NDA 20-622/S-015/S-015
`Page 3
`
`COPAXONE®
`(glatiramer acetate for injection)
`
`DESCRIPTION
`COPAXONE® is the brand name for glatiramer acetate (formerly known as copolymer-1).
`Glatiramer acetate, the active ingredient of COPAXONE®, 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 4,700–11,000 daltons.
`
`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)x(cid:31)xCH3COOH
`(C5H9NO4(cid:31)C3H7NO2(cid:31)C6H14N2O2(cid:31)C9H11NO3)x(cid:31)xC2H4O2
`CAS - 147245-92-9
`
`COPAXONE® is a white to off-white, sterile, lyophilized powder containing 20 mg of glatiramer
`acetate and 40 mg of mannitol. It is supplied in single-use vials for subcutaneous administration
`after reconstitution with the diluent supplied (Sterile Water for Injection).
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`The mechanism(s) by which glatiramer acetate exerts its effects in patients with Multiple
`Sclerosis (MS) is (are) not fully elucidated. However, it is thought to act by modifying immune
`processes that are currently 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 allergic encephalomyelitis (EAE), a condition induced in several
`animal species 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. Results of a limited battery of tests designed to
`evaluate this risk produced no finding of concern; nevertheless, there is no logical way to
`absolutely exclude this possibility (see PRECAUTIONS).
`
`Pharmacokinetics
`Results obtained in pharmacokinetic studies performed in humans (healthy volunteers) and
`animals support the assumption that a substantial fraction of the therapeutic dose delivered
`to patients subcutaneously is hydrolyzed locally. Nevertheless, 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.
`
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`EX1022, Page 1 of 26
`
`

`

`NDA 20-622/S-015
`Page 4
`
`Clinical Trials
`Evidence supporting the effectiveness of glatiramer acetate in decreasing the frequency of
`relapses in patients with Relapsing-Remitting Multiple Sclerosis (RR MS) derives from two
`placebo-controlled trials, both of which used a glatiramer acetate dose of 20 mg/day. (No
`other dose or dosing regimen has been studied in placebo-controlled trials of RR MS.)
`
`One trial was performed at a single center. It enrolled 50 patients who were randomized to
`receive daily doses of either glatiramer acetate, 20 mg subcutaneously, or placebo (glatiramer
`acetate, n=25; placebo, n=25). Patients were diagnosed with RR MS by standard criteria, and
`had had at least 2 exacerbations during the 2 years immediately preceding enrollment. Patients
`were ambulatory, as evidenced by a score of no more than 6 on the Kurtzke Disability Scale
`Score (DSS), a standard scale ranging from 0–Normal to 10–Death due to MS. A score of 6 is
`defined as one at which a patient is still ambulatory with assistance; a score of 7 means the
`patient must use a wheelchair.
`
`Patients were examined every 3 months for 2 years, as well as within several days of a
`presumed exacerbation. To confirm an exacerbation, a 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 2 years of the trial, but two other
`important outcomes were also specified as endpoints: 1) the frequency of attacks during the
`trial, and 2) the change in the number of attacks compared with the number which occurred
`during the previous 2 years.
`
`Table 1 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 1 dose of treatment and who had at least 1 on-treatment
`assessment):
`
`Table 1: Study 1 Efficacy Results
`
`Outcome
`
`% Relapse Free
`Patients
`Mean Relapse
`Frequency
`Reduction in
`Relapse Rate
`Compared to Pre-
`
`Glatiramer Acetate
`(N=25)
`14/25 (56%)
`
`7/25 (28%)
`
`Placebo (N=25)
`
`P-Value
`
`0.6/2 years
`
`2.4/2 years
`
`3.2
`
`1.6
`
`0.085
`
`0.005
`
`0.025
`
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`EX1022, Page 2 of 26
`
`

`

`NDA 20-622/S-015/S-015
`Page 5
`
`20/25 (80%)
`
`0.03
`
`0.07
`
`>700
`
`150
`
`Study
`Median Time to First
`Relapse (days)
`% of Progression-
`Free* Patients
`*Progression was defined as an increase of at least 1 point on the DSS, persisting for at least
`3 consecutive months.
`
`13/25 (52%)
`
`The second trial was a multicenter trial of similar design which was performed in 11 US centers.
`A total of 251 patients (glatiramer acetate, 125; placebo, 126) were enrolled. The primary
`outcome measure was the Mean 2-year Relapse Rate. The table below presents the values of
`this outcome for the intent-to-treat population, as well as several secondary measures.
`
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`EX1022, Page 3 of 26
`
`

`

`NDA 20-622/S-015
`Page 6
`Table 2: Study 2 Efficacy Results
`
`Outcome
`
`Mean No. of
`Relapses
`
`% Relapse Free
`Patients
`
`Median Time to First
`Relapse (days)
`% of Patients
`Progression Free
`Mean Change in
`DSS
`
`Glatiramer Acetate
`(N=125)
`1.19/2 years
`
`Placebo
`(N=126)
`1.68 /2 years
`
`P-Value
`
` 0.055
`
`42/125 (34%)
`
`34/126 (27%)
`
`287
`
`198
`
` 0.25
`
` 0.23
`
`98/125 (78%)
`
`95/126 (75%)
`
` 0.48
`
`-0.05
`
`+0.21
`
` 0.023
`
`In both studies glatiramer acetate exhibited a clear beneficial effect on relapse rate, and it is
`based on this evidence that glatiramer acetate is considered effective.
`
`A third study was a multi-national study in which MRI parameters were used both as primary and
`secondary endpoints. A total of 239 patients with RR MS (119 on glatiramer acetate and 120 on
`placebo) 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 a 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 3 summarizes the
`result for the primary outcome measures monitored during the trial for the intent-to-treat cohort.
`
`
`
`
`
` Table 3: Study 3 MRI Results
`
`
`Outcome
`
`Glatiramer
`
`Placebo
`
`p-value
`
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`EX1022, Page 4 of 26
`
`

`

`NDA 20-622/S-015/S-015
`Page 7
`
`Acetate
`(N=119)
`11
`
`(N=120)
`
`17
`
`Medians of the Cumulative
`Number of T1 Gd-
`Enhancing Lesions
`
` The following figure displays the results of the primary outcome on a monthly basis.
`
`0.0030
`
`Figure 1: Median Cumulative Number of Gd-Enhancing Lesions
`
`
`
`18
`
`16
`
`14
`
`12
`
`Copaxone
`Placebo
`
`Cumulative Number of Enhancing Lesions
`
`10
`
`02468
`
`(median)
`
`0
`
`1
`
`2
`
`3
`
`5
`4
`Months
` p= 0.003 for the difference between the placebo-treated (n=120) and glatiramer acetate-
`treated (n=119) groups.
`
`6
`
`7
`
`8
`
`9
`
` INDICATIONS AND USAGE
`
`
`Petitioner TWi Pharms., Inc.
`EX1022, Page 5 of 26
`
`

`

`Use
`
`of
`
`NDA 20-622/S-015
`Page 8
` COPAXONE® is indicated for reduction of the frequency of relapses in patients with
`Relapsing-Remitting Multiple Sclerosis.
`
` CONTRAINDICATIONS
` COPAXONE® is contraindicated in patients with known hypersensitivity to glatiramer acetate or
`mannitol.
`
` WARNINGS
` The only recommended route of administration of COPAXONE® injection is the subcutaneous
`route. COPAXONE® should not be administered by the intravenous route.
`
` PRECAUTIONS
` General
` Patients should be instructed in self-injection techniques to assure the safe administration of
`COPAXONE® (see PRECAUTIONS: Information for Patients and the COPAXONE® PATIENT
`INFORMATION Booklet). Current data indicate that no special caution is required for patients
`operating an automobile or using complex machinery.
`
`the
`Regarding
` Considerations
`Capable of Modifying Immune Responses
` Because glatiramer acetate can modify immune response, it could possibly interfere with useful
`immune functions. For example, treatment with glatiramer acetate might, in theory, 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 does this, but
`there has as yet been no systematic evaluation of this risk. Because glatiramer acetate 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 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 might result in untoward effects.
`
`Glatiramer acetate-reactive antibodies are formed in practically all patients exposed to daily
`treatment with the recommended dose. 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
`RR MS patients given glatiramer acetate, 20 mg, subcutaneously every day for 2 years, serum
`lgG 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 lgG levels at least
`3 times baseline values, and 90% had levels above baseline by 12 months. The antibodies are
`exclusively of the lgG subtype-and predominantly of the lgG-1 subtype. No lgE 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.
`
`
` Information for Patients
` To assure safe and effective use of COPAXONE®, the following information and instructions
`should be given to patients:
`
`
`Product
`
`a
`
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`EX1022, Page 6 of 26
`
`

`

`NDA 20-622/S-015/S-015
`Page 9
`
` 1.
`
`Inform your physician if you are pregnant, if you are planning to have a child, or if you
`become pregnant while taking this medication.
`
`Inform your physician if you are nursing.
`
`Do not stop taking the drug without consulting your physician.
`
`Do not change the dose or dosing schedule without consulting your physician.
`
`
` 2.
`
` 3.
`
` 4.
`
` Patients should be instructed in the use of aseptic techniques when administering
`COPAXONE®. Appropriate instructions for the reconstitution and self-injection of COPAXONE®
`should be given, including a careful review of the COPAXONE® PATIENT INFORMATION
`Booklet. The first injection should be performed under the supervision of an appropriately
`qualified health care professional. Patient understanding and use of aseptic self-injection
`techniques and procedures should be periodically reevaluated. Patients should be cautioned
`against the reuse of needles or syringes and instructed in safe disposal procedures. They should
`use a puncture-resistant container for disposal of used needles and syringes. Patients should
`be instructed on the safe disposal of full containers according to local laws.
`
` Awareness of Adverse Reactions: Physicians are advised to counsel patients about adverse
`reactions associated with the use of COPAXONE® (see ADVERSE REACTIONS section). In
`addition, patients should be advised to read the COPAXONE® PATIENT INFORMATION
`Booklet and resolve any questions regarding it prior to beginning COPAXONE® therapy.
`
` Laboratory Tests
` Data collected during premarketing development do not suggest the need for routine laboratory
`monitoring.
`
` Drug Interactions
` Interactions between COPAXONE® and other drugs have not been fully evaluated. Results from
`existing clinical trials do not suggest any significant interactions of COPAXONE ® with therapies
`commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days.
`COPAXONE® has not been formally evaluated in combination with Interferon beta.
`
` Drug/Laboratory Test Interactions
` None are known.
`
` Carcinogenesis, Mutagenesis, Impairment of Fertility
` Carcinogenesis
` In a two-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 on a mg/m2
`basis). No increase in systemic neoplasms was observed. In males of the high dose group (60
`mg/kg/day), but not in females, 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.
`
`
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`EX1022, Page 7 of 26
`
`

`

`NDA 20-622/S-015
`Page 10
` In a two-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 systemic neoplasms was observed.
`
` Mutagenesis
` Glatiramer acetate was not mutagenic in four strains of Salmonella typhimurium and two strains
`of Escherichia coli (Ames test) or in the in vitro mouse lymphoma assay in L5178Y cells.
`Glatiramer acetate was clastogenic in two separate in vitro chromosomal aberration assays in
`cultured human lymphocytes; it was not clastogenic in an in vivo mouse bone marrow
`micronucleus assay.
`
` Impairment of Fertility
` In a multigeneration reproduction and fertility study in rats, glatiramer acetate at subcutaneous
`doses of up to 36 mg/kg (18 times the human therapeutic dose on a mg/m2 basis) had no
`adverse effects on reproductive parameters.
`
`Pregnancy: Pregnancy Category B. No adverse effects on embryofetal development
`occurred in Reproduction studies in rats and rabbits receiving subcutaneous doses of up to
`37.5 mg/kg of glatiramer acetate during the period of organogenesis (18 and 36 times the
`therapeutic human dose on a mg/m2 basis respectively). In a prenatal and postnatal study in
`which rats received 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.
`
` There are no adequate and well-controlled studies in pregnant women. Because animal
`reproduction studies are not always predictive of human response, glatiramer acetate should
`be used during pregnancy only if clearly needed.
`
` Labor and Delivery
` In a prenatal and postnatal study, in which rats received subcutaneous glatiramer acetate at
`doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation, no significant effects
`on delivery were observed. The relevance of these findings to humans is unknown.
`
` Nursing Mothers
` It is not known whether glatiramer acetate is excreted in human milk. Because many drugs are
`excreted in human milk, caution should be exercised when COPAXONE® is administered to a
`nursing woman.
`
`
` Pediatric Use
` The safety and efficacy of COPAXONE® have not been established in individuals under 18
`years of age.
`
` Use in the Elderly
` COPAXONE® has not been studied specifically in elderly patients.
`
` Use in Patients with Impaired Renal Function
` The pharmacokinetics of glatiramer acetate in patients with impaired renal function have not
`
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`EX1022, Page 8 of 26
`
`

`

`NDA 20-622/S-015/S-015
`Page 11
`
`been determined.
`
`
` ADVERSE REACTIONS
` During premarketing clinical trials approximately 900 individuals received at least one dose of
`glatiramer acetate.
`
` In controlled clinical trials the most commonly observed adverse experiences associated with
`the use of glatiramer acetate and not seen at an equivalent frequency among placebo-
`treated patients were: injection site reactions, vasodilatation, chest pain, asthenia, infection,
`pain, nausea, arthralgia, anxiety, and hypertonia.
`
` Approximately 8% of the 893 subjects receiving glatiramer acetate discontinued treatment
`because of an adverse reaction. The adverse reactions most commonly associated with
`discontinuation were: injection site reaction (6.5%), vasodilatation, unintended pregnancy,
`depression, dyspnea, urticaria, tachycardia, dizziness, and tremor.
`
`
`
` Immediate Post-Injection Reaction
` Approximately 10% of MS patients exposed to glatiramer acetate in premarketing studies
`experienced a constellation of symptoms immediately after injection that included flushing, chest
`pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. In clinical trials, the
`symptoms were generally transient and self-limited and did not require specific treatment. 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. During the postmarketing period, there have been reports of patients with
`similar symptoms who received emergency medical care.
`
` Whether an immunologic or non-immunologic mechanism mediates these episodes, or whether
`several similar episodes seen in a given patient have identical mechanisms, is unknown.
`
`
` Chest Pain
` Approximately 21% of glatiramer acetate patients in the pre-marketing controlled studies
`(compared to 11% of placebo patients) experienced at least one episode of what was described
`as 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 of glatiramer acetate was not always known. The pain was transient (usually
`lasting only a few minutes), often unassociated with other symptoms, and appeared to have no
`important clinical sequelae. There has been only one episode of chest pain during which a full
`EKG was performed; that EKG showed no evidence of ischemia. 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.
`
` Incidence in Controlled Clinical Studies: The following table lists treatment-emergent signs
`
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`EX1022, Page 9 of 26
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`

`

`NDA 20-622/S-015
`Page 12
`and symptoms that occurred in at least 2% of MS patients treated with glatiramer acetate in the
`pre-marketing placebo-controlled trials. These signs and symptoms were numerically more
`common in patients treated with glatiramer acetate than in patients treated with placebo. These
`trials include the first two controlled trials in RR MS patients and a controlled trial in patients with
`Chronic-Progressive MS. Adverse reactions were usually mild in intensity.
`
` The prescriber should be aware that these figures cannot be used to predict the frequency of
`adverse experiences in the course of usual medical practice where patient characteristics
`and other factors may differ from those prevailing during clinical studies. Similarly, the cited
`frequencies cannot be directly compared with figures obtained from other clinical
`investigations involving different treatments, uses, or investigators. An inspection of these
`frequencies, however, does provide the prescriber with one basis on which to estimate the
`relative contribution of drug and nondrug factors to the adverse reaction incidences in the
`population studied.
`
`
`N
`
`
`
`
`
`
`
` Placebo
` (N = 206)
`
` %
`
`
`
`N
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`83
`33
`11
`43
`8
`5
`12
`17
`38
`101
`132
`11
`26
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`41
`16
`5
`21
`4
`2
`6
`8
`19
`50
`66
`5
`13
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`78
`30
`9
`22
`2
`1
`2
`15
`35
`99
`40
`6
`1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`38
`15
`4
`11
`1
`0
`1
`7
`17
`48
`19
`3
`0
`
` Controlled Trials in Patients with Multiple Sclerosis:
` Incidence of Glatiramer Acetate Adverse Reactions ≥≥≥≥2%
` and More Frequent than Placebo
`
` Glatiramer Acetate
` (N = 201)
`
` %
`
`
`
`
`
`
`
`
`
` Preferred Term
`
`
` Body as a Whole
`
`
` Asthenia
`
`
`
` Back Pain
`
`
`
` Bacterial Infection
`
`
`
` Chest Pain
`
`
`
` Chills
`
`
`
` Cyst
`
`
`
` Face Edema
`
`
`
` Fever
`
`
`
` Flu Syndrome
`
`
`
` Infection
`
`
`
` Injection Site Erythema
`
`
`
` Injection Site Hemorrhage
`
`
`
` Injection Site Induration
`
`
`
`
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`EX1022, Page 10 of 26
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`

`

`NDA 20-622/S-015/S-015
`Page 13
`
`
`
`
`
` Preferred Term
` Injection Site Inflammation
`
`
`
` Injection Site Mass
`
`
`
` Injection Site Pain
`
`
`
` Injection Site Pruritus
`
`
`
` Injection Site Urticaria
`
`
`
` Injection Site Welt
`
`
`
` Neck Pain
`
`
`
` Pain
`
`
`
` Cardiovascular System
`
`
` Migraine
`
`
`
` Palpitations
`
`
`
` Syncope
`
`
`
` Tachycardia
`
`
`
` Vasodilatation
`
`
`
` Digestive System
`
`
` Anorexia
`
`
`
` Diarrhea
`
`
`
` Gastroenteritis
`
`
`
` Gastrointestinal Disorder
`
`
`
` Nausea
`
`
`
` Vomiting
`
`
`
` Hemic and Lymphatic System
`
`
` Ecchymosis
`
`
`
`
`
` Glatiramer Acetate
` (N = 201)
`
` %
`49
`
`
`27
`
`
`73
`
`
`40
`
`
`5
`
`
`11
`
`
`8
`
`
`28
`
`
`
`
`N
`98
`54
`147
`80
`10
`22
`16
`56
`
`10
`35
`10
`11
`55
`
`17
`25
`6
`10
`44
`13
`
`16
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5
`17
`5
`5
`27
`
`8
`12
`3
`5
`22
`6
`
`8
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Placebo
` (N = 206)
`
` %
`11
`
`
`10
`
`
`38
`
`
`6
`
`
`0
`
`
`2
`
`
`4
`
`
`25
`
`
`
`
`N
`22
`21
`78
`12
`0
`5
`9
`52
`
`5
`16
`5
`8
`21
`
`15
`23
`2
`8
`34
`8
`
`13
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
`8
`2
`4
`10
`
`7
`11
`1
`4
`17
`4
`
`6
`
`Petitioner TWi Pharms., Inc.
`EX1022, Page 11 of 26
`
`

`

`NDA 20-622/S-015
`Page 14
`
`
`
`
` Preferred Term
` Lymphadenopathy
`
`
`
`
`
` Metabolic and Nutritional
`
`
` Edema
`
`
`
` Peripheral Edema
`
`
`
` Weight Gain
`
`
`
` Musculoskeletal System
`
`
` Arthralgia
`
`
`
` Nervous System
`
`
` Agitation
`
`
`
` Anxiety
`
`
`
` Confusion
`
`
`
` Foot Drop
`
`
`
` Hypertonia
`
`
`
` Nervousness
`
`
`
` Nystagmus
`
`
`
` Speech Disorder
`
`
`
` Tremor
`
`
`
` Vertigo
`
`
`
` Respiratory System
`
`
` Bronchitis
`
`
`
` Dyspnea
`
`
`
` Laryngismus
`
`
`
` Rhinitis
`
`
`
` Glatiramer Acetate
` (N = 201)
`
` %
`12
`
`
`
`
`N
`25
`
`5
`14
`7
`
`49
`
`8
`46
`5
`6
`44
`4
`5
`5
`14
`12
`
`18
`38
`10
`29
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3
`7
`3
`
`24
`
`4
`23
`2
`3
`22
`2
`2
`2
`7
`6
`
`9
`19
`5
`14
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Placebo
` (N = 206)
`
` %
`6
`
`
`
`
`N
`12
`
`1
`8
`0
`
`39
`
`4
`40
`1
`4
`37
`2
`2
`3
`7
`11
`
`12
`15
`7
`27
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0
`4
`0
`
`19
`
`2
`19
`0
`2
`18
`1
`1
`1
`3
`5
`
`6
`7
`3
`13
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Petitioner TWi Pharms., Inc.
`EX1022, Page 12 of 26
`
`

`

`NDA 20-622/S-015/S-015
`Page 15
`
`
`
`
`
` Preferred Term
`
`
` Skin and Appendages
`
`
` Erythema
`
`
`
` Herpes Simplex
`
`
`
` Pruritus
`
`
`
` Rash
`
`
`
` Skin Nodule
`
`
`
` Sweating
`
`
`
` Urticaria
`
`
`
` Special Senses
`
`
` Ear Pain
`
`
`
` Eye Disorder
`
`
`
` Urogenital System
`
`
` Dysmenorrhea
`
`
`
` Urinary Urgency
`
`
`
` Vaginal Moniliasis
`
`
`
` Glatiramer Acetate
` (N = 201)
`
` %
`
`
`
`N
`
`8
`8
`36
`37
`4
`31
`9
`
`15
`8
`
`12
`20
`16
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`4
`4
`18
`18
`2
`15
`4
`
`7
`4
`
`6
`10
`8
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Placebo
` (N = 206)
`
` %
`
`
`
`N
`
`4
`6
`26
`30
`1
`21
`5
`
`12
`1
`
`10
`17
`9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
`3
`13
`15
`0
`10
`2
`
`6
`0
`
`5
`8
`4
`
`
` Other events which occurred in at least 2% of glatiramer acetate patients but were present at
`equal or greater rates in the placebo group included:
`
` Body as a Whole: Headache, injection site ecchymosis, accidental injury, abdominal pain,
`allergic rhinitis, neck rigidity, and malaise.
`
` Digestive System: Dyspepsia, constipation, dysphagia, fecal incontinence, flatulence, nausea
`and vomiting, gastritis, gingivitis, periodontal abscess, and dry mouth.
`
` Musculoskeletal: Myasthenia and myalgia.
`
` Nervous System: Dizziness, hypesthesia, paresthesia, insomnia, depression, dysesthesia,
`incoordination, somnolence, abnormal gait, amnesia, emotional lability, Lhermitte’s sign,
`
`Petitioner TWi Pharms., Inc.
`EX1022, Page 13 of 26
`
`

`

`NDA 20-622/S-015
`Page 16
`abnormal thinking, twitching, euphoria, and sleep disorder.
`
` Respiratory System: Pharyngitis, sinusitis, increased cough and laryngitis.
`
` Skin and Appendages: Acne, alopecia, and nail disorder.
`
` Special Senses: Abnormal vision, diplopia, amblyopia, eye pain, conjunctivitis, tinnitus, taste
`perversion, and deafness.
`
` Urogenital System: Urinary tract infection, urinary frequency, urinary incontinence, urinary
`retention, dysuria, cystitis, metrorrhagia, breast pain, and vaginitis.
`
` Data on adverse reactions occurring in the controlled clinical trials were analyzed to evaluate
`differences based on sex. No clinically significant differences were identified. Ninety-two percent
`of patients in these clinical trials were Caucasian. This percentage reflects the racial composition
`of the MS population. In addition, the vast majority of patients treated with COPAXONE® 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.
`
` Laboratory analyses were performed on all patients participating in the clinical program for
`glatiramer acetate. Clinically significant laboratory values for hematology, chemistry, and
`urinalysis were similar for both glatiramer acetate and placebo groups in blinded clinical trials.
`No patient receiving glatiramer acetate withdrew from any trial because of abnormal laboratory
`findings.
`
` Other Adverse Events Observed During Clinical Trials
` Glatiramer acetate was administered to 979 individuals during premarketing clinical trials, only
`some of which were placebo-controlled. During these trials, all adverse events were recorded
`by the clinical investigators, using terminology of their own choosing. To provide a meaningful
`estimate of the proportion of individuals having adverse events, similar types of events were
`grouped into standardized categories using COSTART dictionary terminology. All reported
`events occurring at least twice and potentially important events occurring once are listed below,
`except those already listed in the previous table, those too general to be informative, trivial
`events, and other reactions which occurred in at least 2% of treated patients and were present
`at equal or greater rates in the placebo group. Additional adverse reactions reported during the
`post-marketing period are included.
`
` Events are further classified within body system categories and listed in order of decreasing
`frequency using the following definitions: Frequent adverse events are defined as those
`occurring in at least 1/100 patients; Infrequent adverse events are those occurring in 1/100 to
`1/1000 patients; Rare adverse events are those occurring in less than 1/1000 patients.
`
` Body as a Whole:
`R Frequent: Injection site edema, injection site atrophy, abscess, injection site
`hypersensitivity.
`R Infrequent: Injection site hematoma, injection site fibrosis, moon face, cellulitis,
`generalized edema, hernia, injection site abscess, serum sickness, suicide attempt,
`injection site hypertrophy, injection site melanosis, lipoma, and photosensitivity reaction.
`
`
`
`Petitioner TWi Pharms., Inc.
`EX1022, Page 14 of 26
`
`

`

`NDA 20-622/S-015/S-015
`Page 17
`
` Cardiovascular:
`R Frequent: Hypertension.
`R Infrequent: Hypotension, midsystolic click, systolic murmur, atrial fibrillation, bradycardia,
`fourth heart sound, postural hypotension, and varicose veins.
`
`
` Digestive:
`R 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:
`R Infrequent: Goiter, hyperthyroidism, and hypothyroidism.
`
`
` Gastrointestinal:
`R Frequent: Bowel urgency, oral moniliasis, salivary gland enlargement, tooth caries, and
`ulcerative stomatitis.
`
`
` Hemic and Lymphatic:
`R Infrequent: Leukopenia, anemia, cyanosis, eosinophilia, hematemesis, lymphedema,
`pancytopenia, and splenomegaly.
`
`
` Metabolic and Nutritional:
`R Infrequent: Weight loss, alcohol intolerance, Cushing’s syndrome, gout, abnormal healing,
`and xanthoma.
`
`
` Musculoskeletal:
`R Infrequent: Arthritis, muscle atrophy, bone pain, bursitis, kidney pain, muscle disorder,
`myopathy, osteomyelitis, tendon pain, and tenosynovitis.
`
`
` Nervous:
`R Frequent: Abnormal dreams, emotional lability, and stupor.
`R 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:
`R Frequent: Hyperventilation, hay-fever.
`R Infrequent: Asthma, pneumonia, epistaxis, hypoventilation, and voice alteration.
`
`
` Skin and Appendages:
`R Frequent: Eczema, herpes zoster, pustular rash, skin atrophy, and warts.
`R 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
`
`Petitioner TWi Pharms., Inc.
`EX1022, Page 15 of 26
`
`

`

`NDA 20-622/S-015
`Page 18
`rash.
`
`
` Special Senses:
`R Frequent: Visual field defect.
`R Infrequent: Dry eyes, otitis externa, ptosis, cataract, corneal ulcer, mydriasis, optic
`neuritis, photophobia, and taste loss.
`
`
` Urogenital:
`R Frequent: Amenorrhea, hematuria, impotence, menorrhagia, suspicious papanicolaou
`smear, urinary frequency and vaginal hemorrhage.
`R 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.
`
`
`
` Postmarketing Clinical Experience
` Postmarketing experience has shown an adverse event profile similar to that
` presented above. Reports of adverse reactions occurring under treatment with
` COPAXONE ®(glatiramer acetate) not mentioned above that have been received since
`market introduction and that may have or not have causal relationship to the drug include
`the following:
`
`
` Body as a Whole: sepsis; LE syndrome; hydrocephalus; enlarged abdomen; injection site
`hypersensitivity; 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; liver function abnormality; liver
`damage; hepatitis; eructation; cirrhosis of the liver; cholelithiasis
`
` Hemic and Lymphatic System: thrombocytopenia; lymphoma-like reaction; acute leukemia
`
` Metabolic and Nutritional Disorders: hypercholesterolemia
`
` Musculoskeletal System: rheumatoid arthritis; generalized spasm
`
` Nervous Sy