INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Glatopa is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.. Glatopa is indicated for the treatment of relapsing-forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults (1).

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1) 07/2019Warnings and Precautions, Hepatic Injury (5.5) 07/2020. Indications and Usage (1) 07/2019.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. Glatopa(R) (gluh-TOH-puh)(glatiramer acetate injection) for Subcutaneous UseRead this Patient Information before you start using Glatopa and each time you get refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.What is GlatopaGlatopa is prescription medicine that is used to treat relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.It is not known if Glatopa is safe and effective in children under 18 years of age.Who should not use GlatopaoDo not use Glatopa if you are allergic to glatiramer acetate, mannitol or any of the ingredients in Glatopa. See the end of this leaflet for complete list of the ingredients in Glatopa. What should tell my doctor before using Glatopa Before you use Glatopa, tell your doctor if you:oare pregnant or plan to become pregnant. It is not known if glatiramer acetate will harm your unborn baby.oare breastfeeding or plan to breastfeed. It is not known if glatiramer acetate passes into your breast milk. Talk to your doctor about the best way to feed your baby while using Glatopa.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Glatopa may affect the way other medicines work, and other medicines may affect how Glatopa works.Know the medicines you take. Keep list of your medicines with you to show your doctor and pharmacist when you get new medicine.How should use GlatopaoFor detailed instructions, see the Instructions for Use at the end of this leaflet for complete information on how to use Glatopa.oYour doctor will tell you how much Glatopa to use and when to use it.oGlatopa is given by injection under your skin (subcutaneously).oUse Glatopa exactly as your doctor tells you to use it.oSince every body type is different, talk with your doctor about the injection areas that are best for you.oYou should receive your first dose of Glatopa with doctor or nurse present. This might be at your doctors office or with visiting home health nurse who will teach you how to give your Glatopa injections.What are the possible side effects of GlatopaGlatopa may cause serious side effects, including:oImmediate Post-Injection Reactions. Serious side effects may happen right after or within minutes after you inject Glatopa at any time during your course of treatment. Call your doctor right away if you have any of these immediate post-injection reaction symptoms including:redness to your cheeks or other parts of the body (flushing)chest painfast heart beatanxietybreathing problems or tightness in your throatswelling, rash, hives, or itching If you have symptoms of an immediate post-injection reaction, do not give yourself more injections until doctor tells you to.oChest Pain. You can have chest pain as part of an immediate post-injection reaction or by itself. This type of chest pain usually lasts few minutes and can begin around month after you start using Glatopa. Call your doctor right away if you have chest pain while using Glatopa.oDamage to your skin. Damage to the fatty tissue just under your skins surface (lipoatrophy) and, rarely, death of your skin tissue (necrosis) can happen when you use Glatopa. Damage to the fatty tissue under your skin can cause dent at the injection site that may not go away. You can reduce your chance of developing these problems by:following your doctors instructions for how to use Glatopachoosing different injection area each time you use Glatopa. See Step in the Instructions for Use, Choose your injection area. oLiver problems. Liver problems, including liver failure, can occur with Glatopa. Call your healthcare provider right away if you have symptoms, such as: nausealoss of appetitetirednessdark colored urine and pale stoolsyellowing of your skin or the white part of your eyebleeding more easily than normalconfusionsleepinessThe most common side effects of Glatopa include:oskin problems at your injection site including:rednesspainswellingitchinglumpsorashoshortness of breathoflushing (vasodilation)Tell your doctor if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of Glatopa. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store GlatopaoStore Glatopa in the refrigerator between 36F to 46F (2C to 8C).oWhen you are not able to refrigerate Glatopa, you may store it for up to month at room temperature between 59F to 86F (15C to 30C).oProtect Glatopa from light or high temperature.oDo not freeze Glatopa syringes. If syringe freezes, throw it away in sharps disposal container. See Step 13 in the Instructions for Use, Dispose of your needles and syringes.Keep Glatopa and all medicines out of the reach of children.General information about the safe and effective use of Glatopa.Medicines are sometimes prescribed for purposes other than those listed in Patient Information Leaflet. Do not use Glatopa for condition for which it was not prescribed. Do not give Glatopa to other people, even if they have the same symptoms as you have. It may harm them.This Patient Information Leaflet summarizes the most important information about Glatopa. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Glatopa that is written for health professionals.For more information, go to www.glatopa.com or call Sandoz GlatopaCare(R) at 1-855-452-8672.What are the ingredients in GlatopaActive ingredient: glatiramer acetateInactive ingredients: mannitol. oDo not use Glatopa if you are allergic to glatiramer acetate, mannitol or any of the ingredients in Glatopa. See the end of this leaflet for complete list of the ingredients in Glatopa. oare pregnant or plan to become pregnant. It is not known if glatiramer acetate will harm your unborn baby.. oare breastfeeding or plan to breastfeed. It is not known if glatiramer acetate passes into your breast milk. Talk to your doctor about the best way to feed your baby while using Glatopa.. oFor detailed instructions, see the Instructions for Use at the end of this leaflet for complete information on how to use Glatopa.. oYour doctor will tell you how much Glatopa to use and when to use it.. oGlatopa is given by injection under your skin (subcutaneously).. oUse Glatopa exactly as your doctor tells you to use it.. oSince every body type is different, talk with your doctor about the injection areas that are best for you.. oYou should receive your first dose of Glatopa with doctor or nurse present. This might be at your doctors office or with visiting home health nurse who will teach you how to give your Glatopa injections.. oImmediate Post-Injection Reactions. Serious side effects may happen right after or within minutes after you inject Glatopa at any time during your course of treatment. Call your doctor right away if you have any of these immediate post-injection reaction symptoms including:redness to your cheeks or other parts of the body (flushing)chest painfast heart beatanxietybreathing problems or tightness in your throatswelling, rash, hives, or itching redness to your cheeks or other parts of the body (flushing). chest pain. fast heart beat. anxiety. breathing problems or tightness in your throat. swelling, rash, hives, or itching. If you have symptoms of an immediate post-injection reaction, do not give yourself more injections until doctor tells you to.. oChest Pain. You can have chest pain as part of an immediate post-injection reaction or by itself. This type of chest pain usually lasts few minutes and can begin around month after you start using Glatopa. Call your doctor right away if you have chest pain while using Glatopa.. oDamage to your skin. Damage to the fatty tissue just under your skins surface (lipoatrophy) and, rarely, death of your skin tissue (necrosis) can happen when you use Glatopa. Damage to the fatty tissue under your skin can cause dent at the injection site that may not go away. You can reduce your chance of developing these problems by:following your doctors instructions for how to use Glatopachoosing different injection area each time you use Glatopa. See Step in the Instructions for Use, Choose your injection area. following your doctors instructions for how to use Glatopa. choosing different injection area each time you use Glatopa. See Step in the Instructions for Use, Choose your injection area.. oLiver problems. Liver problems, including liver failure, can occur with Glatopa. Call your healthcare provider right away if you have symptoms, such as:. nausea. loss of appetite. tiredness. dark colored urine and pale stools. yellowing of your skin or the white part of your eye. bleeding more easily than normal. confusion. sleepiness. oskin problems at your injection site including:rednesspainswellingitchinglumps. redness. pain. swelling. itching. lumps. orash. oshortness of breath. oflushing (vasodilation). oStore Glatopa in the refrigerator between 36F to 46F (2C to 8C).. oWhen you are not able to refrigerate Glatopa, you may store it for up to month at room temperature between 59F to 86F (15C to 30C).. oProtect Glatopa from light or high temperature.. oDo not freeze Glatopa syringes. If syringe freezes, throw it away in sharps disposal container. See Step 13 in the Instructions for Use, Dispose of your needles and syringes.. INSTRUCTIONS FOR USE Glatopa(R) (gluh-TOH-puh)(glatiramer acetate injection) for Subcutaneous UseFor subcutaneous injection only.Do not inject Glatopa in your veins (intravenously).Do not re-use your Glatopa pre-filled syringes.Do not share your Glatopa pre-filled syringes with another person. You may give another person an infection or get an infection from them.You should receive your first dose of Glatopa with doctor or nurse present. This might be at your doctors office or with visiting home health nurse who will show you how to give your own injections.Glatopa comes in either 20 mg Pre-filled Syringe with needle attached or 40 mg Pre-filled Syringe with needle attached. How often dose is given depends on the product strength that is prescribed. Your doctor will prescribe the correct dose for you.Instructions for Using Your Glatopa 20 mg Pre-filled Syringe:oGlatopa 20 mg is injected time each day, in the fatty layer under your skin (subcutaneously).oEach Glatopa 20 mg pre-filled syringe is for single use (1 time use) only.oThe Glatopa 20 mg dose is packaged in boxes of 30 pre-filled syringes with needles attached. Glatopa 20 mg pre-filled syringes have white plungers.Instructions for Using Your Glatopa 40 mg Pre-filled Syringe:oGlatopa 40 mg is injected times each week, in the fatty layer under your skin (subcutaneously).oGlatopa 40 mg should be given on the same days each week, if possible for example, Monday, Wednesday, and Friday. Give your Glatopa injections at least 48 hours (2 days) apart.oEach Glatopa 40 mg pre-filled syringe is for single use (1 time use) only.oThe Glatopa 40 mg dose is packaged in boxes of 12 pre-filled syringes with needles attached. Glatopa 40 mg pre-filled syringes have blue plungers.How do inject GlatopaStep 1: Gather the supplies you will need to inject Glatopa. See Figure A. o1 blister pack with Glatopa Pre-filled Syringe with needle attachedoAlcohol wipe (not supplied)oDry cotton ball (not supplied)oA place to record your injections, like notebook (not supplied)oSharps disposal container (not supplied). See Step 13 below, Dispose of your needles and syringes.Figure AStep 2: Remove only blister pack from the Glatopa pre-filled syringe carton. See Figure B. Figure BoPlace the supplies you will need on clean, flat surface in well-lit area.oAfter you remove blister pack from the carton, keep all unused syringes in the carton and store them in the refrigerator.oLet the blister pack, with the syringe inside, warm to room temperature for about 20 minutes.oWash your hands. Be careful not to touch your face or hair after washing your hands.Step 3: Look closely at your Glatopa pre-filled syringe.oThere may be small air bubbles in the syringe. Do not try to push the air bubble from the syringe before giving your injection so you do not lose any medicine.oCheck the liquid medicine in the syringe before you give your injection. The liquid in the syringe should look clear, and colorless, and may look slightly yellow. If the liquid is cloudy or contains any particles, do not use the syringe and throw it away in sharps disposal container. See Step 13 below, Dispose of your needles and syringes.Step 4: Choose your injection area. See Figure C. See the injection areas you should use on your body. Talk with your doctor about the injection areas that are best for you.oThe possible injection areas on your body include (See Figure C):your stomach area (abdomen) around the belly buttonthe back of your upper armsupper hips (below your waist)your thighs (above your knees)AbdomenAvoid about inches around the belly buttonBack of Hips and ArmsFleshy areas of the upper hips, always below the waistFleshy areas of the upper back portion of the armsArmsFleshy areas of the upper back portionThighsAbout inches above the knee and inches below the groinFigure CoFor each Glatopa dose, choose different injection area from of the areas shown above. See Figure C.oDo not stick the needle in the same place (site) more than time each week. Each injection area contains multiple injection sites for you to choose from. Avoid injecting in the same site over and over again.oKeep record of the sites where you give your injection each day so you will remember where you already injected.Step 5: Prepare to give your injection.oThere are some injection areas on your body that are hard to reach (like the back of your arm). You may need help from someone who has been instructed on how to give your injection if you cannot reach certain injection areas.oDo not inject in sites where the skin has scarring or dents. Using scarred or dented skin for your injections may make your skin worse.Step 6: Clean your injection site.oClean the injection site using the alcohol wipe and allow your skin to air dry. See Figure D.Figure DStep 7: Pick up the syringe with hand and hold it like pencil. Remove the needle cover with your other hand and set it aside. See Figure E. Figure EStep 8: Pinch about 2 inch fold of skin between your thumb and index finger. See Figure F. Figure FStep 9: Giving your injection.oRest the heel of your hand holding the syringe against your skin at the injection site. Insert the needle at 90 degree angle straight into your skin. See Figure G.Figure GoWhen the needle is all the way into your skin, release the fold of skin. See Figure H.Figure HStep 10: Give your Glatopa injection.To inject the medicine, hold the syringe steady and slowly push down the plunger. See Figure I. Figure IStep 11: Remove the needle.After you have injected all of the medicine, pull the needle straight out. See Figure J. Figure JStep 12: Use clean, dry cotton ball to gently press on the injection site for few seconds. Do not rub the injection site or re-use the needle or syringe. See Figure K. Figure KStep 13: Dispose of your needles and syringes.oPut 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.oIf 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, andproperly labeled to warn of hazardous waste inside the container.oWhen 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.oDo 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.Figure LThis Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.Glatopa(R) and GlatopaCare(R) are registered trademarks of Novartis AG.Rev. July 2020Distributed bySandoz Inc.Princeton, NJ 08540. oGlatopa 20 mg is injected time each day, in the fatty layer under your skin (subcutaneously).. oEach Glatopa 20 mg pre-filled syringe is for single use (1 time use) only.. oThe Glatopa 20 mg dose is packaged in boxes of 30 pre-filled syringes with needles attached. Glatopa 20 mg pre-filled syringes have white plungers.. oGlatopa 40 mg is injected times each week, in the fatty layer under your skin (subcutaneously).. oGlatopa 40 mg should be given on the same days each week, if possible for example, Monday, Wednesday, and Friday. Give your Glatopa injections at least 48 hours (2 days) apart.. oEach Glatopa 40 mg pre-filled syringe is for single use (1 time use) only.. oThe Glatopa 40 mg dose is packaged in boxes of 12 pre-filled syringes with needles attached. Glatopa 40 mg pre-filled syringes have blue plungers.. o1 blister pack with Glatopa Pre-filled Syringe with needle attached. oAlcohol wipe (not supplied). oDry cotton ball (not supplied). oA place to record your injections, like notebook (not supplied). oSharps disposal container (not supplied). See Step 13 below, Dispose of your needles and syringes.. oPlace the supplies you will need on clean, flat surface in well-lit area.. oAfter you remove blister pack from the carton, keep all unused syringes in the carton and store them in the refrigerator.. oLet the blister pack, with the syringe inside, warm to room temperature for about 20 minutes.. oWash your hands. Be careful not to touch your face or hair after washing your hands.. oThere may be small air bubbles in the syringe. Do not try to push the air bubble from the syringe before giving your injection so you do not lose any medicine.. oCheck the liquid medicine in the syringe before you give your injection. The liquid in the syringe should look clear, and colorless, and may look slightly yellow. If the liquid is cloudy or contains any particles, do not use the syringe and throw it away in sharps disposal container. See Step 13 below, Dispose of your needles and syringes.. oThe possible injection areas on your body include (See Figure C):your stomach area (abdomen) around the belly buttonthe back of your upper armsupper hips (below your waist)your thighs (above your knees). your stomach area (abdomen) around the belly button. the back of your upper arms. upper hips (below your waist). your thighs (above your knees). oFor each Glatopa dose, choose different injection area from of the areas shown above. See Figure C.. oDo not stick the needle in the same place (site) more than time each week. Each injection area contains multiple injection sites for you to choose from. Avoid injecting in the same site over and over again.. oKeep record of the sites where you give your injection each day so you will remember where you already injected.. oThere are some injection areas on your body that are hard to reach (like the back of your arm). You may need help from someone who has been instructed on how to give your injection if you cannot reach certain injection areas.. oDo not inject in sites where the skin has scarring or dents. Using scarred or dented skin for your injections may make your skin worse.. oClean the injection site using the alcohol wipe and allow your skin to air dry. See Figure D.. oRest the heel of your hand holding the syringe against your skin at the injection site. Insert the needle at 90 degree angle straight into your skin. See Figure G.. oWhen the needle is all the way into your skin, release the fold of skin. See Figure H.. oPut 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.. oIf 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, andproperly 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.. oWhen 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.. oDo 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.. figurea. figurea. figurecabdomen. figurechipsandarms. figurecarms. figurecthighs. figured. figuree. figuref. figureg. figureh. figurei. figurej. figurek. figurel.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dose. Glatopa is for subcutaneous use only. Do not administer intravenously. The dosing schedule depends on the product strength that is selected. The recommended doses are:oGlatopa 20 mg per mL: administer once per dayoroGlatopa 40 mg per mL: administer three times per week and at least 48 hours apart.Glatopa 20 mg per mL and Glatopa 40 mg per mL are not interchangeable.. oGlatopa 20 mg per mL: administer once per day. oGlatopa 40 mg per mL: administer three times per week and at least 48 hours apart.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described elsewhere in the labeling: oImmediate Post-Injection Reaction [see Warnings and Precautions (5.1)]oChest Pain [see Warnings and Precautions (5.2)]oLipoatrophy and Skin Necrosis [see Warnings and Precautions (5.3)]oPotential Effects on Immune Response [see Warnings and Precautions (5.4)]oHepatic Injury [see Warnings and Precautions (5.5)]. oImmediate Post-Injection Reaction [see Warnings and Precautions (5.1)]. oChest Pain [see Warnings and Precautions (5.2)]. oLipoatrophy and Skin Necrosis [see Warnings and Precautions (5.3)]. oPotential Effects on Immune Response [see Warnings and Precautions (5.4)]. oHepatic Injury [see Warnings and Precautions (5.5)]. oIn controlled studies of glatiramer acetate injection 20 mg/mL, most common adverse reactions (>=10% and >=1.5 times higher than placebo) were: injection site reactions, vasodilatation, rash, dyspnea, and chest pain (6.1)oIn controlled study of glatiramer acetate injection 40 mg/mL, most common adverse reactions (>=10% and >=1.5 times higher than placebo) were: injection site reactions (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oIn controlled studies of glatiramer acetate injection 20 mg/mL, most common adverse reactions (>=10% and >=1.5 times higher than placebo) were: injection site reactions, vasodilatation, rash, dyspnea, and chest pain (6.1). oIn controlled study of glatiramer acetate injection 40 mg/mL, most common adverse reactions (>=10% and >=1.5 times higher than placebo) were: injection site reactions (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Incidence in Controlled Clinical TrialsGlatiramer Acetate Injection 20 mg per mL per dayAmong 563 patients treated with glatiramer acetate injection in blinded placebo-controlled trials, approximately 5% of the subjects discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: injection site reactions, dyspnea, urticaria, vasodilatation, and hypersensitivity. The most common adverse reactions were: injection site reactions, vasodilatation, rash, dyspnea, and chest pain.Table lists signs and symptoms that occurred in at least 2% of patients treated with glatiramer acetate injection 20 mg per mL in the placebo-controlled trials. These signs and symptoms were numerically more common in patients treated with glatiramer acetate injection than in patients treated with placebo. Adverse reactions were usually mild in intensity. Table 1: Adverse Reactions in Controlled Clinical Trials with an Incidence >=2% of Patients and more frequent with Glatiramer Acetate Injection (20 mg per mL daily) than with PlaceboGlatiramerAcetateInjection20 mg/mL(n=563)%Placebo(n=564)%Blood And Lymphatic System DisordersLymphadenopathy73Cardiac DisordersPalpitations94Tachycardia52Eye DisordersEye Disorder31Diplopia32Gastrointestinal DisordersNausea1511Vomiting74Dysphagia21General Disorders And AdministrationInjection Site Erythema4310Site ConditionsInjection Site Pain4020Injection Site Pruritus274Injection Site Mass266Asthenia2221Pain2017Injection Site Edema194Chest Pain136Injection Site Inflammation91Edema82Injection Site Reaction81Pyrexia65Injection Site Hypersensitivity40Local Reaction31Chills31Face Edema31Edema Peripheral32Injection Site Fibrosis21Injection Site AtrophyInjection site atrophy comprises terms relating to localized lipoatrophy at injection site 20Immune System DisordersHypersensitivity32Infections And InfestationsInfection3028Influenza1413Rhinitis75Bronchitis65Gastroenteritis64Vaginal Candidiasis42Metabolism And Nutrition DisordersWeight Increased31Musculoskeletal And ConnectiveBack Pain1210Tissue DisordersNeoplasms Benign, Malignant AndBenign Neoplasm of Skin21Unspecified (Incl Cysts And Polyps)Nervous System DisordersTremor42Migraine42Syncope32Speech Disorder21Psychiatric DisordersAnxiety1310Nervousness21Renal And Urinary DisordersMicturition Urgency54Respiratory, Thoracic And MediastinalDyspnea144DisordersCough65Laryngospasm21Skin And Subcutaneous TissueRash1911DisordersHyperhidrosis75Pruritus54Urticaria31Skin Disorder31Vascular DisordersVasodilatation205Adverse reactions which occurred only in to more subjects in the glatiramer acetate injection group than in the placebo group (less than 1% difference), but for which relationship to glatiramer acetate injection could not be excluded, were arthralgia and herpes simplex.Laboratory analyses were performed on all patients participating in the clinical program for glatiramer acetate injection. Clinically-significant laboratory values for hematology, chemistry, and urinalysis were similar for both glatiramer acetate injection and placebo groups in blinded clinical trials. In controlled trials one patient discontinued treatment due to thrombocytopenia (16 109/L), which resolved after discontinuation of treatment.Data on adverse reactions occurring in the controlled clinical trials of glatiramer acetate injection 20 mg per mL were analyzed to evaluate differences based on sex. No clinically-significant differences were identified. Ninety-six percent of patients in these clinical trials were Caucasian. The majority of patients treated with glatiramer acetate injection were between the ages of 18 and 45. Consequently, data are inadequate to perform an analysis of the adverse reaction incidence related to clinically-relevant age subgroups.Other Adverse ReactionsIn the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled premarketing studies (n=979), the role of glatiramer acetate injection in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used glatiramer acetate injection and reported reaction divided by the total number of patients exposed to glatiramer acetate injection. All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: Frequent adverse reactions are defined as those occurring in at least 1/100 patients and infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients.Body as WholeFrequent: Abscess.Infrequent: Injection site hematoma, moon face, cellulitis, hernia, injection site abscess, serum sickness, suicide attempt, injection site hypertrophy, injection site melanosis, lipoma, and photosensitivity reaction.CardiovascularFrequent: Hypertension.Infrequent: Hypotension, midsystolic click, systolic murmur, atrial fibrillation, bradycardia, fourth heart sound, postural hypotension, and varicose veins.DigestiveInfrequent: Dry mouth, stomatitis, burning sensation on tongue, cholecystitis, colitis, esophageal ulcer, esophagitis, gastrointestinal carcinoma, gum hemorrhage, hepatomegaly, increased appetite, melena, mouth ulceration, pancreas disorder, pancreatitis, rectal hemorrhage, tenesmus, tongue discoloration, and duodenal ulcer.EndocrineInfrequent: Goiter, hyperthyroidism, and hypothyroidism.GastrointestinalFrequent: Bowel urgency, oral moniliasis, salivary gland enlargement, tooth caries, and ulcerative stomatitis.Hemic and LymphaticInfrequent: Leukopenia, anemia, cyanosis, eosinophilia, hematemesis, lymphedema, pancytopenia, and splenomegaly.Metabolic and NutritionalInfrequent: Weight loss, alcohol intolerance, Cushings syndrome, gout, abnormal healing, and xanthoma.MusculoskeletalInfrequent: Arthritis, muscle atrophy, bone pain, bursitis, kidney pain, muscle disorder, myopathy, osteomyelitis, tendon pain, and tenosynovitis.NervousFrequent: Abnormal dreams, emotional lability, and stupor.Infrequent: Aphasia, ataxia, convulsion, circumoral paresthesia, depersonalization, hallucinations, hostility, hypokinesia, coma, concentration disorder, facial paralysis, decreased libido, manic reaction, memory impairment, myoclonus, neuralgia, paranoid reaction, paraplegia, psychotic depression, and transient stupor.RespiratoryFrequent: Hyperventilation and hay fever.Infrequent: Asthma, pneumonia, epistaxis, hypoventilation, and voice alteration.Skin and AppendagesFrequent: Eczema, herpes zoster, pustular rash, skin atrophy, and warts.Infrequent: Dry skin, skin hypertrophy, dermatitis, furunculosis, psoriasis, angioedema, contact dermatitis, erythema nodosum, fungal dermatitis, maculopapular rash, pigmentation, benign skin neoplasm, skin carcinoma, skin striae, and vesiculobullous rash.Special SensesFrequent: Visual field defect.Infrequent: Dry eyes, otitis externa, ptosis, cataract, corneal ulcer, mydriasis, optic neuritis, photophobia, and taste loss.UrogenitalFrequent: Amenorrhea, hematuria, impotence, menorrhagia, suspicious papanicolaou smear, urinary frequency, and vaginal hemorrhage.Infrequent: Vaginitis, flank pain (kidney), abortion, breast engorgement, breast enlargement, carcinoma in situ cervix, fibrocystic breast, kidney calculus, nocturia, ovarian cyst, priapism, pyelonephritis, abnormal sexual function, and urethritis.Glatiramer Acetate Injection 40 mg per mL three times per weekAmong 943 patients treated with glatiramer acetate injection 40 mg per mL three times per week in blinded, placebo-controlled trial, approximately 3% of the subjects discontinued treatment because of an adverse reaction. The most common adverse reactions were injection site reactions, which were also the most common cause of discontinuation.Table lists signs and symptoms that occurred in at least 2% of patients treated with glatiramer acetate injection 40 mg per mL in the blinded, placebo-controlled trial. These signs and symptoms were numerically more common in patients treated with glatiramer acetate injection 40 mg per mL than in patients treated with placebo. Adverse reactions were usually mild in intensity.Table 2: Adverse Reactions in Controlled Clinical Trial with an Incidence >=2% of Patients and more frequent with Glatiramer Acetate Injection (40 mg per mL three times per week) than with PlaceboGlatiramer Acetate Injection40 mg/mL(n=943)%Placebo(n=461)%General Disorders And Administration Site ConditionsInjection Site Erythema222Injection Site Pain102Injection Site Mass60Injection Site Pruritus60Injection Site Edema60Pyrexia32Influenza-like Illness32Injection Site Inflammation20Chills20Chest Pain21Infections And InfestationsNasopharyngitis119Respiratory Tract Infection Viral32Respiratory, Thoracic and Mediastinal DisordersDyspnea30Vascular DisordersVasodilatation30Gastrointestinal DisordersNausea21Skin And Subcutaneous Tissue DisordersErythema20Rash21No new adverse reactions appeared in subjects treated with glatiramer acetate injection 40 mg per mL three times per week as compared to subjects treated with glatiramer acetate injection 20 mg per mL per day in clinical trials and during postmarketing experience. Data on adverse reactions occurring in the controlled clinical trial of glatiramer acetate injection 40 mg per mL were analyzed to evaluate differences based on sex. No clinically significant differences were identified. Ninety-eight percent of patients in this clinical trial were Caucasian and the majority were between the ages of 18 and 50. Consequently, data are inadequate to perform an analysis of the adverse reaction incidence related to clinically-relevant age groups.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of glatiramer acetate injection. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Body as Whole: sepsis; SLE syndrome; hydrocephalus; enlarged abdomen; allergic reaction; anaphylactoid reactionCardiovascular System: thrombosis; peripheral vascular disease; pericardial effusion; myocardial infarct; deep thrombophlebitis; coronary occlusion; congestive heart failure; cardiomyopathy; cardiomegaly; arrhythmia; angina pectorisDigestive System: tongue edema; stomach ulcer; hemorrhage; eructationHemic and Lymphatic System: thrombocytopenia; lymphoma-like reaction; acute leukemiaHepatobiliary Disorders: cholelithiasis; liver function abnormality; cirrhosis of the liver; hepatitis; hepatic injury [see Warnings and Precautions (5.5)] Metabolic and Nutritional Disorders: hypercholesterolemiaMusculoskeletal System: rheumatoid arthritis; generalized spasmNervous System: myelitis; meningitis; CNS neoplasm; cerebrovascular accident; brain edema; abnormal dreams; aphasia; convulsion; neuralgiaRespiratory System: pulmonary embolus; pleural effusion; carcinoma of lungSpecial Senses: glaucoma; blindnessUrogenital System: urogenital neoplasm; urine abnormality; ovarian carcinoma; nephrosis; kidney failure; breast carcinoma; bladder carcinoma; urinary frequency.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 2-year carcinogenicity study, mice were administered up to 60 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose of 20 mg/day on mg/m2 basis). No increase in systemic neoplasms was observed. In males receiving the 60-mg/kg/day dose, there was an increased incidence of fibrosarcomas at the injection sites. These sarcomas were associated with skin damage precipitated by repetitive injections of an irritant over limited skin area.In 2-year carcinogenicity study, rats were administered up to 30 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose on mg/m2 basis). No increase in neoplasms was observed.MutagenesisGlatiramer acetate was not mutagenic in in vitro (Ames test, mouse lymphoma tk) assays. Glatiramer acetate was clastogenic in two separate in vitro chromosomal aberration assays in cultured human lymphocytes but not clastogenic in an in vivo mouse bone marrow micronucleus assay.Impairment of FertilityWhen glatiramer acetate was administered by subcutaneous injection prior to and during mating (males and females) and throughout gestation and lactation (females) at doses up to 36 mg/kg/day (18 times the human therapeutic dose on mg/m2 basis) no adverse effects were observed on reproductive or developmental parameters.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism(s) by which glatiramer acetate exerts its effects in patients with MS are not fully understood. However, glatiramer acetate is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of experimental autoimmune encephalomyelitis, condition induced in animals through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery.Because glatiramer acetate can modify immune functions, concerns exist about its potential to alter naturally-occurring immune responses. There is no evidence that glatiramer acetate does this, but this has not been systematically evaluated [see Warnings and Precautions (5.4)].. 12.3 Pharmacokinetics. Results obtained in pharmacokinetic studies performed in humans (healthy volunteers) and animals support that substantial fraction of the therapeutic dose delivered to patients subcutaneously is hydrolyzed locally. Larger fragments of glatiramer acetate can be recognized by glatiramer acetate-reactive antibodies. Some fraction of the injected material, either intact or partially hydrolyzed, is presumed to enter the lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter the systemic circulation intact.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Evidence supporting the effectiveness of glatiramer acetate injection derives from five placebo-controlled trials, four of which used glatiramer acetate injection dose of 20 mg per mL per day and one of which used glatiramer acetate injection dose of 40 mg per mL three times per week.Glatiramer acetate injection 20 mg per mL per dayStudy was performed at single center. Fifty patients were enrolled and randomized to receive daily doses of either glatiramer acetate injection, 20 mg per mL subcutaneously, or placebo (glatiramer acetate injection: n=25; placebo: n=25). Patients were diagnosed with RRMS by standard criteria, and had at least exacerbations during the years immediately preceding enrollment. Patients were ambulatory, as evidenced by score of no more than on the Kurtzke Disability Scale Score (DSS), standard scale ranging from 0-Normal to 10-Death due to MS. score of is defined as one at which patient is still ambulatory with assistance; score of means the patient must use wheelchair.Patients were examined every months for years, as well as within several days of presumed exacerbation. To confirm an exacerbation, blinded neurologist had to document objective neurologic signs, as well as document the existence of other criteria (e.g., the persistence of the neurological signs for at least 48 hours).The protocol-specified primary outcome measure was the proportion of patients in each treatment group who remained exacerbation free for the years of the trial, but two other important outcomes were also specified as endpoints: the frequency of attacks during the trial, and the change in the number of attacks compared with the number which occurred during the previous years.Table presents the values of the three outcomes described above, as well as several protocol-specified secondary measures. These values are based on the intent-to-treat population (i.e., all patients who received at least dose of treatment and who had at least on-treatment assessment):Table 3: Study Efficacy ResultsGlatiramer AcetateInjection 20 mg/mL(n=25)Placebo(n=25)P-Value% Relapse-Free Patients14/25 (56%)7/25 (28%)0.085Mean Relapse Frequency0.6/2 years2.4/2 years0.005Reduction in Relapse Rate Comparedto Prestudy3.2 1.6 0.025 Median Time to First Relapse (days)>7001500.03% of Progression-FreeProgression was defined as an increase of at least point on the DSS, persisting for at least consecutive months. Patients20/25 (80%)13/25 (52%)0.07Study was multicenter trial of similar design which was performed in 11 US centers. total of 251 patients (glatiramer acetate injection: n=125; placebo: n=126) were enrolled. The primary outcome measure was the Mean 2-Year Relapse Rate. Table presents the values of this outcome for the intent-to-treat population, as well as several secondary measures:Table 4: Study Efficacy ResultsGlatiramer AcetateInjection 20 mg/mL(n=125)Placebo(n=126)P-ValueMean No. of Relapses1.19/2 years1.68/2 years0.055% Relapse-Free Patients42/125 (34%)34/126 (27%)0.25Median Time to First Relapse (days)2871980.23% of Progression-Free Patients98/125 (78%)95/126 (75%)0.48Mean Change in DSS-0.05+0.210.023In both studies, glatiramer acetate injection exhibited clear beneficial effect on relapse rate, and it is based on this evidence that glatiramer acetate injection is considered effective.In Study 3, 481 patients who had recently (within 90 days) experienced an isolated demyelinating event and who had lesions typical of multiple sclerosis on brain MRI were randomized to receive either glatiramer acetate injection 20 mg per mL (n=243) or placebo (n=238). The primary outcome measure was time to development of second exacerbation. Patients were followed for up to three years or until they reached the primary endpoint. Secondary outcomes were brain MRI measures, including number of new T2 lesions and T2 lesion volume.Time to development of second exacerbation was significantly delayed in patients treated with glatiramer acetate injection compared to placebo (Hazard Ratio=0.55; 95% confidence interval 0.40 to 0.77; Figure 1). The Kaplan-Meier estimates of the percentage of patients developing relapse within 36 months were 42.9% in the placebo group and 24.7% in the glatiramer acetate injection group.Figure 1: Time to Second ExacerbationPatients treated with glatiramer acetate injection demonstrated fewer new T2 lesions at the last observation (rate ratio 0.41; confidence interval 0.28 to 0.59; p<0.0001). Additionally, baseline-adjusted T2 lesion volume at the last observation was lower for patients treated with glatiramer acetate injection (ratio of 0.89; confidence interval 0.84 to 0.94; p=0.0001).Study was multinational study in which MRI parameters were used both as primary and secondary endpoints. total of 239 patients with RRMS (glatiramer acetate injection: n=119; and placebo: n=120) were randomized. Inclusion criteria were similar to those in the second study with the additional criterion that patients had to have at least one Gd-enhancing lesion on the screening MRI. The patients were treated in double-blind manner for nine months, during which they underwent monthly MRI scanning. The primary endpoint for the double-blind phase was the total cumulative number of T1 Gd-enhancing lesions over the nine months. Table summarizes the results for the primary outcome measure monitored during the trial for the intent-to-treat cohort.Table 5: Study MRI ResultsGlatiramer AcetateInjection 20 mg/mL(n=119)Placebo(n=120)P-Value Medians of the Cumulative Numberof T1 Gd-Enhancing Lesions 11 17 0.0030 Figure displays the results of the primary outcome on monthly basis.Figure 2: Median Cumulative Number of Gd-Enhancing LesionsGlatiramer Acetate Injection 40 mg per mL three times per weekStudy was double-blind, placebo-controlled, multinational study with total of 1404 patients with RRMS randomized in 2:1 ratio to receive either glatiramer acetate injection 40 mg per mL (n=943) or placebo (n=461) three times week for 12 months. Patients had median of relapses in the years prior to screening and had not received any interferon-beta for at least months prior to screening. Baseline EDSS scores ranged from to 5.5 with median of 2.5. Neurological evaluations were performed at baseline, every three months, and at unscheduled visits for suspected relapse or early termination. MRI was performed at baseline, months and 12, or early termination. total of 91% of those assigned to glatiramer acetate injection and 93% of those assigned to placebo completed treatment at 12 months.The primary outcome measure was the total number of confirmed relapses (persistence of neurological symptoms for at least 48 hours confirmed on examination with objective signs). The effect of glatiramer acetate injection on several magnetic resonance imaging (MRI) variables, including number of new or enlarging T2 lesions and number of enhancing lesions on T1-weighted images, was also measured at months and 12.Table presents the results for the intent-to-treat population.Table 6: Study Efficacy and MRI ResultsGlatiramer AcetateInjection 40 mg/mL(n=943)Placebo(n=461)P-ValueClinical EndpointsNumber of confirmed relapses during the 12-month placebo-controlled phaseAdjusted Mean EstimatesRelative risk reduction0.33134%0.505<0.0001MRI EndpointsCumulative number of new or enlarging T2 lesions at Months and 12Adjusted Mean EstimatesRelative risk reduction3.65035%5.592<0.0001Cumulative number of enhancing lesions on T1-weighted images at Months and 12Adjusted Mean EstimatesRelative risk reduction0.90545%1.639<0.0001. figure01. figure02.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Glatopa is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol.. Known hypersensitivity to glatiramer acetate or mannitol (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Glatiramer acetate, the active ingredient of Glatopa, consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate is 5,000 9,000 daltons. Glatiramer acetate is identified by specific antibodies.Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is:(Glu, Ala, Lys, Tyr)xoxCH3COOH(C5H9NO4oC3H7NO2oC6H14N2O2oC9H11NO3)xoxC2H4O2 CAS 147245-92-9Glatopa is clear, colorless to slightly yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each mL of glatiramer acetate solution contains 20 mg or 40 mg of glatiramer acetate and the following inactive ingredient: 40 mg of mannitol. The pH of the solutions is approximately 5.5 to 7.0. The biological activity of glatiramer acetate is determined by its ability to block the induction of experimental autoimmune encephalomyelitis (EAE) in mice.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oFor subcutaneous injection only; doses are not interchangeable (2.1)oGlatopa 20 mg/mL per day (2.1)oGlatopa 40 mg/mL three times per week (2.1)oBefore use, allow the solution to warm to room temperature (2.2). oFor subcutaneous injection only; doses are not interchangeable (2.1). oGlatopa 20 mg/mL per day (2.1). oGlatopa 40 mg/mL three times per week (2.1). oBefore use, allow the solution to warm to room temperature (2.2). 2.1 Recommended Dose. Glatopa is for subcutaneous use only. Do not administer intravenously. The dosing schedule depends on the product strength that is selected. The recommended doses are:oGlatopa 20 mg per mL: administer once per dayoroGlatopa 40 mg per mL: administer three times per week and at least 48 hours apart.Glatopa 20 mg per mL and Glatopa 40 mg per mL are not interchangeable.. oGlatopa 20 mg per mL: administer once per day. oGlatopa 40 mg per mL: administer three times per week and at least 48 hours apart.. 2.2 Instructions for Use. Remove one blister-packaged pre-filled syringe from the refrigerated carton. Let the pre-filled syringe stand at room temperature for 20 minutes to allow the solution to warm to room temperature. Visually inspect the syringe for particulate matter and discoloration prior to administration. The solution in the syringe should appear clear, colorless to slightly yellow. If particulate matter or discoloration is observed, discard the syringe.Areas for subcutaneous self-injection include arms, abdomen, hips, and thighs. The pre-filled syringe is for single use only. Discard unused portions.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. oInjection: 20 mg per mL in single-dose, pre-filled syringe with white plunger. For subcutaneous use only.oInjection: 40 mg per mL in single-dose, pre-filled syringe with blue plunger. For subcutaneous use only.. oInjection: 20 mg per mL in single-dose, pre-filled syringe with white plunger. For subcutaneous use only.. oInjection: 40 mg per mL in single-dose, pre-filled syringe with blue plunger. For subcutaneous use only.. oInjection: 20 mg per mL in single-dose, pre-filled syringe with white plunger. (3)oInjection: 40 mg per mL in single-dose, pre-filled syringe with blue plunger. (3). oInjection: 20 mg per mL in single-dose, pre-filled syringe with white plunger. (3). oInjection: 40 mg per mL in single-dose, pre-filled syringe with blue plunger. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Interactions between glatiramer acetate injection and other drugs have not been fully evaluated. Results from existing clinical trials do not suggest any significant interactions of glatiramer acetate injection with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days. Glatiramer acetate injection has not been formally evaluated in combination with interferon beta.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Glatopa has not been studied in elderly patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Glatopa (glatiramer acetate injection) is clear, colorless to slightly yellow, sterile, nonpyrogenic solution in 1 mL single-dose glass syringe with attached 1/2 inch length, 29 gauge needle supplied as:o20 mg per mL in single-dose, pre-filled syringe with white plunger, in individual blister packages supplied in 30-count cartons (NDC 0781-3234-34)o40 mg per mL in single-dose, pre-filled syringe with blue plunger, in individual blister packages supplied in 12-count cartons (NDC 0781-3250-89)Store Glatopa refrigerated at 2C to 8C (36F to 46F). If needed, the patient may store Glatopa at room temperature, 15C to 30C (59F to 86F), for up to one month, but refrigeration is preferred. Avoid exposure to higher temperatures or intense light. Do not freeze Glatopa. If Glatopa syringe freezes, it should be discarded.. o20 mg per mL in single-dose, pre-filled syringe with white plunger, in individual blister packages supplied in 30-count cartons (NDC 0781-3234-34). o40 mg per mL in single-dose, pre-filled syringe with blue plunger, in individual blister packages supplied in 12-count cartons (NDC 0781-3250-89).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Immediate Post-Injection ReactionAdvise patients that Glatopa may cause various symptoms after injection, including flushing, chest pain, palpitations, tachycardia, anxiety, dyspnea, constriction of the throat, and urticaria. These symptoms occur within seconds to minutes after injection and are generally transient and self-limited and do not require specific treatment. Inform patients that these symptoms may occur early or may have their onset several months after the initiation of treatment. patient may experience one or several episodes of these symptoms.Chest PainAdvise patients that they may experience transient chest pain either as part of the Immediate Post-Injection Reaction or in isolation. Inform patients that the pain should be transient. Some patients may experience more than one such episode, usually beginning at least one month after the initiation of treatment. Patients should be advised to seek medical attention if they experience chest pain of unusual duration or intensity.Lipoatrophy and Skin Necrosis at Injection SiteAdvise patients that localized lipoatrophy, and rarely, skin necrosis may occur at injection sites. Instruct patients to follow proper injection technique and to rotate injection areas and sites with each injection to minimize these risks.Hepatic InjuryAdvise patients that hepatic injury, including hepatic failure and hepatitis with jaundice, has been reported with the use of Glatopa. Educate patients about the signs and symptoms of hepatic injury and instruct patients to report them immediately to their healthcare provider [see Warning and Precautions 5.5)].Pregnancy Instruct patients that if they are pregnant or plan to become pregnant while taking Glatopa they should inform their physician [see Use in Specific Populations (8.1)].LactationAdvise patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed during Glatopa therapy [see Use in Specific Populations (8.2)]. Instructions for UseInstruct patients to read the Glatopa Patient Information leaflet carefully. Glatopa 20 mg per mL and Glatopa 40 mg per mL are not interchangeable. Glatiramer acetate injection 20 mg per mL is administered daily and glatiramer acetate injection 40 mg per mL is administered three times per week. Caution patients to use aseptic technique. The first injection should be performed under the supervision of health care professional. Instruct patients to rotate injection areas and sites with each injection. Caution patients against the reuse of needles or syringes. Instruct patients in safe disposal procedures.Storage ConditionsAdvise patients that the recommended storage condition for Glatopa is refrigeration at 36F to 46F (2C to 8C). If needed, the patient may store Glatopa at room temperature, 59F to 86F (15C to 30C), for up to one month, but refrigeration is preferred. Glatopa should not be exposed to higher temperatures or intense light. Do not freeze Glatopa.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USE Glatopa(R) (gluh-TOH-puh)(glatiramer acetate injection) for Subcutaneous UseFor subcutaneous injection only.Do not inject Glatopa in your veins (intravenously).Do not re-use your Glatopa pre-filled syringes.Do not share your Glatopa pre-filled syringes with another person. You may give another person an infection or get an infection from them.You should receive your first dose of Glatopa with doctor or nurse present. This might be at your doctors office or with visiting home health nurse who will show you how to give your own injections.Glatopa comes in either 20 mg Pre-filled Syringe with needle attached or 40 mg Pre-filled Syringe with needle attached. How often dose is given depends on the product strength that is prescribed. Your doctor will prescribe the correct dose for you.Instructions for Using Your Glatopa 20 mg Pre-filled Syringe:oGlatopa 20 mg is injected time each day, in the fatty layer under your skin (subcutaneously).oEach Glatopa 20 mg pre-filled syringe is for single use (1 time use) only.oThe Glatopa 20 mg dose is packaged in boxes of 30 pre-filled syringes with needles attached. Glatopa 20 mg pre-filled syringes have white plungers.Instructions for Using Your Glatopa 40 mg Pre-filled Syringe:oGlatopa 40 mg is injected times each week, in the fatty layer under your skin (subcutaneously).oGlatopa 40 mg should be given on the same days each week, if possible for example, Monday, Wednesday, and Friday. Give your Glatopa injections at least 48 hours (2 days) apart.oEach Glatopa 40 mg pre-filled syringe is for single use (1 time use) only.oThe Glatopa 40 mg dose is packaged in boxes of 12 pre-filled syringes with needles attached. Glatopa 40 mg pre-filled syringes have blue plungers.How do inject GlatopaStep 1: Gather the supplies you will need to inject Glatopa. See Figure A. o1 blister pack with Glatopa Pre-filled Syringe with needle attachedoAlcohol wipe (not supplied)oDry cotton ball (not supplied)oA place to record your injections, like notebook (not supplied)oSharps disposal container (not supplied). See Step 13 below, Dispose of your needles and syringes.Figure AStep 2: Remove only blister pack from the Glatopa pre-filled syringe carton. See Figure B. Figure BoPlace the supplies you will need on clean, flat surface in well-lit area.oAfter you remove blister pack from the carton, keep all unused syringes in the carton and store them in the refrigerator.oLet the blister pack, with the syringe inside, warm to room temperature for about 20 minutes.oWash your hands. Be careful not to touch your face or hair after washing your hands.Step 3: Look closely at your Glatopa pre-filled syringe.oThere may be small air bubbles in the syringe. Do not try to push the air bubble from the syringe before giving your injection so you do not lose any medicine.oCheck the liquid medicine in the syringe before you give your injection. The liquid in the syringe should look clear, and colorless, and may look slightly yellow. If the liquid is cloudy or contains any particles, do not use the syringe and throw it away in sharps disposal container. See Step 13 below, Dispose of your needles and syringes.Step 4: Choose your injection area. See Figure C. See the injection areas you should use on your body. Talk with your doctor about the injection areas that are best for you.oThe possible injection areas on your body include (See Figure C):your stomach area (abdomen) around the belly buttonthe back of your upper armsupper hips (below your waist)your thighs (above your knees)AbdomenAvoid about inches around the belly buttonBack of Hips and ArmsFleshy areas of the upper hips, always below the waistFleshy areas of the upper back portion of the armsArmsFleshy areas of the upper back portionThighsAbout inches above the knee and inches below the groinFigure CoFor each Glatopa dose, choose different injection area from of the areas shown above. See Figure C.oDo not stick the needle in the same place (site) more than time each week. Each injection area contains multiple injection sites for you to choose from. Avoid injecting in the same site over and over again.oKeep record of the sites where you give your injection each day so you will remember where you already injected.Step 5: Prepare to give your injection.oThere are some injection areas on your body that are hard to reach (like the back of your arm). You may need help from someone who has been instructed on how to give your injection if you cannot reach certain injection areas.oDo not inject in sites where the skin has scarring or dents. Using scarred or dented skin for your injections may make your skin worse.Step 6: Clean your injection site.oClean the injection site using the alcohol wipe and allow your skin to air dry. See Figure D.Figure DStep 7: Pick up the syringe with hand and hold it like pencil. Remove the needle cover with your other hand and set it aside. See Figure E. Figure EStep 8: Pinch about 2 inch fold of skin between your thumb and index finger. See Figure F. Figure FStep 9: Giving your injection.oRest the heel of your hand holding the syringe against your skin at the injection site. Insert the needle at 90 degree angle straight into your skin. See Figure G.Figure GoWhen the needle is all the way into your skin, release the fold of skin. See Figure H.Figure HStep 10: Give your Glatopa injection.To inject the medicine, hold the syringe steady and slowly push down the plunger. See Figure I. Figure IStep 11: Remove the needle.After you have injected all of the medicine, pull the needle straight out. See Figure J. Figure JStep 12: Use clean, dry cotton ball to gently press on the injection site for few seconds. Do not rub the injection site or re-use the needle or syringe. See Figure K. Figure KStep 13: Dispose of your needles and syringes.oPut 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.oIf 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, andproperly labeled to warn of hazardous waste inside the container.oWhen 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.oDo 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.Figure LThis Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.Glatopa(R) and GlatopaCare(R) are registered trademarks of Novartis AG.Rev. July 2020Distributed bySandoz Inc.Princeton, NJ 08540. oGlatopa 20 mg is injected time each day, in the fatty layer under your skin (subcutaneously).. oEach Glatopa 20 mg pre-filled syringe is for single use (1 time use) only.. oThe Glatopa 20 mg dose is packaged in boxes of 30 pre-filled syringes with needles attached. Glatopa 20 mg pre-filled syringes have white plungers.. oGlatopa 40 mg is injected times each week, in the fatty layer under your skin (subcutaneously).. oGlatopa 40 mg should be given on the same days each week, if possible for example, Monday, Wednesday, and Friday. Give your Glatopa injections at least 48 hours (2 days) apart.. oEach Glatopa 40 mg pre-filled syringe is for single use (1 time use) only.. oThe Glatopa 40 mg dose is packaged in boxes of 12 pre-filled syringes with needles attached. Glatopa 40 mg pre-filled syringes have blue plungers.. o1 blister pack with Glatopa Pre-filled Syringe with needle attached. oAlcohol wipe (not supplied). oDry cotton ball (not supplied). oA place to record your injections, like notebook (not supplied). oSharps disposal container (not supplied). See Step 13 below, Dispose of your needles and syringes.. oPlace the supplies you will need on clean, flat surface in well-lit area.. oAfter you remove blister pack from the carton, keep all unused syringes in the carton and store them in the refrigerator.. oLet the blister pack, with the syringe inside, warm to room temperature for about 20 minutes.. oWash your hands. Be careful not to touch your face or hair after washing your hands.. oThere may be small air bubbles in the syringe. Do not try to push the air bubble from the syringe before giving your injection so you do not lose any medicine.. oCheck the liquid medicine in the syringe before you give your injection. The liquid in the syringe should look clear, and colorless, and may look slightly yellow. If the liquid is cloudy or contains any particles, do not use the syringe and throw it away in sharps disposal container. See Step 13 below, Dispose of your needles and syringes.. oThe possible injection areas on your body include (See Figure C):your stomach area (abdomen) around the belly buttonthe back of your upper armsupper hips (below your waist)your thighs (above your knees). your stomach area (abdomen) around the belly button. the back of your upper arms. upper hips (below your waist). your thighs (above your knees). oFor each Glatopa dose, choose different injection area from of the areas shown above. See Figure C.. oDo not stick the needle in the same place (site) more than time each week. Each injection area contains multiple injection sites for you to choose from. Avoid injecting in the same site over and over again.. oKeep record of the sites where you give your injection each day so you will remember where you already injected.. oThere are some injection areas on your body that are hard to reach (like the back of your arm). You may need help from someone who has been instructed on how to give your injection if you cannot reach certain injection areas.. oDo not inject in sites where the skin has scarring or dents. Using scarred or dented skin for your injections may make your skin worse.. oClean the injection site using the alcohol wipe and allow your skin to air dry. See Figure D.. oRest the heel of your hand holding the syringe against your skin at the injection site. Insert the needle at 90 degree angle straight into your skin. See Figure G.. oWhen the needle is all the way into your skin, release the fold of skin. See Figure H.. oPut 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.. oIf 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, andproperly 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.. oWhen 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.. oDo 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.. figurea. figurea. figurecabdomen. figurechipsandarms. figurecarms. figurecthighs. figured. figuree. figuref. figureg. figureh. figurei. figurej. figurek. figurel.

LABOR & DELIVERY SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of glatiramer acetate in human milk, the effects on breastfed infants, or the effects on milk production.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Glatopa and any potential adverse effects on the breastfed infant from Glatopa or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The mechanism(s) by which glatiramer acetate exerts its effects in patients with MS are not fully understood. However, glatiramer acetate is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of experimental autoimmune encephalomyelitis, condition induced in animals through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery.Because glatiramer acetate can modify immune functions, concerns exist about its potential to alter naturally-occurring immune responses. There is no evidence that glatiramer acetate does this, but this has not been systematically evaluated [see Warnings and Precautions (5.4)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 2-year carcinogenicity study, mice were administered up to 60 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose of 20 mg/day on mg/m2 basis). No increase in systemic neoplasms was observed. In males receiving the 60-mg/kg/day dose, there was an increased incidence of fibrosarcomas at the injection sites. These sarcomas were associated with skin damage precipitated by repetitive injections of an irritant over limited skin area.In 2-year carcinogenicity study, rats were administered up to 30 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose on mg/m2 basis). No increase in neoplasms was observed.MutagenesisGlatiramer acetate was not mutagenic in in vitro (Ames test, mouse lymphoma tk) assays. Glatiramer acetate was clastogenic in two separate in vitro chromosomal aberration assays in cultured human lymphocytes but not clastogenic in an in vivo mouse bone marrow micronucleus assay.Impairment of FertilityWhen glatiramer acetate was administered by subcutaneous injection prior to and during mating (males and females) and throughout gestation and lactation (females) at doses up to 36 mg/kg/day (18 times the human therapeutic dose on mg/m2 basis) no adverse effects were observed on reproductive or developmental parameters.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

20 mg Carton. NDC 0781-3234-34ONCE DAILYGlatopa(R) (glatiramer acetate injection)20 mg/mL For Subcutaneous Injection OnlyRx onlyKeep refrigerated to 8C (36 to 46F). Protect from light.Retain in carton.Contains 30 Single-Dose PRE-FILLED SyringesSANDOZ. glatopa20mgcarton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Glatopa have not been established in patients under 18 years of age.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Results obtained in pharmacokinetic studies performed in humans (healthy volunteers) and animals support that substantial fraction of the therapeutic dose delivered to patients subcutaneously is hydrolyzed locally. Larger fragments of glatiramer acetate can be recognized by glatiramer acetate-reactive antibodies. Some fraction of the injected material, either intact or partially hydrolyzed, is presumed to enter the lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter the systemic circulation intact.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary. Available human data on the use of Glatopa in pregnant women are not sufficient to support conclusions about drug-associated risk for major birth defects and miscarriage. Administration of glatiramer acetate by subcutaneous injection to pregnant rats and rabbits resulted in no adverse effects on embryo-fetal or offspring development (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human DataThere are no adequate and well-controlled studies of Glatopa in pregnant women. The available postmarketing reports, case series, and small cohort studies do not provide sufficient information to support conclusions about drug-associated risk for major birth defects and miscarriage.Animal DataIn rats or rabbits receiving glatiramer acetate by subcutaneous injection during the period of organogenesis, no adverse effects on embryo-fetal development were observed at doses up to 37.5 mg/kg/day (18 and 36 times, respectively, the therapeutic human dose of 20 mg/day on mg/m2 basis). In rats receiving subcutaneous glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation, no significant effects on delivery or on offspring growth and development were observed.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary. Available human data on the use of Glatopa in pregnant women are not sufficient to support conclusions about drug-associated risk for major birth defects and miscarriage. Administration of glatiramer acetate by subcutaneous injection to pregnant rats and rabbits resulted in no adverse effects on embryo-fetal or offspring development (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human DataThere are no adequate and well-controlled studies of Glatopa in pregnant women. The available postmarketing reports, case series, and small cohort studies do not provide sufficient information to support conclusions about drug-associated risk for major birth defects and miscarriage.Animal DataIn rats or rabbits receiving glatiramer acetate by subcutaneous injection during the period of organogenesis, no adverse effects on embryo-fetal development were observed at doses up to 37.5 mg/kg/day (18 and 36 times, respectively, the therapeutic human dose of 20 mg/day on mg/m2 basis). In rats receiving subcutaneous glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation, no significant effects on delivery or on offspring growth and development were observed.. 8.2 Lactation. Risk SummaryThere are no data on the presence of glatiramer acetate in human milk, the effects on breastfed infants, or the effects on milk production.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Glatopa and any potential adverse effects on the breastfed infant from Glatopa or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of Glatopa have not been established in patients under 18 years of age.. 8.5 Geriatric Use. Glatopa has not been studied in elderly patients.. 8.6 Use in Patients with Impaired Renal Function. The pharmacokinetics of glatiramer acetate in patients with impaired renal function have not been determined.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oImmediate Post-Injection Reaction (flushing, chest pain, palpitations, tachycardia, anxiety, dyspnea, throat constriction, and/or urticaria), may occur within seconds to minutes after injection and are generally transient and self-limiting (5.1)oChest pain, usually transient (5.2)oLipoatrophy and skin necrosis may occur. Instruct patients in proper injection technique and to rotate injection sites (5.3)oGlatopa can modify immune response (5.4)oHepatic Injury: if signs or symptoms of hepatic dysfunction occur, consider discontinuing Glatopa (5.5). oImmediate Post-Injection Reaction (flushing, chest pain, palpitations, tachycardia, anxiety, dyspnea, throat constriction, and/or urticaria), may occur within seconds to minutes after injection and are generally transient and self-limiting (5.1). oChest pain, usually transient (5.2). oLipoatrophy and skin necrosis may occur. Instruct patients in proper injection technique and to rotate injection sites (5.3). oGlatopa can modify immune response (5.4). oHepatic Injury: if signs or symptoms of hepatic dysfunction occur, consider discontinuing Glatopa (5.5). 5.1 Immediate Post-Injection Reaction. Approximately 16% of patients exposed to glatiramer acetate injection 20 mg per mL in the five placebo-controlled trials compared to 4% of those on placebo, and approximately 2% of patients exposed to glatiramer acetate injection 40 mg per mL in placebo-controlled trial compared to none on placebo, experienced constellation of symptoms that may occur immediately (within seconds to minutes, with the majority of symptoms observed within hour) after injection and included at least two of the following: flushing, chest pain, palpitations, tachycardia, anxiety, dyspnea, constriction of the throat, and urticaria. In general, these symptoms have their onset several months after the initiation of treatment, although they may occur earlier, and given patient may experience one or several episodes of these symptoms. Whether or not any of these symptoms actually represent specific syndrome is uncertain. Typically, the symptoms were transient and self-limited and did not require treatment; however, there have been reports of patients with similar symptoms who received emergency medical care. Whether an immunologic or nonimmunologic mechanism mediates these episodes, or whether several similar episodes seen in given patient have identical mechanisms, is unknown.. 5.2 Chest Pain. Approximately 13% of glatiramer acetate injection 20 mg per mL patients in the five placebo-controlled studies compared to 6% of placebo patients, and approximately 2% of patients exposed to glatiramer acetate injection 40 mg per mL in placebo-controlled trial compared to 1% of placebo patients, experienced at least one episode of transient chest pain. While some of these episodes occurred in the context of the Immediate Post-Injection Reaction described above, many did not. The temporal relationship of this chest pain to an injection was not always known. The pain was usually transient, often unassociated with other symptoms, and appeared to have no clinical sequelae. Some patients experienced more than one such episode, and episodes usually began at least month after the initiation of treatment. The pathogenesis of this symptom is unknown.. 5.3 Lipoatrophy and Skin Necrosis. At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis may occur. Lipoatrophy occurred in approximately 2% of patients exposed to glatiramer acetate injection 20 mg per mL in the five placebo-controlled trials compared to none on placebo, and 0.5% of patients exposed to glatiramer acetate injection 40 mg per mL in single placebo-controlled trial and none on placebo. Skin necrosis has only been observed in the post-marketing setting. Lipoatrophy may occur at various times after treatment onset (sometimes after several months) and is thought to be permanent. There is no known therapy for lipoatrophy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites with each injection.. 5.4 Potential Effects on Immune Response. Because glatiramer acetate injection can modify immune response, it may interfere with immune functions. For example, treatment with glatiramer acetate injection may interfere with the recognition of foreign antigens in way that would undermine the bodys tumor surveillance and its defenses against infection. There is no evidence that glatiramer acetate injection does this, but there has not been systematic evaluation of this risk. Because glatiramer acetate injection is an antigenic material, it is possible that its use may lead to the induction of host responses that are untoward, but systematic surveillance for these effects has not been undertaken.Although glatiramer acetate injection is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with glatiramer acetate injection may result in untoward effects.Glatiramer acetate-reactive antibodies are formed in most patients receiving glatiramer acetate. Studies in both the rat and monkey have suggested that immune complexes are deposited in the renal glomeruli. Furthermore, in controlled trial of 125 RRMS patients given glatiramer acetate injection 20 mg per mL, subcutaneously every day for years, serum IgG levels reached at least times baseline values in 80% of patients by months of initiation of treatment. By 12 months of treatment, however, 30% of patients still had IgG levels at least times baseline values, and 90% had levels above baseline by 12 months. The antibodies are exclusively of the IgG subtype and predominantly of the IgG-1 subtype. No IgE type antibodies could be detected in any of the 94 sera tested; nevertheless, anaphylaxis can be associated with the administration of most any foreign substance, and therefore, this risk cannot be excluded.. 5.5 Hepatic Injury Cases of hepatic injury, some severe, including liver failure and hepatitis with jaundice, have been reported with Glatopa. Hepatic injury has occurred from days to years after initiating treatment with Glatopa. If signs or symptoms of liver dysfunction occur, consider discontinuation of Glatopa.