Drug Safety-related Labeling Changes (SrLC)

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COPAXONE (NDA-020622)

(GLATIRAMER ACETATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/22/2025 (SUPPL-118)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Available data from pharmacovigilance and published observational studies over decades of use with glatiramer acetate during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes (see Data). Administration of glatiramer acetate by subcutaneous injection to pregnant rats and rabbits resulted in no adverse effects on embryofetal or offspring development (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other outcomes. 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 Data

Data from pharmacovigilance and published observational studies have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes when glatiramer acetate was used during pregnancy. However, the published comparative observational studies have methodological limitations, such as short exposure duration during pregnancy, confounding, selection bias, and exposure misclassification.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

Read this Medication Guide before you start using COPAXONE and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

…

Before you use COPAXONE, tell your healthcare provider about all of your medical conditions, including if you:

• are pregnant or plan to become pregnant. Talk to your healthcare provider who will advise if you should take COPAXONE during your pregnancy.

01/22/2025 (SUPPL-119)

Approved Drug Label (PDF)

Boxed Warning

Newly added section

WARNING: ANAPHYLACTIC REACTIONS

Cases of life-threatening and fatal anaphylaxis have been reported with COPAXONE. Anaphylaxis can occur at any time following initiation of therapy, from as early as after the first dose, up to years following initiation of therapy.

• Make patients aware of the symptoms of anaphylaxis, which may overlap with those of an immediate post-injection reaction; instruct them to seek immediate medical care should these symptoms occur. Prompt identification of anaphylaxis is important to avoid a delay in treatment [see Warnings and Precautions (5.1)].

• COPAXONE is contraindicated in patients with a history of hypersensitivity reactions to COPAXONE, including anaphylaxis. If an anaphylactic reaction occurs, treatment with COPAXONE must be immediately discontinued. Unless a clear alternative etiology is identified, COPAXONE must be permanently discontinued [see Contraindications (4) and Warnings and Precautions (5.1)].

4 Contraindications

Additions and/or revisions underlined:

COPAXONE is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)].

5 Warnings and Precautions

5.1 Anaphylactic Reactions

Newly added subsection

Life-threatening and fatal anaphylaxis has been reported with COPAXONE [see Adverse Reactions (6.2)]. COPAXONE is contraindicated in patients with a history of hypersensitivity reactions to COPAXONE, including anaphylaxis [see Contraindications (4)]. Anaphylaxis can occur at any time following initiation of COPAXONE therapy, from as early as after the first dose, up to years after initiation of treatment. Anaphylaxis occurred within an hour of a COPAXONE injection in most of the reported cases.

Some signs and symptoms of anaphylactic reactions may overlap with those of immediate post-injection reactions [see Warnings and Precautions (5.2)]. All patients receiving treatment with COPAXONE and caregivers should be informed about the signs and symptoms of anaphylactic reactions, and that they must seek immediate emergency medical care in case of experiencing such symptoms. If an anaphylactic reaction occurs, treatment with COPAXONE must be immediately discontinued. Unless a clear alternative etiology is identified, COPAXONE must be permanently discontinued [see Contraindications (4)].

5.2 Immediate Post-Injection Reaction

Additions and/or revisions underlined:

Approximately 16% of patients exposed to COPAXONE 20 mg per mL in the 5 placebo-controlled trials compared to 4% of those on placebo, and approximately 2% of patients exposed to COPAXONE 40 mg per mL in a placebo-controlled trial compared to none on placebo, experienced a constellation of symptoms that may occur immediately (within seconds to minutes, with the majority of symptoms observed within 1 hour) after injection and included at least two of the following: flushing, chest pain, palpitations, tachycardia, anxiety, dyspnea, constriction of the throat, and urticaria. These events are termed immediate post-injection reactions.

The symptoms of an immediate post-injection reaction may overlap with those of anaphylaxis; prompt identification of anaphylaxis is important to avoid a delay in treatment. In general, symptoms of an immediate post-injection reaction have onset several months after the initiation of treatment, although they may occur earlier, and a given patient may experience one or several episodes of these symptoms. Whether or not any of these symptoms actually represent a 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 developed fatal anaphylaxis and/or received emergency medical care. Whether an immunologic or nonimmunologic mechanism mediates these episodes, or whether several similar episodes seen in a given patient have identical mechanisms, is unknown.

…

5.5 Potential Effects on Immune Response

Additions and/or revisions underlined:

…

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 a controlled trial of 125 RRMS patients given COPAXONE 20 mg per mL, subcutaneously every day for 2 years, serum IgG levels reached at least 3 times baseline values in 80% of patients by 3 months of initiation of treatment. By 12 months of treatment, however, 30% of patients still had IgG levels at least 3 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 has been reported with COPAXONE [see Warnings and Precautions (5.1)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Anaphylactic Reactions [see Warnings and Precautions (5.1)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Immune System Disorders: hypersensitivity reactions (including anaphylactic reactions) [see Boxed Warning and Warnings and Precautions (5.1)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use

…

Anaphylactic Reactions

Advise patients and their caregivers that COPAXONE may cause life-threatening and fatal anaphylactic reactions shortly after injection, and that reactions may occur months to years after initiation of treatment [see Warnings and Precautions (5.1)]. Inform patients and their caregivers about the signs and symptoms specific for anaphylactic reactions, and that signs and symptoms of anaphylactic reactions may overlap with those of immediate post-injection reactions. Instruct them to seek immediate emergency medical care if they experience any signs or symptoms of an anaphylactic reaction [see Warnings and Precautions (5.1, 5.2)]. Patients should be advised to also contact their healthcare provider, and that treatment should be discontinued immediately and permanently if anaphylactic reactions occur.

Immediate Post-Injection Reaction

Advise patients that COPAXONE may cause immediate post-injection reactions, characterized by various symptoms after injection, including flushing, chest pain, palpitations, tachycardia, anxiety, dyspnea, constriction of the throat, and urticaria [see Warnings and Precautions (5.2)]. These symptoms occur within seconds to minutes after injection and are generally transient, 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. A patient may experience one or several episodes of these symptoms.

Advise patients that the symptoms of an immediate post-injection reaction may overlap with those of an anaphylactic reaction. Advise patients to contact their healthcare provider if they experience any signs or symptoms of an immediate post-injection reaction [see Warnings and Precautions (5.1, 5.2)].

MEDICATION GUIDE

Additions and/or revisions underlined:

Read this Medication Guide before you start using COPAXONE and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about COPAXONE?

• Serious allergic reactions (anaphylactic reactions). Serious allergic reactions that may be life-threatening or lead to death may happen any time after you start using COPAXONE. These reactions may happen right after your first dose up to years after starting treatment with COPAXONE, even if you never had an allergic reaction before. Many reactions have happened within 1 hour of using COPAXONE. Some signs and symptoms may be the same as those of an immediate post-injection reaction. See What are the possible side effects of COPAXONE?

  Stop using COPAXONE and get emergency help right away if you have:

• widespread rash

• swelling of the face, eyelids, lips, mouth, throat, or tongue

• sudden shortness of breath, difficulty breathing, or wheezing

• uncontrolled shaking (convulsions)

• trouble swallowing or speaking

• fainting, feeling dizzy or faint

What are the possible side effects of COPAXONE?

COPAXONE may cause serious side effects, including:

• Immediate Post-Injection Reactions. Serious side effects may happen right after or within minutes after you inject COPAXONE at any time during your course of treatment. Some signs and symptoms may be the same as those of a serious allergic reaction (anaphylaxis).

…

11/16/2023 (SUPPL-116)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Glatiramer Acetate Products and Administration Errors

New subsection added:

Medication errors have occurred when glatiramer acetate products are administered with incompatible autoinjectors. Some glatiramer acetate products can be administered by an optional compatible autoinjector, should one be available; however, not all glatiramer acetate products have a marketed optional compatible autoinjector for administration [see Dosage and Administration (2.2) and How Supplied/Storage and Handling (16)].

Using an optional autoinjector that is not compatible for use with TEVA’s COPAXONE may increase the risk for medication errors, such as dose omission or administration of a partial dose.

If using an optional autoinjector for administration, ensure the device is compatible for use with the specific glatiramer acetate product by referring to the autoinjector labeling. The availability of compatible autoinjectors for each glatiramer acetate product may change with time.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Important Administration Instructions

Advise patients with new or existing glatiramer acetate prescriptions to consult their pharmacist or healthcare provider if they would like information about using an optional compatible autoinjector device, if available.

Additionally, advise patients who would like to use an autoinjector for administration, should one be available, that not all available autoinjectors are compatible with all glatiramer acetate products and the availability of compatible autoinjectors may change with time. If you have questions about the availability or compatibility of an autoinjector, contact the manufacturer of the prescribed glatiramer acetate product for more information.

Advise patients that using an optional autoinjector that is not compatible with the glatiramer acetate product may increase the risk for medication errors, such as missing a dose or administration of a partial dose [see Warnings and Precautions (5.6)].

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PATIENT INFORMATION

Additions and/or revisions underlined:

…

How should I use COPAXONE?

…

• Some glatiramer acetate products can be used with an optional compatible autoinjector. Compatible autoinjectors are supplied separately if available, but the availability of compatible autoinjectors may change with time.

  • Check with your healthcare provider when you fill or refill your medicine to make sure the autoinjector you have is meant to be used with your glatiramer acetate product. Not all optional autoinjectors are meant to be used with all glatiramer acetate products. If you use the wrong autoinjector, you might not get the correct dose of your medicine. Contact the manufacturer of your glatiramer acetate product to find out if there is an autoinjector that is meant to be used with your glatiramer acetate product.

    …

    What are the possible side effects of COPAXONE?

    COPAXONE may cause serious side effects, including:

    …

     

    The most common side effects of COPAXONE are:

    …

• chest pain

  …

             

04/15/2022 (SUPPL-114)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.2 Lactation

Additions and revisions underlined:

Risk Summary

There are no data on the presence of glatiramer acetate in human milk. Based on the low systemic exposure because of substantial local hydrolysis of glatiramer acetate following subcutaneous administration, breastfeeding is not expected to result in clinically relevant exposure of the infant to the drug [see Clinical Pharmacology (12.3)]. There are no data on the effects of glatiramer acetate on milk production.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

Additions and revisions underlined:

What should I tell my doctor before using COPAXONE? Before you use COPAXONE, tell your doctor if you:

·  are pregnant or plan to become pregnant. It is not known if COPAXONE will harm your unborn baby.

·  are breastfeeding or plan to breastfeed. It is not known if COPAXONE passes into your breast milk, but any amount is expected to be low if it does. Talk to your doctor about the best way to feed your baby while using COPAXONE.

01/28/2022 (SUPPL-113)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined: 

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

Optional Autoinjector

Advise patients with new or existing glatiramer acetate prescriptions to consult their pharmacist or healthcare provider about using an optional prescribed compatible autoinjector device. Advise patients that not all optional prescribed autoinjectors are compatible with all glatiramer acetate products and using an autoinjector that is not compatible may increase the risk for medication errors, such as missing a dose or administration of a partial dose.

Additions and/or revisions underlined: 

How should I use COPAXONE?

• COPAXONE can be given using a prefilled syringe or an optional autoinjector that your healthcare provider may prescribe separately for use with COPAXONE.

  If you use an autoinjector to give COPAXONE:

  • Check with your healthcare provider when you fill or refill your medicine. Make sure the autoinjector you have is the right one for your COPAXONE. Not all optional autoinjectors can be used with all glatiramer acetate products. If you use the wrong autoinjector, you might not get enough medicine from your dose.

  • Read your autoinjector Instructions for Use and talk to your healthcare provider about the best way for you to use COPAXONE.

07/22/2020 (SUPPL-110)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Hepatic Injury

(Newly added section)

Cases of hepatic injury, some severe, including  liver failure and hepatitis with jaundice, have been reported with COPAXONE. Hepatic injury has occurred from days to years after initiating treatment with COPAXONE. If signs or symptoms of liver dysfunction occur, consider discontinuation  of COPAXONE.

6 Adverse Reactions

6.2 Postmarketing Experience

(Newly added information)

Hepatobiliary Disorders: cholelithiasis;  liver function abnormality;  cirrhosis of the liver; hepatitis; hepatic injury [see Warnings and Precautions (5.5)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Counseling Information

Hepatic Injury

(Newly added information)

Advise patients that hepatic injury, including hepatic failure and hepatitis with jaundice, has been reported with the use of COPAXONE. Educate patients about the signs and symptoms of hepatic injury and instruct patients to report them immediately  to their healthcare provider [see Warnings and Precautions (5.5)].

Patient Information

(Newly added information)

• Liver problems. Liver problems, including liver failure, can occur with COPAXONE. 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

12/27/2019 (SUPPL-107)

Approved Drug Label (PDF)

8 Use in Specific Populations

Lactation

(PLLR conversion. Please refer to label for complete information.)

Pregnancy

(PLLR conversion. Please refer to label for complete information.)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Newly added information)

Lactation

Advise patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed during COPAXONE therapy [see Use in Specific Populations (8.2)].

07/19/2019 (SUPPL-106)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(additions underlined)

…

 

What is COPAXONE?

COPAXONE is a 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.

…

09/07/2018 (SUPPL-104)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Immediate Post-Injection Reaction

(Additions and/or revisions are underlined)

 Approximately 16% of patients exposed to COPAXONE 20 mg per mL in the 5 placebo- controlled trials compared to 4% of those on placebo, and approximately 2% of patients exposed to COPAXONE 40 mg per mL in a placebo-controlled trial compared to none on placebo, experienced a constellation of symptoms that may occur immediately (within seconds to minutes, with the majority of symptoms observed within 1 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 a given patient may experience one or several episodes of these symptoms. Whether or not any of these symptoms actually represent a 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 a given patient have identical mechanisms, is unknown.

5.2 Chest Pain

(Additions and/or revisions are underlined)

Approximately 13% of COPAXONE 20 mg per mL patients in the 5 placebo-controlled studies compared to 6% of placebo patients, and approximately 2% of patients exposed to COPAXONE 40 mg per mL in a 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. ….

6 Adverse Reactions

6 ADVERSE REACTIONS

(Additions and/or revisions are underlined)

The following serious adverse reactions are described elsewhere in the labeling:

• Immediate Post-Injection Reaction

• Chest Pain

• Lipoatrophy and Skin Necrosis

• Potential Effects on Immune Response

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

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

Immediate Post-Injection Reaction

Advise patients that COPAXONE 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. A patient may experience one or several episodes of these symptoms.

Chest Pain

Advise 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.

 

Patient Information

(Additions and/or revisions are underlined)

What are the possible side effects of COPAXONE? COPAXONE may cause serious side effects, including:

• Immediate Post-Injection Reactions. Serious side effects may happen right after or within minutes after you inject COPAXONE 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 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 a doctor tells you to.

• Chest Pain. You can have chest pain as part of an immediate post- injection reaction or by itself. This type of chest pain usually lasts a few minutes and can begin around 1 month after you start using COPAXONE. Call your doctor right away if you have chest pain while using COPAXONE.

   

01/23/2018 (SUPPL-102)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Post-Injection Reaction

(Additions and/or revisions are underlined)

Approximately 16% of patients exposed to COPAXONE 20 mg per mL in the 5 placebo- controlled trials compared to 4% of those on placebo, and approximately 2% of patients exposed to COPAXONE 40 mg per mL in a placebo-controlled trial compared to none on placebo, experienced a constellation of symptoms that may occur within minutes after injection and included at least two of the following: flushing, chest pain, palpitations, tachycardia, anxiety, dyspnea, constriction of the throat, and urticaria…

6 Adverse Reactions

(Newly added subsection)

The following serious adverse reactions are described elsewhere in the labeling:

• Post-Injection Reaction

• Chest Pain

• Lipoatrophy and Skin Necrosis

• Potential Effects on Immune Response

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during postapproval use of COPAXONE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Post-Injection Reaction

Advise patients that COPAXONE may cause various symptoms after injection, including flushing, chest pain, palpitations, tachycardia, anxiety, dyspnea, constriction of the throat, and urticaria…

Patient Information

(Additions and/or revisions are underlined)

What are the possible side effects of COPAXONE? COPAXONE may cause serious side effects, including:

• Post-Injection Reactions. Serious side effects may happen within minutes after you inject COPAXONE at any time during your course of treatment…

How should I store COPAXONE?

…

• Do not freeze COPAXONE syringes. If a syringe freezes, throw it away in a sharps disposal container. See Step 13 in the Instructions for Use, “Dispose of your needles and syringes”.