/25 contains 100 units of insulin lispro; dibasic sodium phosphate (2.0 mg), glycerin (16 mg), metacresol (1.76 mg), phenol (0.715 mg), protamine sulfate (0.28 mg), zinc oxide content adjusted to provide zinc ion (0.025 mg), and Water for Injection, USP. The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid is added during manufacture to adjust the pH.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

PATIENT PACKAGE INSERT

SPL PATIENT PACKAGE INSERT SECTION

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 07/2023 PATIENT INFORMATION Insulin Lispro Protamine and Insulin Lispro [IHN-soo-lihn LIYS-proh] injectable suspension, for subcutaneous use This product is HUMALOG ® Mix75/25™ (insulin lispro protamine and insulin lispro). Do not share your Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them. What is Insulin Lispro Protamine and Insulin Lispro Mix75/25? Insulin Lispro Protamine and Insulin Lispro Mix75/25 is a man-made insulin that is used to control high blood sugar in adults with diabetes mellitus. It is not known if Insulin Lispro Protamine and Insulin Lispro Mix75/25 is safe and effective in children under 18 years of age. Who should not take Insulin Lispro Protamine and Insulin Lispro Mix75/25? Do not take Insulin Lispro Protamine and Insulin Lispro Mix75/25 if you: are having an episode of low blood sugar (hypoglycemia). have an allergy to Insulin Lispro Protamine and Insulin Lispro Mix75/25 or any of the ingredients in Insulin Lispro Protamine and Insulin Lispro Mix75/25. See the end of this Patient Information leaflet for a complete list of ingredients in Insulin Lispro Protamine and Insulin Lispro Mix75/25. What should I tell my healthcare provider before taking Insulin Lispro Protamine and Insulin Lispro Mix75/25? Before taking Insulin Lispro Protamine and Insulin Lispro Mix75/25, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems. take any other medicines, especially ones called TZDs (thiazolidinediones). have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with Insulin Lispro Protamine and Insulin Lispro Mix75/25. are pregnant or plan 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 breastfeeding or plan to breastfeed. Talk with your healthcare provider about the best way to feed your baby while taking Insulin Lispro Protamine and Insulin Lispro Mix75/25. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Before you start taking Insulin Lispro Protamine and Insulin Lispro Mix75/25, talk to your healthcare provider about low blood sugar and how to manage it. How should I take Insulin Lispro Protamine and Insulin Lispro Mix75/25? Read the Instructions for Use that comes with your Insulin Lispro Protamine and Insulin Lispro Mix75/25. Take Insulin Lispro Protamine and Insulin Lispro Mix75/25 exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much Insulin Lispro Protamine and Insulin Lispro Mix75/25 to take and when to take it. Insulin Lispro Protamine and Insulin Lispro Mix75/25 starts acting fast. Inject Insulin Lispro Protamine and Insulin Lispro Mix75/25 within 15 minutes before you eat a meal. Know the type, strength, and amount of insulin you take. Do not change the type or amount of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin. Check your insulin label each time you give your injection to make sure you are taking the correct insulin. Inject Insulin Lispro Protamine and Insulin Lispro Mix75/25 under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs or upper arms. Do not inject Insulin Lispro Protamine and Insulin Lispro Mix75/25 into your vein (intravenously) or use in an insulin infusion pump. 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. Do not mix Insulin Lispro Protamine and Insulin Lispro Mix75/25 with other insulins or liquids. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. Keep Insulin Lispro Protamine and Insulin Lispro Mix75/25 and all medicines out of the reach of children. Your dose of Insulin Lispro Protamine and Insulin Lispro Mix75/25 may need to change because of a: • change in physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take. What should I avoid while taking Insulin Lispro Protamine and Insulin Lispro Mix75/25? While taking Insulin Lispro Protamine and Insulin Lispro Mix75/25 do not: drive or operate heavy machinery until you know how Insulin Lispro Protamine and Insulin Lispro Mix75/25 affects you. drink alcohol or take prescription or over-the-counter medicines that contain alcohol. What are the possible side effects of Insulin Lispro Protamine and Insulin Lispro Mix75/25? Insulin Lispro Protamine and Insulin Lispro Mix75/25 may cause serious side effects that can lead to death, including: low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include: dizziness or light-headedness sweating confusion headache blurred vision slurred speech shakiness fast heartbeat anxiety, irritability or mood changes hunger Your healthcare provider may prescribe a glucagon product for emergency use so that someone else can give you glucagon if your blood sugar becomes too low (severe hypoglycemia) and you are unable to take sugar by mouth. severe allergic reaction (whole body reaction). Get medical help right away, if you have any of these signs or symptoms of a severe allergic reaction: a rash over your whole body trouble breathing a fast heartbeat sweating low potassium in your blood (hypokalemia). heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with Insulin Lispro Protamine and Insulin Lispro Mix75/25 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25. Your healthcare provider should monitor you closely while you are taking TZDs with Insulin Lispro Protamine and Insulin Lispro Mix75/25. 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 include: low blood sugar (hypoglycemia) reactions at your injection site skin thickening or pits at the injection site (lipodystrophy) weight gain swelling in your hands or feet itching rash These are not all the possible side effects of Insulin Lispro Protamine and Insulin Lispro Mix75/25. 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take Insulin Lispro Prot...

KWIKPEN INSTRUCTIONS FOR USE

INSTRUCTIONS FOR USE SECTION

INSTRUCTIONS FOR USE Insulin Lispro Protamine and Insulin Lispro [IHN-soo-lihn LIYS-proh] Mix75/25™ KwikPen ® injectable suspension, for subcutaneous use 3 mL single-patient-use pen (100 units per mL) This product is HUMALOG ® Mix75/25™ (insulin lispro protamine and insulin lispro). Read this Instructions for Use before you start taking Insulin Lispro Protamine and Insulin Lispro Mix75/25 and each time you get another KwikPen. 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 Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them. Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen (“Pen”) is a disposable single-patient-use prefilled pen containing 300 units of Insulin Lispro Protamine and Insulin Lispro Mix75/25. You can give yourself more than 1 dose from the Pen. By turning the Dose Knob, you can dial doses from 1 to 60 units in 1 unit increments. If your dose is more than 60 units, you will need to give yourself more than 1 injection. The Plunger only moves a little with each injection, and you may not notice that it moves. The Plunger will only reach the end of the cartridge when you have used all 300 units in the Pen. People who are blind or have vision problems should not use this Pen without help from a person trained to use the Pen. How to recognize your Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen Pen color: Dark blue Dose Knob: Dark blue Labels: White label with yellow stripe Supplies you will need to give your injection Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles recommended) Alcohol swab Gauze Preparing your Pen Wash your hands with soap and water. Check your Pen to make sure you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin. Always use a new needle for each injection to help prevent infections and blocked needles. Do not reuse or share your needles with other people. You may give other people a serious infection or get a serious infection from them. Step 1: Pull the Pen Cap straight off. - Do not remove the Pen Label. Wipe the Rubber Seal with an alcohol swab. - Do not attach the Needle before mixing. Step 2: Gently roll the Pen between your hands at least 10 times. Step 3: Move the Pen up and down (invert) at least 10 times. Mixing by rolling and inverting the Pen is important to make sure you get the right dose. After mixing Insulin Lispro Protamine and Insulin Lispro Mix75/25, inject your dose right away. If you wait to inject your dose, the insulin will need to be mixed again. Step 4: Check the liquid in the Pen. Insulin Lispro Protamine and Insulin Lispro Mix75/25 should look white and cloudy after mixing. Do not use if it looks clear or has any lumps or particles in it. Step 5: Select a new Needle. Pull off the Paper Tab from the Outer Needle Shield. Step 6: Push the capped Needle straight onto the Pen and twist the Needle on until it is tight. Step 7: Pull off the Outer Needle Shield. Do not throw it away. Pull off the Inner Needle Shield and throw it away. Priming your Pen Prime your Pen before each injection. Priming your Pen means removing the air from the Needle and Cartridge that may collect during normal use and ensures that the Pen is working correctly. If you do not prime before each injection, you may get too much or too little insulin. Step 8: To prime your Pen, turn the Dose Knob to select 2 units. Step 9: Hold your Pen with the Needle pointing up. Tap the Cartridge Holder gently to collect air bubbles at the top. Step 10: Continue holding your Pen with Needle pointing up. Push the Dose Knob in until it stops, and “0” is seen in the Dose Window. Hold the Dose Knob in and count to 5 slowly . You should see insulin at the tip of the Needle. - If you do not see insulin, repeat priming steps 8 to 10, no more than 4 times. - If you still do not see insulin, change the Needle and repeat priming steps 8 to 10. Small air bubbles are normal and will not affect your dose. Selecting your dose You can give from 1 to 60 units in a single injection. If your dose is more than 60 units, you will need to give more than one injection. - If you need help with dividing up your dose the right way, ask your healthcare provider. - Use a new Needle for each injection and repeat the priming steps. Step 11: Turn the Dose Knob to select the number of units you need to inject. The Dose Indicator should line up with your dose. - The Pen dials 1 unit at a time. - The Dose Knob clicks as you turn it. - Do not dial your dose by counting the clicks. You may dial the wrong dose. This may lead to you getting too much insulin or not enough insulin. - The dose can be corrected by turning the Dose Knob in either direction until the correct dose lines up with the Dose Indicator. - The even numbers (for example, 12) are printed on the dial. - The odd numbers, (for example, 25) after the number 1, are shown as full lines. Always check the number in the Dose Window to make sure you have dialed the correct dose. (Example: 12 units shown in the Dose Window) (Example: 25 units shown in the Dose Window) The Pen will not let you dial more than the number of units left in the Pen. If you need to inject more than the number of units left in the Pen, you may either: - inject the amount left in your Pen and then use a new Pen to give the rest of your dose, or - get a new Pen and inject the full dose. It is normal to see a small amount of insulin left in the Pen that you can not inject. Giving your injection Inject your insulin 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. Do not try to change your dose while injecting. Step 12: Choose your injection site. Insulin Lispro Protamine and Insulin Lispro Mix75/25 is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. Wipe your skin with an alcohol swab, and let your skin dry before you inject your dose. Step 13: Insert the Needle into your skin. Push the Dose Knob all the way in. Continue to hold the Dose Knob in and slowly count to 5 before removing the Needle. Do not try to inject your insulin by turning the Dose Knob. You will not receive your insulin by turning the Dose Knob. Step 14: Pull the Needle out of your skin. A drop of insulin at the Needle tip is normal. It will not affect your dose. Check the number in the Dose Window. - If you see “0” in the Dose Window, you have received the full amount you dialed. - If you do not see “0” in the Dose Window, do not redial. Insert the Needle into your skin and finish your injection. - If you still do not think you received the full amount you dialed for your injection, do not start over or repeat the injection. Monitor your blood glucose as instructed by your healthcare provider. - If you normally need to give 2 injections for your full dose, be sure to give your second injection. The Plunger only moves a little with each injection, and you may not notice that it moves. If you see blood after you take the Needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area. After your injection Step 15: Carefully replace the Outer Needle Shield. Step 16: Unscrew the capped Needle and throw it away (see Disposing of Pens and Needles section). Do not store t...

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE CARTON – Insulin Lispro Protamine and Insulin Lispro Injectable Suspension KwikPen Mix75/25™ 5ct NDC 0002-8233-05 Insulin Lispro Protamine and Insulin Lispro KwikPen Mix75/25™ Injectable Suspension For Single Patient Use Only Dispense in this sealed carton. Needles not included 100 units per mL (U-100) This device is recommended for use with Becton, Dickinson and Company's insulin pen needles For subcutaneous use only. prefilled insulin delivery device Rx only This product is Humalog Mix75/25. 5 x 3 mL Prefilled Pens Read Insulin Delivery Device Instructions for Use