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:

•

Glatopa 20 mg per mL: administer once per day

or

•

Glatopa 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.

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.

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 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

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 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. 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 1 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 a 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 a way that would undermine the body’s tumor surveillance and its defenses against infection. There is no evidence that glatiramer acetate injection does this, but there has not been a 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 a controlled trial of 125 RRMS patients given glatiramer acetate injection 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 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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Incidence in Controlled Clinical Trials

Glatiramer Acetate Injection 20 mg per mL per day

Among 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 1 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 Placebo

Adverse reactions which occurred only in 4 to 5 more subjects in the glatiramer acetate injection group than in the placebo group (less than 1% difference), but for which a 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 x 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 Reactions

In 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 a 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 a Whole

Frequent: 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.

Cardiovascular

Frequent: Hypertension.

Infrequent: Hypotension, midsystolic click, systolic murmur, atrial fibrillation, bradycardia, fourth heart sound, postural hypotension, and varicose veins.

Digestive

Infrequent: 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.

Endocrine

Infrequent: Goiter, hyperthyroidism, and hypothyroidism.

Gastrointestinal

Frequent: Bowel urgency, oral moniliasis, salivary gland enlargement, tooth caries, and ulcerative stomatitis.

Hemic and Lymphatic

Infrequent: Leukopenia, anemia, cyanosis, eosinophilia, hematemesis, lymphedema, pancytopenia, and splenomegaly.

Metabolic and Nutritional

Infrequent: Weight loss, alcohol intolerance, Cushing’s syndrome, gout, abnormal healing, and xanthoma.

Musculoskeletal

Infrequent: Arthritis, muscle atrophy, bone pain, bursitis, kidney pain, muscle disorder, myopathy, osteomyelitis, tendon pain, and tenosynovitis.

Nervous

Frequent: 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.

Respiratory

Frequent: Hyperventilation and hay fever.

Infrequent: Asthma, pneumonia, epistaxis, hypoventilation, and voice alteration.

Skin and Appendages

Frequent: 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 Senses

Frequent: Visual field defect.

Infrequent: Dry eyes, otitis externa, ptosis, cataract, corneal ulcer, mydriasis, optic neuritis, photophobia, and taste loss.

Urogenital

Frequent: 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 week

Among 943 patients treated with glatiramer acetate injection 40 mg per mL three times per week in a 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 2 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 a 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 Placebo

No 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: sepsis; SLE syndrome; hydrocephalus; enlarged abdomen; allergic reaction; anaphylactoid reaction

Cardiovascular System: thrombosis; peripheral vascular disease; pericardial effusion; myocardial infarct; deep thrombophlebitis; coronary occlusion; congestive heart failure; cardiomyopathy; cardiomegaly; arrhythmia; angina pectoris

Digestive System: tongue edema; stomach ulcer; hemorrhage; eructation

Hemic and Lymphatic System: thrombocytopenia; lymphoma-like reaction; acute leukemia

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

Metabolic and Nutritional Disorders: hypercholesterolemia

Musculoskeletal System: rheumatoid arthritis; generalized spasm

Nervous System: myelitis; meningitis; CNS neoplasm; cerebrovascular accident; brain edema; abnormal dreams; aphasia; convulsion; neuralgia

Respiratory System: pulmonary embolus; pleural effusion; carcinoma of lung

Special Senses: glaucoma; blindness

Urogenital System: urogenital neoplasm; urine abnormality; ovarian carcinoma; nephrosis; kidney failure; breast carcinoma; bladder carcinoma; urinary frequency

8.1 Pregnancy

8.2 Lactation

Risk Summary

There 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 mother’s 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.

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, a 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 a 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 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 a 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 a limited skin area.

In a 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 a mg/m2 basis). No increase in neoplasms was observed.

Mutagenesis

Glatiramer 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 Fertility

When 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 a mg/m2 basis) no adverse effects were observed on reproductive or developmental parameters.

INSTRUCTIONS FOR USE

Glatopa®
(gluh-TOH-puh)
(glatiramer acetate injection) for Subcutaneous Use

For 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 a doctor or nurse present. This might be at your doctor’s office or with a visiting home health nurse who will show you how to give your own injections.

Glatopa comes in either a 20 mg Pre-filled Syringe with needle attached or a 40 mg Pre-filled Syringe with needle attached. How often a 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:

•

Glatopa 20 mg is injected 1 time each day, in the fatty layer under your skin (subcutaneously).

•

Each Glatopa 20 mg pre-filled syringe is for single use (1 time use) only.

•

The 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:

•

Glatopa 40 mg is injected 3 times each week, in the fatty layer under your skin (subcutaneously).

•

Glatopa 40 mg should be given on the same 3 days each week, if possible for example, Monday, Wednesday, and Friday. Give your Glatopa injections at least 48 hours (2 days) apart.

•

Each Glatopa 40 mg pre-filled syringe is for single use (1 time use) only.

•

The 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 I inject Glatopa?

Step 1: Gather the supplies you will need to inject Glatopa. See Figure A.

•

1 blister pack with a Glatopa Pre-filled Syringe with needle attached

•

Alcohol wipe (not supplied)

•

Dry cotton ball (not supplied)

•

A place to record your injections, like a notebook (not supplied)

•

Sharps disposal container (not supplied). See Step 13 below, “Dispose of your needles and syringes”.

Figure A

Step 2: Remove only 1 blister pack from the Glatopa pre-filled syringe carton. See Figure B.

Figure B

•

Place the supplies you will need on a clean, flat surface in a well-lit area.

•

After you remove 1 blister pack from the carton, keep all unused syringes in the carton and store them in the refrigerator.

•

Let the blister pack, with the syringe inside, warm to room temperature for about 20 minutes.

•

Wash 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.

•

There 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.

•

Check 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 a 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.

•

The possible injection areas on your body include (See Figure C):

∘

your stomach area (abdomen) around the belly button

∘

the back of your upper arms

∘

upper hips (below your waist)

∘

your thighs (above your knees)

Abdomen

Avoid about 2 inches around the belly button

Back of Hips and Arms

Fleshy areas of the upper hips, always below the waist

Fleshy areas of the upper back portion of the arms

Arms

Fleshy areas of the upper back portion

Thighs

About 2 inches above the knee and 2 inches below the groin

Figure C

•

For each Glatopa dose, choose a different injection area from 1 of the areas shown above. See Figure C.

•

Do not stick the needle in the same place (site) more than 1 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.

•

Keep a 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.

•

There 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.

•

Do 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.

•

Clean the injection site using the alcohol wipe and allow your skin to air dry. See Figure D.

Figure D

Step 7: Pick up the syringe with 1 hand and hold it like a pencil. Remove the needle cover with your other hand and set it aside. See Figure E.

Figure E

Step 8: Pinch about a 2 inch fold of skin between your thumb and index finger. See Figure F.

Figure F

Step 9: Giving your injection.

•

Rest the heel of your hand holding the syringe against your skin at the injection site. Insert the needle at a 90 degree angle straight into your skin. See Figure G.

Figure G

•

When the needle is all the way into your skin, release the fold of skin. See Figure H.

Figure H

Step 10: Give your Glatopa injection.

To inject the medicine, hold the syringe steady and slowly push down the plunger. See Figure I.

Figure I

Step 11: Remove the needle.

After you have injected all of the medicine, pull the needle straight out. See Figure J.

Figure J

Step 12: Use a clean, dry cotton ball to gently press on the injection site for a few seconds. Do not rub the injection site or re-use the needle or syringe. See Figure K.

Figure K

Step 13: Dispose of your needles and syringes.

•

Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.

•

If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:

∘

made of a heavy-duty plastic,

∘

can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,

∘

upright and stable during use,

∘

leak-resistant, and

∘

properly labeled to warn of hazardous waste inside the container.

•

When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.

•

Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

Figure L

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Glatopa® and GlatopaCare® are registered trademarks of Novartis AG.

Rev. July 2020

Distributed by

Sandoz Inc.

Princeton, NJ 08540