ADLYXIN

ADLYXIN is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

ADLYXIN (lixisenatide) injection is a clear and colorless solution supplied in a 3 mL singlepatient-use pen. The green starter pen is 50 mcg/mL and delivers 14 doses of 10 mcg. The burgundy maintenance pen is 100 mcg/mL and delivers 14 doses of 20 mcg. The following packages are available: • Starter Pack, NDC 0024-5745-02: For treatment initiation, Starter Pack contains 1 singlepatient-use prefilled green pen of ADLYXIN 10 mcg (NDC 0024-5741-01) and 1 singleReference ID: 5761754 patient-use prefilled burgundy pen of ADLYXIN 20 mcg (NDC 0024-5740-00). • Maintenance Pack, NDC 0024-5747-02: Contains 2 single-patient-use prefilled burgundy pens for ADLYXIN 20 mcg (NDC 0024-5740-00). 16.2 Storage and Handling Prior to first use, ADLYXIN should be stored in a refrigerator, 36°F to 46°F (2°C to 8°C). Do not freeze. Keep the prefilled pen in the original package to protect it from light. After first use, store up to 86°F (30°C). Replace the pen cap after each use to protect from light. Discard pen 14 days after first use.

2.1 Dosing Instructions • The starting dose of ADLYXIN is 10 mcg subcutaneously once daily for 14 days. Initiation with the 10 mcg once daily dosage is intended to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] and is not effective for glycemic control in adults. • Increase the dose to the maintenance dose of 20 mcg once daily starting on Day 15. 2.2 Important Administration Instructions • Instruct patients and caregivers on the preparation and use of the pen prior to first use of ADLYXIN. Training should include a practice injection. • Inspect ADLYXIN visually before use. It should appear clear and colorless. Do not use ADLYXIN if particulate matter or coloration is seen. • Administer ADLYXIN by subcutaneous injection in the abdomen, thigh or upper arm once daily. • Rotate injections sites with each dose. Do not use the same site for each injection. • Instruct patients to administer an injection of ADLYXIN within one hour before the first meal of the day preferably the same meal each day. If a dose is missed, administer ADLYXIN within one hour prior to the next meal.

ADLYXIN is contraindicated in patients with known severe hypersensitivity to lixisenatide or to any component of ADLYXIN. Hypersensitivity reactions including anaphylaxis have occurred with ADLYXIN [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Anaphylaxis and Serious Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions, including anaphylaxis, have been reported in clinical trials of ADLYXIN and during postmarketing use of GLP-1 receptor agonists. If symptoms of hypersensitivity reactions occur, inform patients that they must stop taking ADLYXIN and seek medical advice promptly [see Warnings and Precautions (5.1)]. Acute Pancreatitis Inform patients of the potential risk for acute pancreatitis and its symptoms: severe abdominal pain that may radiate to the back, and which may or may not be accompanied by nausea or vomiting. Instruct patients to discontinue ADLYXIN promptly and contact their physician if pancreatitis is suspected [see Warnings and Precautions (5.2)]. Never Share ADLYXIN Pen Between Patients Advise patients that they should never share ADLYXIN pen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.3)]. Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Inform patients that the risk of hypoglycemia increased when ADLYXIN is used in combination with a sulfonylurea or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)]. Acute Kidney Injury Due to Volume Depletion Inform patients of the potential risk of acute kidney injury due to dehydration associated with gastrointestinal adverse reactions. Advise patients to take precautions to avoid fluid depletion. Inform patients of the signs and symptoms of acute kidney injury and instruct them to promptly report any of these signs or symptoms or persistent (or extended) nausea, vomiting, and diarrhea to their healthcare provider [see Warnings and Precautions (5.5)]. Severe Gastrointestinal Adverse Reactions Reference ID: 5761754 Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.6)]. Acute Gallbladder Disease Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up [see Warnings and Precautions (5.8)]. Pulmonary Aspiration During General Anesthesia or Deep Sedation Inform patients that ADLYXIN may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking ADLYXIN [see Warnings and Precautions (5.9)]. Use in Pregnancy Advise patients to inform their physicians if they are pregnant or intend to become pregnant [see Use in Specific Populations (8.1)]. Manufactured by: sanofi-aventis U.S. LLC Morristown, NJ 07960 A SANOFI COMPANY U.S. License No. 1752 ©2026 sanofi-aventis U.S. LLC Reference ID: 5761754 MEDICATION GUIDE ADLYXIN® (ad-LIX-in) (lixisenatide) injection, for subcutaneous use What is the most important information I should know about ADLYXIN? ADLYXIN may cause serious side effects including inflammation of the pancreas (pancreatitis), Stop using ADLYXIN and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without nausea or vomiting. You may feel the pain from your abdomen to your back. What is ADLYXIN? ADLYXIN is an injectable prescription medicine that is used along with diet and exercise to improve blood sugar (glucose) in adults with type 2 diabetes. It is not known if ADLYXIN is safe and effective in children. Who should not use ADLYXIN? Do not use ADLYXIN if you: • have had a serious allergic reaction to lixisenatide or any of the ingredients in ADLYXIN. See the end of this Medication Guide for a complete list of ingredients in ADLYXIN. See “What are the possible side effects of ADLYXIN?” for symptoms of a serious allergic reaction. Before using ADLYXIN, tell your healthcare provider about all of your medical conditions, including if you: • have or have had problems with your pancreas. • have severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems with digesting food. • are scheduled to have surgery or other procedures that use general anesthesia or deep sleepiness (deep sedation). • are pregnant or plan to become pregnant. It is not known if ADLYXIN will harm your unborn baby. Tell your healthcare provider if you are pregnant or plan to become pregnant while using ADLYXIN. • are breastfeeding or plan to breastfeed. It is not known if ADLYXIN passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you use ADLYXIN. Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins and herbal supplements. ADLYXIN may affect the way some medicines work and some medicines may affect the way ADLYXIN works. Before using ADLYXIN, talk to your healthcare provider about low blood sugar and how to manage it. Tell your healthcare provider if you are taking other medicines to treat diabetes, including insulin or sulfonylureas. Especially tell your healthcare provider if you take: • antibiotics or the pain reliever, acetaminophen. Take these medicines at least 1 hour before using ADLYXIN. If you must take these medicines, take them with a meal or a snack. You should not take these medicines at the same time that you take ADLYXIN. • birth control pills that are taken by mouth (oral contraceptives). ADLYXIN may lower the amount of the medicine in your blood from your birth control pills and they may not work as well to prevent pregnancy. Take your birth control pill at least 1 hour before your injection of ADLYXIN or at least 11 hours after your ADLYXIN injection. Reference ID: 5761754 Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. How should I use ADLYXIN? • Read the Instructions for Use that comes with ADLYXIN. • Use ADLYXIN exactly as your healthcare provider tells you to. • Do not change your dose unless your healthcare provider has told you to change your dose. • Your healthcare provider should teach you how to inject ADLYXIN before you use it for the first time. • Inject your dose of ADLYXIN under the skin (subcutaneously) of your abdomen, thigh or upper arm. Do not inject into a muscle (intramuscularly) or vein (intravenously). • Use ADLYXIN 1 time each day within 60 minutes (1 hour) before the first meal of the day and at the same time each day. • If you miss a dose of ADLYXIN, take it within 1 hour before your next meal. • Check the label on the pen each time you give your ADLYXIN injection to make sure you are using the correct medicine. • You must activate each ADLYXIN pen before you use it for the first time. • Change (rotate) your injection sites within the area you chose with each dose. Do not use the same spot for each injection. • Do not re-use or share your needles with other people. You may give other people a serious infection or get a serious infection from them • If you take too much ADLYXIN, call your healthcare provider or the Poison Help line at 1-800222-1222 or go to the nearest hospital emergency room right away. What are the possible side effects of ADLYXIN? ADLYXIN may cause serious side effects including: • See “What is the most important information I should know about ADLYXIN?” • severe allergic reactions. Stop taking ADLYXIN and get medical help right away if you have any symptoms of a severe allergic reaction including: o swelling of your face, lips, tongue or o fainting or feeling dizzy throat o very rapid heartbeat o problems breathing or swallowing o severe rash or itching • low blood sugar (hypoglycemia). Your risk for getting low blood sugar is higher if you use ADLYXIN with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. The dose of your sulfonylurea or insulin medicine may need to be lowered while you use ADLYXIN. Signs and symptoms of low blood sugar may include: o Dizziness or light- o blurred vision o anxiety, irritability, or headedness o slurred speech mood changes o sweating o shakiness o hunger o confusion or o fast heartbeat o weakness drowsiness o feeling jittery o headache • dehydration leading to kidney problems. Diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems. It is important for you to drink fluids to help reduce your chance of dehydration. Tell your healthcare provider right away if you have nausea, vomiting, or diarrhea that does not go away. • severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use ADLYXIN. Tell your healthcare provider if you have stomach problems that are severe or will not go away. • gallbladder problems. Gallbladder problems have happened in some people who take ADLYXIN. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include: Reference ID: 5761754 o pain in your upper stomach (abdomen) o yellowing of skin or eyes (jaundice) o fever o clay-colored stools • food or liquid getting into the lungs during surgery or other procedures that use general anesthesia or deep sleepiness (deep sedation). ADLYXIN may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking ADLYXIN before you are scheduled to have surgery or other procedures. The most common side effects of ADLYXIN include: • nausea • diarrhea • vomiting • feeling dizzy • headache Talk to your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of ADLYXIN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ADLYXIN? • Store your new, unused ADLYXIN pen in the refrigerator at 36°F to 46°F (2°C to 8°C). • After activation, store your ADLYXIN pen at room temperature no higher than 86°F (30°C). • Do not freeze ADLYXIN pens and do not use ADLYXIN if it has been frozen. • Protect the pen from light. • Replace the pen cap after each use to protect the container window from light. • After activation, use the ADLYXIN pen for up to 14 days. Throw away the used ADLYXIN pen after 14 days, even if there is some medicine left in the pen. • Do not use ADLYXIN past the expiration date printed on the label of the carton and pen. • Do not store the ADLYXIN pen with the needle attached. If the needle is left on, this might lead to contamination and cause air bubbles which might affect your dose of medicine. • See the Instructions for Use about the right way to throw away the ADLYXIN pen. Keep your ADLYXIN pen, pen needles, and all medicines out of the reach of children. General information about the safe and effective use of ADLYXIN. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ADLYXIN for a condition for which it was not prescribed. Do not give ADLYXIN to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ADLYXIN that is written for health professionals. What are the ingredients in ADLYXIN? Active ingredient: lixisenatide Inactive ingredients: glycerol 85%, metacresol, methionine, sodium acetate trihydrate, and Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide solution are added as needed to adjust the pH. Manufactured by: sanofi-aventis U.S. LLC, Morristown, NJ 07960, A SANOFI COMPANY U.S. License No.1752 For more information, go to www.ADLYXIN.com or call sanofi-aventis at 1-800-633-1610. This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: March 2026 Reference ID: 5761754 INSTRUCTIONS FOR USE ADLYXIN® (ad-LIX-in) (lixisenatide) Injection, for subcutaneous use One pre-filled pen contains 14 doses, each dose contains 20 micrograms (mcg) in 0.2 mL. Section 1 – Important Information Read these instructions carefully before using your ADLYXIN pen. Keep this leaflet for future reference. Do not share your ADLYXIN pen 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. ADLYXIN pen Information x ADLYXIN comes as a single-patient-use prefilled pen for injection. x Inject 1 dose per day. x There is no need to measure each dose. x Talk with your healthcare provider about how to use the ADLYXIN pen and to inject correctly before using it. x If you cannot follow all the instructions completely on your own or are not able to handle the pen (for example, if you have vision problems), only use it if you have help. About Your ADLYXIN Pen Burgundy 20 mcg ADLYXIN pen The plunger will move along the dose scale after each injection. In the example above, the dose number shows there are 13 injections left in the ADLYXIN pen. 1 Reference ID: 5761754 x Always check the label to make sure you have the correct ADLYXIN pen. Also, check that it has not passed the expiration date printed on the ADLYXIN pen. Do not use ADLYXIN past the expiration date. Using the wrong medicine could be harmful to your health. x Inject ADLYXIN only by using this pen injector. Never use a syringe to withdraw ADLYXIN from the pen. About your pen needles (supplied separately) x Pen needles are not included with your pen. x Always use a new needle for each injection. This helps prevent contamination of ADLYXIN or possible needle blockage. x Only use needles that have been approved for use with ADLYXIN. The ADLYXIN pen may be used with certain pen needles from Becton Dickinson, Ypsomed, and Owen Mumford that are 8 mm long or shorter. Ask your healthcare provider which needle gauge and length is best for you. x Do not reuse or share needles with another person. Section 2 – Getting Started x Activate the pen on the same day as your first injection with your new pen. First activate your new pen x Before injecting the first dose of ADLYXIN, you must activate the new pen. This is a one-time process called “activation.” Step 1 to Step 5 below show you how to do this. x Activation is done to make sure that the pen is working correctly and that the dose for your first injection is correct. x Do not repeat the activation process or you will not receive 14 doses from your ADLYXIN pen. The pictures below show how the injection button of your pen changes after activation. Before activation After activation (orange window) (white window) The pen is not activated when the activation The pen is activated and window is orange. The pen must be ready for injections when the activation activated before injecting your first dose of window is white. ADLYXIN. 2 Reference ID: 5761754 How to activate your new ADLYXIN pen Step 1. Pull off the pen cap and check the pen Step 2. Screw needle on and remove needle caps x Always use a new needle for activation. x Remove the protective seal from the outer needle cap. x Line up the needle with the pen. Push the outer needle cap containing the needle straight onto the pen, then screw the needle on until secure. x Pull off (do not unscrew) the outer needle cap. o Pull off the inner needle cap and throw it away. o Keep the outer needle cap to remove the needle later. x Take care not to injure yourself when the needle is exposed. Step 3. Pull the injection button out 3 Reference ID: 5761754 The arrow in the window will be pointing towards the injection button. Pull the injection button out firmly until it stops. The arrow will now be pointing towards the needle. Step 4. Firmly press and hold the injection button to remove the liquid x Do not inject into the body. x Point the needle into a container (like a paper cup or tissue). x Firmly press the injection button all the way in to discard the liquid. You may feel or hear a “click.” x Keep the injection button pressed in and slowly count to 2, which is equal to 2 seconds. x If no liquid comes out of your pen, see the Questions and Answers section at the end of this Instructions for Use. x Check that the activation window is now white. Step 5. The pen is now ready for use. x Do not activate this pen again. For your first injection, go directly to Section 3 – Step 3. x You do not need to replace the needle between activation and first injection if you inject yourself immediately after activation. Section 3 – Daily use of pen Inject only 1 dose each day. 4 Reference ID: 5761754 Check to make sure the activation window is white before continuing in this section. Step 1. Pull off pen cap and check pen Step 2. Attach a new needle and remove the needle caps x Always use a new needle for each injection. x Remove the protective seal from the outer needle cap. x Line up the needle with the pen. Put the outer needle cap containing the needle straight on the pen, then screw the needle on until secure. x Pull off (do not unscrew) the outer needle cap. o Pull off the inner needle cap and throw it away. o Keep the outer needle cap to remove the needle later. 5 Reference ID: 5761754 x Take care not to injure yourself when the needle is exposed. Step 3. Pull the injection button out The arrow in the window will be pointing towards the injection button. Pull the injection button out firmly until it stops. The arrow will now be pointing towards the needle. Step 4. Choosing Injection Sites Injection sites BackFront ADLYXIN must be injected under the skin and can be injected in any of the areas shown above in blue. These areas include the thigh, abdomen, or upper arm. Ask your healthcare provider about how to inject correctly. Step 5. Press and hold the injection button to inject the dose 6 Reference ID: 5761754 x Grasp a fold of skin and insert the needle (see the Injection sites section about where to inject). x Press the injection button all the way in. You may feel or hear a “click.” x Keep the injection button pressed in, hold the pen in place and slowly count to 2, which is equal to 2 seconds, before you pull the needle out of the skin. If you do not hold the injection button in or if you remove the injector too early you may not get the full dose. Your dose has now been given. Pull the needle out of your skin. Step 6. Remove and throw away needle after each injection x Grip the widest part of the outer needle cap. Keep the needle straight and guide it into the outer needle cap. x Then push firmly on. x The needle can puncture the cap if it is recapped at an angle. x Grip and squeeze the widest part of the outer needle cap. Turn your pen several times with your other hand to remove the needle. x Try again if the needle does not come off the first time. x Replace the pen cap. x Put the needle in a puncture-resistant container (or as instructed by your healthcare provider). Step 7. Repeat all steps in Section 3 for each injection. 7 Reference ID: 5761754 Throw away a pen 14 days after activation, even if there is some medicine left. Table of activation and disposal In the table, write the date when you activated your pen and the date to throw it away 14 days later. Pen Date of activation Date to throw away 1 2 3 4 5 6 Storage General information x Keep your ADLYXIN pen in a safe place out of the reach and sight of children. x Protect your ADLYXIN pen from dust and dirt. x Replace the pen cap after each use in order to protect the container window from light. x Protect the ADLYXIN pen from light. x Do not use ADLYXIN after the expiration date, which is stated on the label and on the carton. The expiration date refers to the last day of that month. Before activation of the pen: x Store your unused ADLYXIN pens in the refrigerator at 36°F to 46°F (2°C to 8°C). x Do not freeze ADLYXIN pens and do not use ADLYXIN if it has been frozen. x Allow your pen to warm at room temperature before using. After activation of the pen: x After activation, store your ADLYXIN pen at room temperature no higher than 86°F (30°C). x Do not store your ADLYXIN pen with the needle attached. An attached needle might lead to contamination and may cause air bubbles which might affect your dose of medicine. x After your ADLYXIN pen is activated it can be used for up to 14 days. Throw away a used ADLYXIN pen after 14 days. Do this even if there is some medicine left in the pen. Throwing your pen away x Replace the pen cap before throwing away (disposing of) your ADLYXIN pen. x Put the used ADLYXIN pen in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the ADLYXIN pen and loose needles in your household trash. x If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. o 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. 8 Reference ID: 5761754 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 FDA's website at: http://www.fda.gov/safesharpsdisposal. x 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. Maintenance x Handle your ADLYXIN pen with care. x You can clean the outside of your ADLYXIN pen by wiping it with a damp cloth. x Do not soak, wash, or put liquid on (lubricate) your ADLYXIN pen. This may damage it. x If you think your ADLYXIN pen may be damaged, do not use it. Get a new one. Do not try to repair the pen. Questions and Answers What do I do if I forget to activate the ADLYXIN pen or inject myself before activation? If you have injected yourself before activating the pen, do not correct this by giving yourself a second injection. Contact your healthcare provider for advice on checking your blood sugar. What do I do if there are air bubbles in the container? Small air bubbles in the container are normal and they will not harm you. Your dose will be correct and you can keep following the instructions. Contact your healthcare provider if you need help. What do I do if no liquid comes out during activation? The needle may be blocked or not properly attached. Remove the needle from the pen, attach a new needle, and repeat Step 4 and Step 5 of Section 2 only. If still no liquid comes out, your ADLYXIN pen may be damaged. Do not use this ADLYXIN pen. Contact your healthcare provider for help. What do I do if it is hard to press the injection button all the way in? The needle may be blocked or not properly attached. Pull the needle out of your skin and remove the needle from the pen. Attach a new needle and repeat Step 5 and Step 6 of Section 3 only. If it is still hard to press in the injection button, your ADLYXIN pen may be damaged. Do not use this ADLYXIN pen. Contact your healthcare provider for help. Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY U.S. License No. 1752 ©202x sanofi-aventis U.S. LLC If you have any questions about ADLYXIN or about diabetes, ask your healthcare provider or call sanofi-aventis U.S. LLC at 1-800-633-1610. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: July 2021 9 Reference ID: 5761754 INSTRUCTIONS FOR USE ADLYXIN® (ad-LIX-in) (lixisenatide) Injection, for subcutaneous use Starter pack - Contains 2 prefilled pens each with 14 doses. One 10 microgram (mcg) pen, each dose contains 10 mcg in 0.2 mL. One 20 microgram (mcg) pen, each dose contains 20 mcg in 0.2 mL. Section 1 – Important Information Read these instructions carefully before using your ADLYXIN pens. Keep this leaflet for future reference. Do not share your ADLYXIN pen 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. ADLYXIN pen Information x ADLYXIN comes as a single-patient-use prefilled pen for injection. x Inject 1 dose per day. x There is no need to measure each dose. x Talk with your healthcare provider about how to use the ADLYXIN pen and to inject correctly before using it. x If you cannot follow all the instructions completely on your own or are not able to handle the pen (for example, if you have vision problems), only use it if you have help. About Your ADLYXIN Starter Pack The ADLYXIN Starter pack includes 2 different colored pens that contain different strengths of ADLYXIN. Both pens are used in the same way. x The green pen contains 14 pre-set doses. Each dose contains 10 mcg of ADLYXIN. x The burgundy pen contains 14 pre-set doses. Each dose contains 20 mcg of ADLYXIN. You must start your treatment with the green 10 mcg ADLYXIN pen. You must first use all 14 doses from this pen. Then use the burgundy 20 mcg ADLYXIN pen. About Your ADLYXIN Pens Green 10 mcg ADLYXIN pen 1 Reference ID: 5761754 The plunger will move along the dose scale after each injection. In the example above, the dose number shows there are 13 injections left in the ADLYXIN pen. Burgundy 20 mcg ADLYXIN pen x Always check the label to make sure you have the correct ADLYXIN pen. Also, check that it has not passed the expiration date printed on the ADLYXIN pen. Do not use ADLYXIN past the expiration date. Using the wrong medicine could be harmful to your health. x Inject ADLYXIN only by using this pen injector. Never use a syringe to withdraw ADLYXIN from the pen. About your pen needles (supplied separately) x Pen needles are not included with your pen. x Always use a new needle for each injection. This helps prevent contamination of ADLYXIN or possible needle blockage. Reference ID: 5761754 2 x Only use needles that have been approved for use with ADLYXIN. The ADLYXIN pen may be used with certain pen needles from Becton Dickinson, Ypsomed, and Owen Mumford that are 8 mm long or shorter. Ask your healthcare provider which needle gauge and length is best for you. x Do not reuse or share needles with another person. Section 2 – Getting Started x Begin with the green 10 mcg ADLYXIN pen. x Do not activate the burgundy 20 mcg ADLYXIN pen until you have finished the green pen. First activate your new pen x Before injecting the first dose of ADLYXIN, you must activate the new pen. This is a onetime process called “activation.” Step 1 to Step 5 below show you how to do this. x Activation is done to make sure that the pen is working correctly and that the dose for your first injection is correct. x Do not repeat the activation process or you will not receive 14 doses from your ADLYXIN pen. The pictures below show how the injection button of your pen changes after activation. Before activation (orange window) After activation (white window) The pen is not activated when the activation The pen is activated and ready for injections window is orange. The pen must be activated when the activation window is white. before injecting your first dose of ADLYXIN. How to activate your new ADLYXIN pen Step 1. Pull off the pen cap and check the pen Reference ID: 5761754 3 Step 2. Screw needle on and remove needle caps x Always use a new needle for activation. x Remove the protective seal from the outer needle cap. x Line up the needle with the pen. Push the outer needle cap containing the needle straight onto the pen, then screw the needle on until secure. x Pull off (do not unscrew) the outer needle cap. o Pull off the inner needle cap and throw it away. o Keep the outer needle cap to remove the needle later. x Take care not to injure yourself when the needle is exposed. Step 3. Pull the injection button out The arrow in the window will be pointing towards the injection button. Reference ID: 5761754 4 Pull the injection button out firmly until it stops. The arrow will now be pointing towards the needle. Step 4. Firmly press and hold the injection button to remove the liquid x Do not inject into the body. x Point the needle into a container (like a paper cup or tissue). x Firmly press the injection button all the way in to discard the liquid. You may feel or hear a “click.” x Keep the injection button pressed in and slowly count to 2, which is equal to 2 seconds. x If no liquid comes out of your pen, see the Questions and Answers section at the end of this Instructions for Use. x Check that the activation window is now white. Step 5. The pen is now ready for use. x Do not activate this pen again. For your first injection, go directly to Section 3 – Step 3. x You do not need to replace the needle between activation and first injection if you inject yourself immediately after activation. Section 3 – Daily use of pen Inject only 1 dose each day. Reference ID: 5761754 5 Check to make sure the activation window is white before continuing in this section. Step 1. Pull off pen cap and check pen Step 2. Attach a new needle and remove the needle caps x Always use a new needle for each injection. x Remove the protective seal from the outer needle cap. x Line up the needle with the pen. Put the outer needle cap containing the needle straight on the pen, then screw the needle on until secure. x Pull off (do not unscrew) the outer needle cap. o Pull off the inner needle cap and throw it away. o Keep the outer needle cap to remove the needle later. x Take care not to injure yourself when the needle is exposed. Step 3. Pull the injection button out Reference ID: 5761754 6 The arrow in the window will be pointing towards the injection button. Pull the injection button out firmly until it stops. The arrow will now be pointing towards the needle. Step 4. Choosing Injection Sites Injection sites Front Back ADLYXIN must be injected under the skin and can be injected in any of the areas shown above in blue. These areas include the thigh, abdomen, or upper arm. Ask your healthcare provider about how to inject correctly. Step 5. Press and hold the injection button to inject the dose Reference ID: 5761754 7 x Grasp a fold of skin and insert the needle (see the Injection sites section about where to inject). x Press the injection button all the way in. You may feel or hear a “click.” x Keep the injection button pressed in, hold the pen in place and slowly count to 2, which is equal to 2 seconds, before you pull the needle out of the skin. If you do not hold the injection button in or if you remove the injector too early you may not get the full dose. Your dose has now been given. Pull the needle out of your skin. Step 6. Remove and throw away needle after each injection x Grip the widest part of the outer needle cap. Keep the needle straight and guide it into the outer needle cap. x Then push firmly on. x The needle can puncture the cap if it is recapped at an angle. x Grip and squeeze the widest part of the outer needle cap. Turn your pen several times with your other hand to remove the needle. x Try again if the needle does not come off the first time. x Replace the pen cap. Reference ID: 5761754 8 x Put the needle in a puncture-resistant container (or as instructed by your healthcare provider). Step 7. Repeat all steps in Section 3 for each injection. Throw away a pen 14 days after activation, even if there is some medicine left. After the green pen is thrown away continue to Section 4 to begin using the burgundy pen. Section 4 – Moving to the burgundy pen Completed use of the green 10 mcg pen The green 10 mcg ADLYXIN pen is empty when the black plunger has reached “0” on the dose scale and the injection button cannot be pulled out fully. After the green 10 mcg ADLYXIN pen is empty you must continue your treatment the next day using the burgundy 20 mcg ADLYXIN pen. This is used in exactly the same way. Use of burgundy 20 mcg pen Burgundy 20 mcg pen activation The burgundy 20 mcg ADLYXIN pen must also be activated before use. Follow all steps in Section 2. Burgundy 20 mcg pen use To inject a dose with the burgundy 20 mcg ADLYXIN pen, follow all steps in Section 3. Repeat Section 3 for your daily injections until your pen is empty. Table of activation and disposal In the table write the date when you activated your pen and the date to throw it away 14 days later. Pen Date of activation Date to throw away 10 mcg ___ / ___ / ___ ___ / ___ / ___ Reference ID: 5761754 9 20 mcg ___ / ___ / ___ ___ / ___ / ___ Storage General information x Keep your ADLYXIN pens in a safe place out of the reach and sight of children. x Protect your ADLYXIN pens from dust and dirt. x Replace the pen cap after each use in order to protect the container window from light. x Protect the ADLYXIN pen from light. x Do not use ADLYXIN after the expiration date, which is stated on the label and on the carton. The expiration date refers to the last day of that month. Before activation of the pen: x Store your unused ADLYXIN pens in the refrigerator at 36°F to 46°F (2°C to 8°C). x Do not freeze ADLYXIN pens and do not use ADLYXIN if it has been frozen. x Allow your pen to warm at room temperature before using. After activation of the pen: x After activation, store your ADLYXIN pen at room temperature no higher than 86°F (30°C). x Do not store your ADLYXIN pen with the needle attached. An attached needle might lead to contamination and may cause air bubbles which might affect your dose of medicine. x After your ADLYXIN pen is activated it can be used for up to 14 days. Throw away a used ADLYXIN pen after 14 days. Do this even if there is some medicine left in the pen. Throwing your pen away x Replace the pen cap before throwing away (disposing of) your ADLYXIN pen. x Put the used ADLYXIN pen in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the ADLYXIN pen and loose needles in your household trash. x If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. o 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 FDA's website at: http://www.fda.gov/safesharpsdisposal. x 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. Maintenance x Handle your ADLYXIN pen with care. x You can clean the outside of your ADLYXIN pen by wiping it with a damp cloth. Reference ID: 5761754 10 x Do not soak, wash, or put liquid on (lubricate) your ADLYXIN pen. This may damage it. x If you think your ADLYXIN pen may be damaged, do not use it. Get a new one. Do not try to repair the pen. Questions and Answers What do I do if I forget to activate the ADLYXIN pen or inject myself before activation? If you have injected yourself before activating the pen, do not correct this by giving yourself a second injection. Contact your healthcare provider for advice on checking your blood sugar. What do I do if there are air bubbles in the container? Small air bubbles in the container are normal and they will not harm you. Your dose will be correct and you can keep following the instructions. Contact your healthcare provider if you need help. What do I do if no liquid comes out during activation? The needle may be blocked or not properly attached. Remove the needle from the pen, attach a new needle, and repeat Step 4 and Step 5 of Section 2 only. If still no liquid comes out, your ADLYXIN pen may be damaged. Do not use this ADLYXIN Starter pack. Contact your healthcare provider for help. What do I do if it is hard to press the injection button all the way in? The needle may be blocked or not properly attached. Pull the needle out of your skin and remove the needle from the pen. Attach a new needle and repeat Step 5 and Step 6 of Section 3 only. If it is still hard to press in the injection button, your ADLYXIN pen may be damaged. Do not use this ADLYXIN starter pack. Contact your healthcare provider for help. Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY U.S. License No. 1752 ©202x sanofi-aventis U.S. LLC If you have any questions about ADLYXIN or about diabetes, ask your healthcare provider or call sanofi-aventis U.S. LLC at 1-800-633-1610. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: July 2021 Reference ID: 5761754 11

7.1 Delayed Gastric Emptying Effects on Oral Medications ADLYXIN delays gastric emptying which may reduce the rate of absorption of orally administered medications. Use caution when coadministering oral medications that have a narrow therapeutic ratio or that require careful clinical monitoring. These medications should be adequately monitored when concomitantly administered with ADLYXIN. If such medications are to be administered with food, patients should be advised to take them with a meal or snack when ADLYXIN is not administered. Oral medications that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, or medications for which a delay in effect is undesirable, such as acetaminophen, should be administered at least 1 hour before ADLYXIN injection [see Clinical Pharmacology (12.3)]. Patients taking oral contraceptives should be advised to take them at least 1 hour before ADLYXIN administration or at least 11 hours after the dose of ADLYXIN [see Clinical Pharmacology (12.3)]. 7.2 Dosage Adjustment of Sulfonylurea or Insulin with Concomitant Use with ADLYXIN When initiating ADLYXIN, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

Carcinogenesis Carcinogenicity studies of 2-years durations were conducted in CD-1 mice and Sprague-Dawley rats with twice daily subcutaneous doses of 40, 200, or 1,000 mcg/kg. A statistically significant increase in thyroid C-cell adenomas was observed in male mice at 2,000 mcg/kg/day, resulting in systemic exposures that are >180-times the human exposure achieved at 20 mcg/day based on plasma AUC. Statistically significant increases in thyroid C-cell adenomas were seen at all doses in rats, resulting in systemic exposures that are ≥15-times the human exposure achieved at 20 mcg/day based on plasma AUC. A numerical increase in thyroid C-cell carcinomas was observed in rats at ≥400 mcg/kg/day, resulting in systemic exposures that are >56-times the human exposure Reference ID: 5761754 achieved at 20 mcg/day based on plasma AUC. Mutagenesis Lixisenatide was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity (Ames), human lymphocyte chromosome aberration, mouse bone marrow micronucleus). Impairment of Fertility Studies in which male and female rats received twice daily subcutaneous doses of 2, 29, or 414 mcg/kg/dose prior to pairing through gestation day 6 did not indicate any adverse effects on male or female fertility in rats up to the highest dose tested, 414 mcg/kg/dose, which is approximately 400-times the clinical dose at 20 mcg/day based on mcg/m2.

Risk Summary The limited available data with lixisenatide in pregnant women are not sufficient to inform a drug-associated risk of major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. Based on animal reproduction studies, there may be risks to the fetus from exposure to lixisenatide during pregnancy. ADLYXIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Lixisenatide administered to pregnant rats and rabbits during organogenesis was associated with visceral closure and skeletal defects at systemic exposures that decreased maternal food intake and weight gain during gestation, and that are 1-time and 6-times higher than the 20 mcg/day clinical dose, respectively, based on plasma AUC [see Data]. The estimated background risk of major birth defects is 6-10% in women with pregestational diabetes with a HbA1c >7 and has been reported to be as high as 20%-25% in women with a 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. Reference ID: 5761754 Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal data In pregnant rats receiving twice daily subcutaneous doses of 2.5, 35, or 500 mcg/kg during organogenesis (gestation day 6 to 17), fetuses were present with visceral closure defects (e.g., microphthalmia, bilateral anophthalmia, diaphragmatic hernia) and stunted growth. Impaired ossification associated with skeletal malformations (e.g., bent limbs, scapula, clavicle, and pelvis) were observed at ≥5 mcg/kg/day, resulting in systemic exposure that is 1-time the 20 mcg/day clinical dose, based on plasma AUC. Decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the adverse fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. Placental transfer of lixisenatide to developing rat fetuses is low with a concentration ratio in fetal/maternal plasma of 0.1%. In pregnant rabbits receiving twice daily subcutaneous doses of 2.5, 25, 250 mcg/kg during organogenesis (gestation day 6 to 18), fetuses were present with multiple visceral and skeletal malformations, including closure defects, at ≥5 mcg/kg/day or systemic exposures that are 6times the 20 mcg/day clinical dose, based on plasma AUC. Decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. Placental transfer of lixisenatide to developing rabbit fetuses is low with a concentration ratio in fetal/maternal plasma of ≤0.3%. In a second study in pregnant rabbits, no drug-related malformations were observed from twice daily subcutaneous doses of 0.15, 1.0, and 2.5 mcg/kg administered during organogenesis, resulting in systemic exposures up to 9-times the clinical exposure at 20 mcg/day, based on plasma AUC. In pregnant rats given twice daily subcutaneous doses of 2, 20, or 200 mcg/kg from gestation day 6 through lactation, decreases in maternal body weight, food consumption, motor activity were observed at all doses. Skeletal malformations and increased pup mortality were observed at 400 mcg/kg/day, which is approximately 200-times the 20 mcg/day clinical dose, based on mcg/m2.

Safety and effectiveness of ADLYXIN have not been established in pediatric patients.

In clinical studies of ADLYXIN, a total of 1837 (25%) of the patients exposed to the study medication were 65 years of age and over and 288 (4%) were 75 years of age and over. No overall differences were observed in safety or effectiveness between these patients and younger patients, but individual sensitivity cannot be ruled out.

The following serious reactions are described below or elsewhere in the prescribing information: • Anaphylaxis and Serious Hypersensitivity Reactions [see Warnings and Precautions (5.1)] • Acute Pancreatitis [see Warnings and Precautions (5.2)] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.4)] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions (5.5)] Reference ID: 5761754 • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.6)] • Immunogenicity [see Warnings and Precautions (5.7)] • Acute Gallbladder Disease [see Warnings and Precautions (5.8)] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Placebo-Controlled Trials The data in Table 1 are derived from the placebo-controlled trials [see Clinical Studies (14)]. These data reflect exposure of 2869 patients to ADLYXIN and a mean duration of exposure to ADLYXIN of 21.7 weeks. Across the treatment arms, the mean age of patients was 56.1 years, 2.3% were 75 years or older and 48.2% were male. The population in these studies was 63.7% White, 2.6% Black or African American, 32.0% Asian, and 18.9% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.2 years and had a mean HbA1c of 8.1%. At baseline, 11.2% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m2) in 95.3% of the pooled study populations. Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of ADLYXIN in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on ADLYXIN than on placebo, and occurred in at least 5% of patients treated with ADLYXIN. Table 1: Adverse Reactions Reported in ≥5% of ADLYXIN-Treated Patients with Type 2 Diabetes Mellitus and Occurring More Frequently Compared to Placebo Adverse Reaction Placebo (N=1639) ADLYXIN (N=2869) Nausea 6% 25% Vomiting 2% 10% Headache 6% 9% Diarrhea 6% 8% Dizziness 4% 7% * hypoglycemia is discussed separately. Other Adverse Reactions Gastrointestinal adverse reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving ADLYXIN than placebo (placebo 18.4%, ADLYXIN 39.7%). More patients receiving ADLYXIN (4.3%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.5%). Investigators graded Reference ID: 5761754 the severity of gastrointestinal adverse reactions occurring on ADLYXIN as “mild” in 64.2% of cases, “moderate” in 32.3% of cases, or “severe” in 3.5% of cases. The majority of these adverse reactions occurred during the first 3 weeks after starting treatment. In addition to the reactions in Table 1, the following adverse reactions were reported in >2% of patients and more frequently in ADLYXIN-treated patients than placebo (frequencies listed, respectively, as: placebo; ADLYXIN): dyspepsia (0.2%; 3.2%), constipation (1.8%; 2.8%), abdominal distension (0.9%; 2.2%), abdominal pain upper (0.9%; 2.2%), abdominal pain (1.5%; 2.0%). Hypoglycemia Symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose <60 mg/dL or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose value was available. Severe symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemia in which the patient required the assistance of another person, associated with a plasma glucose level below 36 mg/dL or, associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose was available. Table 2 summarizes the incidence of symptomatic hypoglycemia and severe hypoglycemia in seven placebo-controlled efficacy/safety studies. Table 2: Incidence (%) of Symptomatic Hypoglycemia and Severe Hypoglycemia in Patients with Type 2 Diabetes Mellitus during the 24-week Main Treatment Period Background Therapy Placebo ADLYXIN Monotherapy* N=122 N=239 Symptomatic (%) 2 2 Severe (%) 0 0 With Metformin N=432 N=946 Symptomatic (%) 1 3 Severe (%) 0 0 With Sulfonylurea +/- metformin N=377 N=656 Symptomatic (%) 11 15 Severe (%) 0 0.2 With Pioglitazone +/- metformin N=161 N=323 Symptomatic (%) 1 3 Severe (%) 0 0 With Basal insulin +/- metformin N=213 N=374 Symptomatic (%) 23 28 Severe (%) 0 1 With Basal insulin +/- sulfonylurea N=111 N=108 Symptomatic (%) 22 47 Severe (%) 0 0 With Insulin Glargine and metformin +/- thiazolidinedione N=223 N=223 Symptomatic (%) 14 22 Severe (%) 0 0.4 * 12-week treatment duration. Reference ID: 5761754 Injection site reactions Injections site reactions (e.g., pain, pruritus, and erythema) were reported more frequently in ADLYXIN-treated patients (4%) than placebo treated patients (2%). A higher incidence of injection site reactions occurred in anti-lixisenatide antibody positive patients [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.6)]. Anaphylaxis and hypersensitivity In the ADLYXIN development program anaphylaxis cases were adjudicated. Anaphylaxis was defined as a skin or mucosal lesion of acute onset associated with at least 1 other organ system involvement. Symptoms such as hypotension, laryngeal edema or severe bronchospasm could be present but were not required for the case definition. More cases adjudicated as meeting the definition for anaphylaxis occurred in ADLYXIN-treated patients (incidence rate of 0.2% or 16 cases per 10,000 patient years) than placebo treated patient (incidence rate of 0.1% or 7 cases per 10,000 patient years). Allergic reactions (such as anaphylactic reaction, angioedema and urticaria) adjudicated as possibly related to the study medication were observed more frequently in ADLYXIN-treated patients (0.4%) than placebo-treated patient (0.2%). A higher incidence of allergic reactions occurred in anti-lixisenatide antibody positive patients [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.6)]. Pancreatitis In clinical trials of ADLYXIN, there were 21 cases of pancreatitis among ADLYXIN-treated patients and 14 cases in comparator-treated patients (incidence rate of 21 vs. 17 per 10,000 patient-years). ADLYXIN cases were reported as acute pancreatitis (n=3), pancreatitis (n=12), chronic pancreatitis (n=5), and edematous pancreatitis (n=1). Some patients had risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. Acute Gallbladder Disease In the ELIXA study [see Clinical Studies (14.6)], cholelithiasis occurred in 0.4% of ADLYXINtreated patients versus 0.2% in placebo-treated patients and acute cholecystitis in 0.3% of ADLYXIN-treated patients versus 0.2% in placebo-treated patients. 6.2 Post-Marketing Experience The following additional adverse reactions have been reported during post-approval use of ADLYXIN. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: acute pancreatitis, hemorrhagic and necrotizing pancreatitis, ileus, intestinal obstruction, severe constipation including fecal impaction Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy Neurologic: dysgeusia, dysesthesia Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. Renal: Acute renal failure or worsening of chronic renal failure, sometimes requiring Reference ID: 5761754 hemodialysis Skin and Subcutaneous Tissue: alopecia

In case of overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Initiate appropriate supportive treatment according to the patient’s clinical signs and symptoms.