INDICATIONS
GLATOPA™ IS INDICATED FOR THE TREATMENT OF PATIENTS WITH RELAPSING FORMS OFMULTIPLE SCLEROSIS.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
" INJECTION: 20 MG PER ML IN A SINGLE-DOSE, PREFILLED SYRINGE WITH A WHITE PLUNGER. FOR SUBCUTANEOUS USE ONLY.
STORAGE AND HANDLING
GLATOPA (GLATIRAMER ACETATE INJECTION) IS A CLEAR, COLORLESS TO SLIGHTLY YELLOW, STERILE, NONPYROGENIC SOLUTION IN A 1 ML SINGLE-DOSE GLASS SYRINGE WITH ATTACHED ½ INCH LENGTH AND 29 GAUGE NEEDLE SUPPLIED AS:
20 MG PER ML IN A SINGLE-DOSE, PREFILLED SYRINGE WITH A WHITE PLUNGER, IN INDIVIDUAL BLISTER PACKAGES SUPPLIED IN 30- COUNT CARTONS WITH 34 ALCOHOL PREPS (NDC 0781-3234-34)
STORE GLATOPA REFRIGERATED AT 2°C TO 8°C (36°F TO 46°F). IF NEEDED, THE PATIENT MAY STORE GLATOPA AT ROOM TEMPERATURE, 15°C TO 30°C (59°F TO 86°F), FOR UP TO ONE MONTH, BUT REFRIGERATION IS PREFERRED. AVOID EXPOSURE TO HIGHER TEMPERATURES OR INTENSE LIGHT. DO NOT FREEZE GLATOPA. IF A GLATOPA SYRINGE FREEZES, IT SHOULD BE DISCARDED.
DISTRIBUTED BY: SANDOZ INC., PRINCETON, NJ 08540. REVISED: MARCH 2014
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSE
GLATOPA IS FOR SUBCUTANEOUS USE ONLY. DO NOT ADMINISTER INTRAVENOUSLY. THE RECOMMENDED DOSE IS:
" GLATOPA 20 MG PER ML: ADMINISTER ONCE PER DAY
GLATOPA 20 MG PER ML AND GLATIRAMER ACETATE INJECTION 40 MG PER ML ARE NOT INTERCHANGEABLE.
INSTRUCTIONS FOR USE
REMOVE ONE BLISTER-PACKAGED PREFILLED SYRINGE FROM THE REFRIGERATED CARTON. LET THE PREFILLED 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 PREFILLED SYRINGE IS FOR SINGLE USE ONLY. DISCARD UNUSED PORTIONS.
SIDE EFFECTS
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 DIRECTLYCOMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN CLINICAL 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 TREATMENT-EMERGENT 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
GLATIRAMER ACETATE INJECTION 20 MG/ML
(N=563) PLACEBO
(N=564)
BLOOD AND LYMPHATIC SYSTEM DISORDERS LYMPHADENOPATHY 7% 3%
CARDIAC DISORDERS PALPITATIONS 9% 4%
TACHYCARDIA 5% 2%
EYE DISORDERS EYE DISORDER 3% 1%
DIPLOPIA 3% 2%
GASTROINTESTINAL DISORDERS NAUSEA 15% 11%
VOMITING 7% 4%
DYSPHAGIA 2% 1%
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS INJECTION SITE ERYTHEMA 43% 10%
INJECTION SITE PAIN 40% 20%
INJECTION SITE PRURITUS 27% 4%
INJECTION SITE MASS 26% 6%
ASTHENIA 22% 21%
PAIN 20% 17%
INJECTION SITE EDEMA 19% 4%
CHEST PAIN 13% 6%
INJECTION SITE INFLAMMATION 9% 1%
EDEMA 8% 2%
INJECTION SITE REACTION 8% 1%
PYREXIA 6% 5%
INJECTION SITE HYPERSENSITIVITY 4% 0%
LOCAL REACTION 3% 1%
CHILLS 3% 1%
FACE EDEMA 3% 1%
EDEMA PERIPHERAL 3% 2%
INJECTION SITE FIBROSIS 2% 1%
INJECTION SITE ATROPHY1 2% 0%
IMMUNE SYSTEM DISORDERS HYPERSENSITIVITY 3% 2%
INFECTIONS AND INFESTATIONS INFECTION 30% 28%
INFLUENZA 14% 13%
RHINITIS 7% 5%
BRONCHITIS 6% 5%
GASTROENTERITIS 6% 4%
VAGINAL CANDIDIASIS 4% 2%
METABOLISM AND NUTRITION DISORDERS WEIGHT INCREASED 3% 1%
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS BACK PAIN 12% 10%
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) BENIGN NEOPLASM OF SKIN 2% 1%
NERVOUS SYSTEM DISORDERS TREMOR 4% 2%
MIGRAINE 4% 2%
SYNCOPE 3% 2%
SPEECH DISORDER 2% 1%
PSYCHIATRIC DISORDERS ANXIETY 13% 10%
NERVOUSNESS 2% 1%
RENAL AND URINARY DISORDERS MICTURITION URGENCY 5% 4%
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS DYSPNEA 14% 4%
COUGH 6% 5%
LARYNGOSPASM 2% 1%
SKIN AND SUBCUTANEOUS TISSUE DISORDERS RASH 19% 11%
HYPERHIDROSIS 7% 5%
PRURITUS 5% 4%
URTICARIA 3% 1%
SKIN DISORDER 3% 1%
VASCULAR DISORDERS VASODILATATION 20% 5%
1 INJECTION SITE ATROPHY COMPRISES TERMS RELATING TO LOCALIZED LIPOATROPHY AT INJECTION SITE
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 TOTHROMBOCYTOPENIA (16 X109/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, GASTROINTESTINALCARCINOMA, 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.
POSTMARKETING EXPERIENCE
THE FOLLOWING ADVERSE EVENTS OCCURRING UNDER TREATMENT WITH GLATIRAMER ACETATE INJECTION 20 MG PER ML SINCE MARKET INTRODUCTION AND NOT MENTIONED ABOVE HAVE BEEN IDENTIFIED DURING POSTAPPROVAL USE OF GLATIRAMER ACETATE INJECTION.
BECAUSE THESE EVENTS 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; CORONARYOCCLUSION; 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 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
READ THE GLATOPA (GLATIRAMER ACETATE INJECTION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
CLINICAL PHARMACOLOGY
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 THROUGHIMMUNIZATION AGAINST CENTRAL NERVOUS SYSTEM DERIVED MATERIAL CONTAININGMYELIN 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 TCELLS ARE INDUCED AND ACTIVATED IN THEPERIPHERY.
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].
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.
CLINICAL STUDIES
EVIDENCE SUPPORTING THE EFFECTIVENESS OF GLATIRAMER ACETATE INJECTION DERIVES FROM FOUR PLACEBO-CONTROLLED TRIALS WHICH USED A GLATIRAMER ACETATE INJECTION DOSE OF 20 MG PER ML PER DAY.
GLATIRAMER ACETATE INJECTION 20 MG PER ML PER DAY
STUDY 1 WAS PERFORMED AT A 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 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: THE FREQUENCY OF ATTACKS DURING THE TRIAL, AND THE CHANGE IN THE NUMBER OF ATTACKSCOMPARED WITH THE NUMBER WHICH OCCURRED DURING THE PREVIOUS 2 YEARS.
TABLE 2 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 2: STUDY 1 EFFICACY RESULTS
GLATIRAMER ACETATE INJECTION 20 MG/ML
(N=25) PLACEBO
(N=25) P-VALUE
% RELAPSE-FREE PATIENTS 14/25 (56%) 7/25 (28%) 0.085
MEAN RELAPSE FREQUENCY 0.6/2 YEARS 2.4/2 YEARS 0.005
REDUCTION IN RELAPSE RATECOMPARED TO PRESTUDY 3.2 1.6 0.025
MEDIAN TIME TO FIRST RELAPSE (DAYS) > 700 150 0.03
% OF PROGRESSION-FREE1PATIENTS 20/25 (80%) 13/25 (52%) 0.07
1 PROGRESSION WAS DEFINED AS AN INCREASE OF AT LEAST 1 POINT ON THE DSS, PERSISTING FOR AT LEAST 3 CONSECUTIVE MONTHS.
STUDY 2 WAS A MULTICENTER TRIAL OF SIMILAR DESIGN WHICH WAS PERFORMED IN 11 US CENTERS. A 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 3 PRESENTS THE VALUES OF THIS OUTCOME FOR THE INTENT-TO-TREAT POPULATION, AS WELL AS SEVERAL SECONDARY MEASURES:
TABLE 3: STUDY 2 EFFICACY RESULTS
GLATIRAMER ACETATE INJECTION 20 MG/ML
(N=125) PLACEBO
(N=126) P-VALUE
MEAN NO. OF RELAPSES 1.19/2 YEARS 1.68 /2 YEARS 0.055
% RELAPSE-FREE PATIENTS 42/125 (34%) 34/126 (27%) 0.25
MEDIAN TIME TO FIRST RELAPSE (DAYS) 287 198 0.23
% OF PROGRESSION-FREE PATIENTS 98/125 (78%) 95/126 (75%) 0.48
MEAN CHANGE IN DSS -0.05 +0.21 0.023
IN BOTH STUDIES, GLATIRAMER ACETATE INJECTION EXHIBITED A 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 SCLEROSISON 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 A 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 A SECOND EXACERBATION WAS SIGNIFICANTLY DELAYED IN PATIENTS TREATED WITH GLATIRAMER ACETATE INJECTIONCOMPARED 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 A 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 EXACERBATION
PATIENTS 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 4 WAS A MULTINATIONAL STUDY IN WHICH MRI PARAMETERS WERE USED BOTH AS PRIMARY AND SECONDARY ENDPOINTS. A 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 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 4 SUMMARIZES THE RESULTS FOR THE PRIMARY OUTCOME MEASURE MONITORED DURING THE TRIAL FOR THE INTENT-TO-TREAT COHORT.
TABLE 4: STUDY 4 MRI RESULTS
GLATIRAMER ACETATE INJECTION 20 MG/ML
(N=119) PLACEBO
(N=120) P-VALUE
MEDIANS OF THE CUMULATIVE NUMBER OF T1 GD-ENHANCING LESIONS 11 17 0.0030
FIGURE 2 DISPLAYS THE RESULTS OF THE PRIMARY OUTCOME ON A MONTHLY BASIS.
FIGURE 2: MEDIAN CUMULATIVE NUMBER OF GD-ENHANCING LESIONS