INDICATIONS
RAYOS IS INDICATED IN THE TREATMENT OF THE FOLLOWING DISEASES OR CONDITIONS:
ALLERGIC CONDITIONS
CONTROL OF SEVERE OR INCAPACITATING ALLERGIC CONDITIONS INTRACTABLE TO ADEQUATE TRIALS OF CONVENTIONAL TREATMENT IN ADULTS AND PEDIATRIC POPULATIONS WITH:
ATOPIC DERMATITIS
DRUG HYPERSENSITIVITY REACTIONS
SEASONAL OR PERENNIAL ALLERGIC RHINITIS
SERUM SICKNESS
DERMATOLOGIC DISEASES
BULLOUS DERMATITIS HERPETIFORMIS
CONTACT DERMATITIS
EXFOLIATIVE ERYTHRODERMA
MYCOSIS FUNGOIDES
PEMPHIGUS
SEVERE ERYTHEMA MULTIFORME (STEVENS-JOHNSON SYNDROME)
ENDOCRINE CONDITIONS
CONGENITAL ADRENAL HYPERPLASIA
HYPERCALCEMIA OF MALIGNANCY
NONSUPPURATIVE THYROIDITIS
PRIMARY OR SECONDARY ADRENOCORTICAL INSUFFICIENCY: HYDROCORTISONE OR CORTISONE IS THE FIRST CHOICE: SYNTHETIC ANALOGS MAY BE USED IN CONJUNCTION WITH MINERALOCORTICOIDS WHERE APPLICABLE
GASTROINTESTINAL DISEASES
DURING ACUTE EPISODES IN:
CROHN'S DISEASE
ULCERATIVE COLITIS
HEMATOLOGIC DISEASES
ACQUIRED (AUTOIMMUNE) HEMOLYTIC ANEMIA
DIAMOND-BLACKFAN ANEMIA
IDIOPATHIC THROMBOCYTOPENIC PURPURA IN ADULTS
PURE RED CELL APLASIA
SECONDARY THROMBOCYTOPENIA IN ADULTS
NEOPLASTIC CONDITIONS
FOR THE TREATMENT OF:
ACUTE LEUKEMIA
AGGRESSIVE LYMPHOMAS
NERVOUS SYSTEM CONDITIONS
ACUTE EXACERBATIONS OF MULTIPLE SCLEROSIS
CEREBRAL EDEMA ASSOCIATED WITH PRIMARY OR METASTATIC BRAIN TUMOR, CRANIOTOMY OR HEAD INJURY
OPHTHALMIC CONDITIONS
SYMPATHETIC OPHTHALMIA
UVEITIS AND OCULAR INFLAMMATORY CONDITIONS UNRESPONSIVE TO TOPICAL STEROIDS
CONDITIONS RELATED TO ORGAN TRANSPLANTATION
ACUTE OR CHRONIC SOLID ORGAN REJECTION
PULMONARY DISEASES
ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
ASPIRATION PNEUMONITIS
ASTHMA
FULMINATING OR DISSEMINATED PULMONARY TUBERCULOSIS WHEN USED CONCURRENTLY WITH APPROPRIATE CHEMOTHERAPY
HYPERSENSITIVITY PNEUMONITIS
IDIOPATHIC BRONCHIOLITIS OBLITERANS WITH ORGANIZING PNEUMONIA
IDIOPATHIC EOSINOPHILIC PNEUMONIAS
IDIOPATHIC PULMONARY FIBROSIS
PNEUMOCYSTIS CARINII PNEUMONIA (PCP) ASSOCIATED WITH HYPOXEMIA OCCURRING IN AN HIV(+) INDIVIDUAL WHO IS ALSO UNDER TREATMENT WITH APPROPRIATE ANTI-PCP ANTIBIOTICS.
SYMPTOMATIC SARCOIDOSIS
RENAL CONDITIONS
TO INDUCE A DIURESIS OR REMISSION OF PROTEINURIA IN NEPHROTIC SYNDROME, WITHOUT UREMIA, OF THE IDIOPATHIC TYPE OR THAT DUE TO LUPUS ERYTHEMATOSUS
RHEUMATOLOGIC CONDITIONS
AS ADJUNCTIVE THERAPY FOR SHORT-TERM ADMINISTRATION (TO TIDE THE PATIENT OVER AN ACUTE EPISODE OR EXACERBATION) IN:
ACUTE GOUTY ARTHRITIS
DURING AN EXACERBATION OR AS MAINTENANCE THERAPY IN SELECTED CASES OF:
ANKYLOSING SPONDYLITIS
DERMATOMYOSITIS/POLYMYOSITIS
POLYMYALGIA RHEUMATICA
PSORIATIC ARTHRITIS
RELAPSING POLYCHONDRITIS
RHEUMATOID ARTHRITIS, INCLUDING JUVENILE RHEUMATOID ARTHRITIS (SELECTED CASES MAY REQUIRE LOW DOSE MAINTENANCE THERAPY)
SJOGREN'S SYNDROME
SYSTEMIC LUPUS ERYTHEMATOSUS
VASCULITIS
SPECIFIC INFECTIOUS DISEASES
TRICHINOSIS WITH NEUROLOGIC OR MYOCARDIAL INVOLVEMENT.
TUBERCULOUS MENINGITIS WITH SUBARACHNOID BLOCK OR IMPENDING BLOCK USED CONCURRENTLY WITH APPROPRIATE ANTITUBERCULOUS CHEMOTHERAPY.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
DELAYED-RELEASE TABLETS
RAYOS 1 MG PREDNISONE: PALE YELLOWISH-WHITE, ROUND, UNSCORED DELAYED-RELEASE TABLET EMBOSSED WITH βNP 1β ON ONE SIDE.
RAYOS 2 MG PREDNISONE: YELLOWISH-WHITE, ROUND, UNSCORED DELAYED-RELEASE TABLET EMBOSSED WITH βNP 2β ON ONE SIDE.
RAYOS 5 MG PREDNISONE: LIGHT YELLOW, ROUND, UNSCORED DELAYED-RELEASE TABLET EMBOSSED WITH βNP 5β ON ONE SIDE.
STORAGE AND HANDLING
RAYOS DELAYED-RELEASE TABLETS (1 MG PREDNISONE) ARE PALE YELLOWISH-WHITE, ROUND, UNSCORED TABLETS EMBOSSED WITH βNP 1β ON ONE SIDE AND SUPPLIED AS:
NDC NUMBER
SIZE
75987-020-01
BOTTLE OF 30 TABLETS
75987-020-02
BOTTLE OF 100 TABLETS
RAYOS DELAYED-RELEASE TABLETS (2 MG PREDNISONE) ARE YELLOWISH-WHITE, ROUND, UNSCORED TABLETS EMBOSSED WITH βNP 2β ON ONE SIDE AND SUPPLIED AS:
NDC NUMBER
SIZE
75987-021-01
BOTTLE OF 30 TABLETS
75987-021-02
BOTTLE OF 100 TABLETS
RAYOS DELAYED-RELEASE TABLETS (5 MG PREDNISONE) ARE LIGHT YELLOW, ROUND, UNSCORED TABLETS EMBOSSED WITH βNP 5β ON ONE SIDE AND SUPPLIED AS:
NDC NUMBER
SIZE
75987-022-01
BOTTLE OF 30 TABLETS
75987-022-02
BOTTLE OF 100 TABLETS
STORE AT 25Β°C (77Β°F); EXCURSIONS PERMITTED TO 15-30Β°C (59-86Β°F). [SEE USP CONTROLLED ROOM TEMPERATURE].
PROTECT RAYOS TABLETS FROM LIGHT AND MOISTURE.
DISPENSE IN A TIGHT, LIGHT-RESISTANT CONTAINER AS DEFINED IN THE USP USING A CHILD-RESISTANT CLOSURE.
DISTRIBUTED BY: HORIZON PHARMA USA, INC. 520 LAKE COOK ROAD, SUITE 520 DEERFIELD, IL 60015. REVISED: JUNE 2013
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSING
DOSAGE OF RAYOS SHOULD BE INDIVIDUALIZED ACCORDING TO THE SEVERITY OF THE DISEASE AND THE RESPONSE OF THE PATIENT. FOR PEDIATRIC PATIENTS, THE RECOMMENDED DOSAGE SHOULD BE GOVERNED BY THE SAME CONSIDERATIONS RATHER THAN STRICT ADHERENCE TO THE RATIO INDICATED BY AGE OR BODY WEIGHT.
THE MAXIMAL ACTIVITY OF THE ADRENAL CORTEX IS BETWEEN 2 AM AND 8 AM AND IS MINIMAL BETWEEN 4 PM AND MIDNIGHT. EXOGENOUS CORTICOSTEROIDS SUPPRESS ADRENOCORTICOID ACTIVITY THE LEAST WHEN GIVEN AT THE TIME OF MAXIMAL ACTIVITY. RAYOS IS A DELAYED-RELEASE FORMULATION OF PREDNISONE WHICH RELEASES THE ACTIVE SUBSTANCE BEGINNING APPROXIMATELY 4 HOURS AFTER INTAKE [SEE CLINICAL PHARMACOKINETICS]. THE TIMING OF RAYOS ADMINISTRATION SHOULD TAKE INTO ACCOUNT THE DELAYED-RELEASE PHARMACOKINETICS AND THE DISEASE OR CONDITION BEING TREATED.
THE INITIAL DOSAGE OF RAYOS MAY VARY FROM 5 TO 60 MG PER DAY DEPENDING ON THE SPECIFIC DISEASE ENTITY BEING TREATED. PATIENTS CURRENTLY ON IMMEDIATE RELEASE PREDNISONE, PREDNISOLONE, OR METHYLPREDNISOLONE SHOULD BE SWITCHED TO RAYOS AT AN EQUIVALENT DOSE BASED ON RELATIVE POTENCY (2.4).
IN SITUATIONS OF LESS SEVERITY, LOWER DOSES WILL GENERALLY SUFFICE WHILE IN SELECTED PATIENTS HIGHER INITIAL DOSES MAY BE REQUIRED. THE INITIAL DOSAGE SHOULD BE MAINTAINED OR ADJUSTED UNTIL A SATISFACTORY RESPONSE IS NOTED. IF AFTER A REASONABLE PERIOD THERE IS A LACK OF SATISFACTORY CLINICAL RESPONSE, RAYOS SHOULD BE DISCONTINUED AND THE PATIENT TRANSFERRED TO OTHER APPROPRIATE THERAPY. IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT.
AFTER A FAVORABLE RESPONSE IS NOTED, THE PROPER MAINTENANCE DOSAGE SHOULD BE DETERMINED BY DECREASING THE INITIAL DRUG DOSAGE IN SMALL DECREMENTS AT APPROPRIATE TIME INTERVALS UNTIL THE LOWEST DOSAGE WHICH WILL MAINTAIN AN ADEQUATE CLINICAL RESPONSE IS REACHED. IT SHOULD BE KEPT IN MIND THAT CONSTANT MONITORING IS NEEDED IN REGARD TO DRUG DOSAGE. INCLUDED IN THE SITUATIONS WHICH MAY MAKE DOSAGE ADJUSTMENTS NECESSARY ARE CHANGES IN CLINICAL STATUS SECONDARY TO REMISSIONS OR EXACERBATIONS IN THE DISEASE PROCESS, THE PATIENT'S INDIVIDUAL DRUG RESPONSIVENESS, AND THE EFFECT OF PATIENT EXPOSURE TO STRESSFUL SITUATIONS NOT DIRECTLY RELATED TO THE DISEASE ENTITY UNDER TREATMENT. IN THIS LATTER SITUATION IT MAY BE NECESSARY TO INCREASE THE DOSAGE OF RAYOS FOR A PERIOD OF TIME CONSISTENT WITH THE PATIENT'S CONDITION. IF A PERIOD OF SPONTANEOUS REMISSION OCCURS IN A CHRONIC CONDITION, TREATMENT SHOULD BE DISCONTINUED. IF AFTER LONG-TERM THERAPY THE DRUG IS TO BE STOPPED, IT IS RECOMMENDED THAT IT BE WITHDRAWN GRADUALLY RATHER THAN ABRUPTLY.
RECOMMENDED MONITORING
BLOOD PRESSURE, BODY WEIGHT, ROUTINE LABORATORY STUDIES (INCLUDING 2-HOUR POSTPRANDIAL BLOOD GLUCOSE AND SERUM POTASSIUM), AND CHEST X-RAY SHOULD BE OBTAINED AT REGULAR INTERVALS DURING PROLONGED THERAPY WITH RAYOS. UPPER GI X-RAYS ARE DESIRABLE IN PATIENTS WITH KNOWN OR SUSPECTED PEPTIC ULCER DISEASE.
METHOD OF ADMINISTRATION
RAYOS IS FOR ORAL ADMINISTRATION.
RAYOS SHOULD BE TAKEN DAILY WITH FOOD. [SEE CLINICAL PHARMACOKINETICS]
RAYOS TABLETS SHOULD NOT BE BROKEN, DIVIDED, OR CHEWED BECAUSE THE DELAYED RELEASE OF PREDNISONE IS DEPENDENT ON AN INTACT COATING.
CORTICOSTEROID COMPARISON CHART
FOR THE PURPOSE OF COMPARISON, ONE 5 MG RAYOS TABLET IS THE EQUIVALENT MILLIGRAM DOSAGE OF THE FOLLOWING VARIOUS CORTICOSTEROIDS:
BETAMETHASONE, 0.75 MG
PARAMETHASONE, 2 MG
CORTISONE, 25 MG
PREDNISOLONE, 5 MG
DEXAMETHASONE, 0.75 MG
PREDNISONE, 5 MG
HYDROCORTISONE, 20 MG
TRIAMCINOLONE, 4 MG
METHYLPREDNISOLONE, 4 MG
Β
THESE DOSE RELATIONSHIPS APPLY ONLY TO ORAL OR INTRAVENOUS ADMINISTRATION OF THESE COMPOUNDS. WHEN THESE SUBSTANCES OR THEIR DERIVATIVES ARE INJECTED INTRAMUSCULARLY OR INTO JOINT SPACES, THEIR RELATIVE PROPERTIES MAY BE GREATLY ALTERED.
SIDE EFFECTS
COMMON ADVERSE REACTIONS FOR CORTICOSTEROIDS INCLUDE FLUID RETENTION, ALTERATION IN GLUCOSE TOLERANCE, ELEVATION IN BLOOD PRESSURE, BEHAVIORAL AND MOOD CHANGES, INCREASED APPETITE AND WEIGHT GAIN.
ALLERGIC REACTIONS: ANAPHYLAXIS, ANGIOEDEMA
CARDIOVASCULAR: BRADYCARDIA, CARDIAC ARREST, CARDIAC ARRHYTHMIAS, CARDIAC ENLARGEMENT, CIRCULATORY COLLAPSE, CONGESTIVE HEART FAILURE, FAT EMBOLISM, HYPERTENSION, HYPERTROPHIC CARDIOMYOPATHY IN PREMATURE INFANTS, MYOCARDIAL RUPTURE FOLLOWING RECENT MYOCARDIAL INFARCTION, PULMONARY EDEMA, SYNCOPE, TACHYCARDIA, THROMBOEMBOLISM, THROMBOPHLEBITIS, VASCULITIS
DERMATOLOGIC: ACNE, ALLERGIC DERMATITIS, CUTANEOUS AND SUBCUTANEOUS ATROPHY, DRY SCALP, EDEMA, FACIAL ERYTHEMA, HYPER OR HYPO-PIGMENTATION, IMPAIRED WOUND HEALING, INCREASED SWEATING, PETECHIAE AND ECCHYMOSES, RASH, STERILE ABSCESS, STRIAE, SUPPRESSED REACTIONS TO SKIN TESTS, THIN FRAGILE SKIN, THINNING SCALP HAIR, URTICARIA
ENDOCRINE: ABNORMAL FAT DEPOSITS, DECREASED CARBOHYDRATE TOLERANCE, DEVELOPMENT OF CUSHINGOID STATE, HIRSUTISM, MANIFESTATIONS OF LATENT DIABETES MELLITUS AND INCREASED REQUIREMENTS FOR INSULIN OR ORAL HYPOGLYCEMIC AGENTS IN DIABETICS, MENSTRUAL IRREGULARITIES, MOON FACIES, SECONDARY ADRENOCORTICAL AND PITUITARY UNRESPONSIVENESS (PARTICULARLY IN TIMES OF STRESS, AS IN TRAUMA, SURGERY OR ILLNESS), SUPPRESSION OF GROWTH IN CHILDREN
FLUID AND ELECTROLYTE DISTURBANCES: FLUID RETENTION, POTASSIUM LOSS, HYPERTENSION, HYPOKALEMIC ALKALOSIS, SODIUM RETENTION
GASTROINTESTINAL: ABDOMINAL DISTENTION, ELEVATION IN SERUM LIVER ENZYMES LEVELS (USUALLY REVERSIBLE UPON DISCONTINUATION), HEPATOMEGALY, HICCUPS, MALAISE, NAUSEA, PANCREATITIS, PEPTIC ULCER WITH POSSIBLE PERFORATION AND HEMORRHAGE, ULCERATIVE ESOPHAGITIS
GENERAL: INCREASED APPETITE AND WEIGHT GAIN
METABOLIC: NEGATIVE NITROGEN BALANCE DUE TO PROTEIN CATABOLISM
MUSCULOSKELETAL: OSTEONECROSIS OF FEMORAL AND HUMERAL HEADS, CHARCOT-LIKE ARTHROPATHY, LOSS OF MUSCLE MASS, MUSCLE WEAKNESS, OSTEOPOROSIS, PATHOLOGIC FRACTURE OF LONG BONES, STEROID MYOPATHY, TENDON RUPTURE, VERTEBRAL COMPRESSION FRACTURES
NEUROLOGICAL: ARACHNOIDITIS, CONVULSIONS, DEPRESSION, EMOTIONAL INSTABILITY, EUPHORIA, HEADACHE, INCREASED INTRACRANIAL PRESSURE WITH PAPILLEDEMA (PSEUDO-TUMOR CEREBRI) USUALLY FOLLOWING DISCONTINUATION OF TREATMENT, INSOMNIA, MENINGITIS, MOOD SWINGS, NEURITIS, NEUROPATHY, PARAPARESIS/PARAPLEGIA, PARESTHESIA, PERSONALITY CHANGES, SENSORY DISTURBANCES, VERTIGO
OPHTHALMIC: EXOPHTHALMOS, GLAUCOMA, INCREASED INTRAOCULAR PRESSURE, POSTERIOR SUBCAPSULAR CATARACTS, AND CENTRAL SEROUS CHORIORETINOPATHY
REPRODUCTIVE: ALTERATION IN MOTILITY AND NUMBER OF SPERMATOZOA
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.
THE SAFETY OF RAYOS WAS EVALUATED IN 375 RHEUMATOID ARTHRITIS PATIENTS IN TWO CONTROLLED TRIALS. PATIENTS TREATED WITH RAYOS RANGED IN AGE FROM 20 TO 80 YEARS (MEDIAN AGE 56 YEARS), WITH 85% FEMALE, 99% CAUCASIAN, 1% AFRICAN-AMERICAN, AND < 1% ASIAN.
PATIENTS RECEIVED RAYOS 3 MG TO 10 MG ONCE DAILY AT 10 PM; THE MAJORITY (84%) RECEIVED = 5 MG. THE CLINICAL TRIAL EXPERIENCE DID NOT RAISE NEW SAFETY CONCERNS BEYOND THOSE ALREADY ESTABLISHED FOR IMMEDIATE-RELEASE PREDNISONE.
POSTMARKETING EXPERIENCE
ADVERSE REACTIONS HAVE BEEN IDENTIFIED DURING POST APPROVAL USE OF RAYOS. 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. THE POSTMARKETING EXPERIENCE HAS NOT RAISED NEW SAFETY CONCERNS BEYOND THOSE ALREADY ESTABLISHED FOR IMMEDIATE-RELEASE PREDNISONE.
READ THE RAYOS (PREDNISONE DELAYED-RELEASE TABLETS) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
THE EFFECTS OF ACCIDENTAL INGESTION OF LARGE QUANTITIES OF PREDNISONE OVER A VERY SHORT PERIOD OF TIME HAVE NOT BEEN REPORTED, BUT PROLONGED USE OF THE DRUG CAN PRODUCE MENTAL SYMPTOMS, MOON FACE, ABNORMAL FAT DEPOSITS, FLUID RETENTION, EXCESSIVE APPETITE, WEIGHT GAIN, HYPERTRICHOSIS, ACNE, STRIAE, ECCHYMOSIS, INCREASED SWEATING, PIGMENTATION, DRY SCALY SKIN, THINNING SCALP HAIR, INCREASED BLOOD PRESSURE, TACHYCARDIA, THROMBOPHLEBITIS, DECREASED RESISTANCE TO INFECTION, NEGATIVE NITROGEN BALANCE WITH DELAYED BONE AND WOUND HEALING, HEADACHE, WEAKNESS, MENSTRUAL DISORDERS, ACCENTUATED MENOPAUSAL SYMPTOMS, NEUROPATHY, FRACTURES, OSTEOPOROSIS, PEPTIC ULCER, DECREASED GLUCOSE TOLERANCE, HYPOKALEMIA, AND ADRENAL INSUFFICIENCY. HEPATOMEGALY AND ABDOMINAL DISTENTION HAVE BEEN OBSERVED IN CHILDREN.
TREATMENT OF ACUTE OVERDOSAGE IS BY IMMEDIATE GASTRIC LAVAGE OR EMESIS FOLLOWED BY SUPPORTIVE AND SYMPTOMATIC THERAPY. FOR CHRONIC OVERDOSAGE IN THE FACE OF SEVERE DISEASE REQUIRING CONTINUOUS STEROID THERAPY THE DOSAGE OF PREDNISONE MAY BE REDUCED ONLY TEMPORARILY, OR ALTERNATE DAY TREATMENT MAY BE INTRODUCED.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
NATURALLY OCCURRING CORTICOSTEROIDS (HYDROCORTISONE AND CORTISONE), WHICH ALSO HAVE SALT-RETAINING PROPERTIES, ARE USED AS REPLACEMENT THERAPY IN ADRENOCORTICAL DEFICIENCY STATES. THEIR SYNTHETIC ANALOGS, SUCH AS PREDNISONE, ARE PRIMARILY USED FOR THEIR POTENT ANTI-INFLAMMATORY EFFECTS IN DISORDERS OF MANY ORGAN SYSTEMS.
CORTICOSTEROIDS, SUCH AS PREDNISONE, CAUSE PROFOUND AND VARIED METABOLIC EFFECTS. IN ADDITION, THEY MODIFY THE BODY'S IMMUNE RESPONSES TO DIVERSE STIMULI.
PREDNISONE IS A SYNTHETIC ADRENOCORTICAL STEROID DRUG WITH PREDOMINANTLY CORTICOSTEROID PROPERTIES. SOME OF THESE PROPERTIES REPRODUCE THE PHYSIOLOGICAL ACTIONS OF ENDOGENOUS GLUCOCORTICOSTEROIDS, BUT OTHERS DO NOT NECESSARILY REFLECT ANY OF THE ADRENAL HORMONES' NORMAL FUNCTIONS; THEY ARE SEEN ONLY AFTER ADMINISTRATION OF LARGE THERAPEUTIC DOSES OF THE DRUG. THE PHARMACOLOGICAL EFFECTS OF PREDNISONE WHICH ARE DUE TO ITS CORTICOSTEROID PROPERTIES INCLUDE: PROMOTION OF GLUCONEOGENESIS; INCREASED DEPOSITION OF GLYCOGEN IN THE LIVER; INHIBITION OF THE UTILIZATION OF GLUCOSE; ANTI-INSULIN ACTIVITY; INCREASED CATABOLISM OF PROTEIN; INCREASED LIPOLYSIS; STIMULATION OF FAT SYNTHESIS AND STORAGE; INCREASED GLOMERULAR FILTRATION RATE AND RESULTING INCREASE IN URINARY EXCRETION OF URATE (CREATININE EXCRETION REMAINS UNCHANGED); AND INCREASED CALCIUM EXCRETION.
DEPRESSED PRODUCTION OF EOSINOPHILS AND LYMPHOCYTES OCCURS, BUT ERYTHROPOIESIS AND PRODUCTION OF POLYMORPHONUCLEAR LEUKOCYTES ARE STIMULATED. INFLAMMATORY PROCESSES (EDEMA, FIBRIN DEPOSITION, CAPILLARY DILATATION, MIGRATION OF LEUKOCYTES AND PHAGOCYTOSIS) AND THE LATER STAGES OF WOUND HEALING (CAPILLARY PROLIFERATION, DEPOSITION OF COLLAGEN, CICATRIZATION) ARE INHIBITED.
PREDNISONE CAN STIMULATE SECRETION OF VARIOUS COMPONENTS OF GASTRIC JUICE. SUPPRESSION OF THE PRODUCTION OF CORTICOTROPIN MAY LEAD TO SUPPRESSION OF ENDOGENOUS CORTICOSTEROIDS. PREDNISONE HAS SLIGHT MINERALOCORTICOID ACTIVITY, WHEREBY ENTRY OF SODIUM INTO CELLS AND LOSS OF INTRACELLULAR POTASSIUM IS STIMULATED. THIS IS PARTICULARLY EVIDENT IN THE KIDNEY, WHERE RAPID ION EXCHANGE LEADS TO SODIUM RETENTION AND HYPERTENSION.
PHARMACOKINETICS
THE PHARMACOKINETIC PROFILE OF RAYOS HAS AN APPROXIMATELY 4-HOUR LAG TIME FROM THAT OF IMMEDIATE-RELEASE PREDNISONE FORMULATIONS. WHILE THE PHARMACOKINETIC PROFILE OF RAYOS WHEN GIVEN WITH FOOD DIFFERS IN TERMS OF LAG TIME FROM IR PREDNISONE, ITS ABSORPTION, DISTRIBUTION, AND ELIMINATION PROCESSES ARE COMPARABLE.
ABSORPTION
PREDNISONE IS RELEASED FROM RAYOS WHEN TAKEN WITH FOOD APPROXIMATELY 4 HOURS AFTER ORAL INGESTION. THIS CAUSES A DELAY IN THE TIME UNTIL PEAK PLASMA CONCENTRATIONS (TMAX) ARE ACHIEVED. MEDIAN TMAX OF RAYOS IN 27 HEALTHY MALE SUBJECTS WAS 6.0 - 6.5 HOURS COMPARED TO 2.0 HOURS FOR AN IMMEDIATE-RELEASE (IR) FORMULATION. SUBSEQUENTLY, PREDNISONE WAS ABSORBED AT THE SAME RATE AS THE IR FORMULATION. PEAK PLASMA CONCENTRATIONS (CMAX) AND EXPOSURE, AS INDICATED BY AUC0-LAST AND AUC0-8, WERE COMPARABLE FOR BOTH PREDNISONE IR AND RAYOS ADMINISTERED 2.5 HOURS AFTER A LIGHT MEAL OR WITH NORMAL MEAL (FIGURE 1).
FIGURE 1: MEAN PLASMA LEVELS OF PREDNISONE AFTER A SINGLE DOSE OF 5 MG PREDNISONE ADMINISTERED AS A 5 MG RAYOS TABLET OR A 5 MG IMMEDIATE-RELEASE (IR) TABLET
A: 5 MG IR TABLET UNDER FASTING CONDITIONS, ADMINISTERED AT 2 AM, B: 5 MG RAYOS, ADMINISTERED 2.5 HOURS AFTER A LIGHT EVENING MEAL, AND C: 5 MG RAYOS ADMINISTERED IMMEDIATELY AFTER DINNER
IN A STUDY WITH 24 HEALTHY SUBJECTS, ORAL ABSORPTION OF PREDNISONE FROM RAYOS WAS SIGNIFICANTLY AFFECTED BY THE INTAKE OF FOOD. UNDER STANDARD FASTING CONDITIONS, BOTH THE MAXIMUM PLASMA CONCENTRATION (CMAX) AND THE BIOAVAILABILITY OF RAYOS WERE SIGNIFICANTLY LOWER THAN UNDER FED CONDITIONS, SHORTLY AFTER INTAKE OF A HIGH FAT MEAL.
RAYOS AT DOSE LEVELS OF 1 MG, 2 MG, AND 5 MG SHOWED DOSE-PROPORTIONALITY IN TERMS OF PEAK AND SYSTEMIC EXPOSURE (CMAX, AUC0-8, AND AUC0-LAST) FOR THE PARENT DRUG PREDNISONE AS WELL AS FOR THE ACTIVE METABOLITE PREDNISOLONE.
METABOLISM
PREDNISONE IS COMPLETELY CONVERTED TO THE ACTIVE METABOLITE PREDNISOLONE, WHICH IS FURTHER METABOLIZED MAINLY IN THE LIVER AND EXCRETED IN THE URINE AS SULFATE AND GLUCURONIDE CONJUGATES. THE EXPOSURE OF PREDNISOLONE IS 4-6 FOLD HIGHER THAN THAT OF PREDNISONE.
EXCRETION
THE TERMINAL HALF-LIFE OF BOTH PREDNISONE AND PREDNISOLONE FROM THE ADMINISTRATION OF RAYOS WAS 2-3 HOURS, WHICH IS COMPARABLE TO THAT FROM THE IR FORMULATION.
SPECIAL POPULATIONS
THE EFFECTS OF GENDER, AGE, RENAL IMPAIRMENT, AND HEPATIC IMPAIRMENT ON THE PHARMACOKINETICS OF PREDNISONE OR PREDNISOLONE AFTER ADMINISTRATION OF RAYOS HAVE NOT BEEN EVALUATED.
CLINICAL STUDIES
THE EFFICACY OF RAYOS IN THE TREATMENT OF RHEUMATOID ARTHRITIS WAS ASSESSED IN ONE MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED, 12-WEEK TRIAL IN PATIENTS = 18 YEARS WITH ACTIVE RHEUMATOID ARTHRITIS DIAGNOSED ACCORDING TO AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) CRITERIA. PATIENTS WERE ENROLLED WHO WERE NOT CURRENTLY TREATED WITH CORTICOSTEROIDS BUT HAD RECEIVED NON-BIOLOGIC DMARD THERAPY FOR AT LEAST 6 MONTHS BEFORE RECEIPT OF STUDY MEDICATION, AND HAD AN INCOMPLETE RESPONSE TO DMARD THERAPY ALONE. PATIENTS WERE RANDOMIZED IN A 2:1 RATIO TO TREATMENT WITH RAYOS 5 MG (N=231) OR PLACEBO (N=119) ADMINISTERED AT 10 PM. A TOTAL OF 350 PATIENTS WERE ENROLLED AND RANGED IN AGE FROM 27 TO 80 YEARS (MEDIAN AGE 57 YEARS) WITH 84% FEMALES. RACE WAS DISTRIBUTED AS FOLLOWS: 98% CAUCASIAN, 1% AFRICAN-AMERICAN, AND < 1% ASIAN.
THE PERCENTAGE OF PATIENTS WITH IMPROVEMENT IN RHEUMATOID ARTHRITIS AT 12 WEEKS USING ACR RESPONSE CRITERIA (ACR20) WAS ASSESSED AS THE PRIMARY ENDPOINT, AND ACR20, ACR50 AND ACR70 RESPONSES FOR PATIENTS TREATED WITH RAYOS 5 MG VERSUS PLACEBO ARE SHOWN IN TABLE 1. THE RELATIVE EFFICACY OF RAYOS COMPARED TO IMMEDIATE-RELEASE PREDNISONE HAS NOT BEEN ESTABLISHED.
TABLE 1: ACR RESPONSES (PERCENTAGE OF PATIENTS)
ACR RESPONSE AT 12 WEEKS
RAYOS 5 MG
N=231
PLACEBO
N=119
RAYOS 5 MG β PLACEBO (95% CI)
ACR20
47%
29%
17% (7.2, 27.6)
ACR50
22%
10%
12% (4.4, 19.6)
ACR70
7%
3%
4% (0.1, 8.7)
ALL MISSING VALUES WERE IMPUTED AS NON-RESPONDERS.
THE RESULTS OF THE COMPONENTS OF THE ACR RESPONSE CRITERIA ARE SHOWN IN TABLE 2.
TABLE 2: COMPONENTS OF ACR RESPONSE
PARAMETER
RAYOS 5 MG + DMARD
N=231
PLACEBO + DMARD
N=119
BASELINE
WEEK 12
BASELINE
WEEK 12
TENDER JOINT COUNTA
12.6 (6.2)
7.9 (6.8)
12.5 (5.9)
9.8 (6.7)
SWOLLEN JOINT COUNTA
8.4 (4.4)
4.8 (4.8)
8.6 (4.7)
6.1 (5.4)
PATIENT ASSESSMENT OF PAINB
55.3 (21.9)
33.0 (24.5)
50.5 (23.3)
39.6 (24.7)
PATIENT GLOBAL ASSESSMENTC
57.4 (20.1)
36.2 (24.5)
50.9 (20.9)
43.0 (22.4)
PHYSICIAN GLOBAL ASSESSMENTC
55.2 (16.1)
31.9 (19.7)
54.1 (17.4)
40.4 (21.8)
DISABILITY INDEX (HAQ-DI)D
1.3 (0.6)
1.1 (0.6)
1.3 (0.6)
1.2 (0.6)
ESR (MM/HR)
33.0 (16.6)
25.2 (16.8)
32.9 (20.0)
26.5 (19.7)
CRP (MG/DL)
9.3 (13.2)
7.5 (10.7)
11.8(18.0)
9.7 (12.1)
MEAN (SD) IS PRESENTED. BASELINE VALUES WERE CARRIED FORWARD FOR PATIENTS WITH MISSING DATA AT WEEK 12.
A28-JOINT COUNT
BPATIENT ASSESSMENT OF ARTHRITIS PAIN. VISUAL ANALOG SCALE: 0 = NO PAIN, 100 = VERY INTENSIVE PAIN
CPATIENT OR PHYSICIAN GLOBAL ASSESSMENT OF DISEASE ACTIVITY. VISUAL ANALOG SCALE: 0 = NOT ACTIVE AT ALL, 100 = EXTREMELY ACTIVE
DHEALTH ASSESSMENT QUESTIONNAIRE DISABILITY INDEX; 0=BEST, 3=WORST, MEASURES THE PATIENT'S ABILITY TO PERFORM THE FOLLOWING: DRESS/GROOM, ARISE, EAT, WALK, REACH, GRIP, MAINTAIN HYGIENE, AND MAINTAIN DAILY ACTIVITY
THE PERCENTAGE OF PATIENTS ACHIEVING ACR20 RESPONSES BY VISIT IS SHOWN IN FIGURE 2.
FIGURE 2: ACR20 RESPONSE OVER 12 WEEKSA
ATHE SAME PATIENTS MAY NOT HAVE RESPONDED AT EACH TIME POINT.
THE PERCENT CHANGE FROM BASELINE IN THE DURATION OF MORNING STIFFNESS AT 12 WEEKS WAS ASSESSED AS A PRESPECIFIED SECONDARY ENDPOINT. PATIENTS TREATED WITH RAYOS HAD A MEDIAN DECREASE IN THE DURATION OF MORNING STIFFNESS OF 55% COMPARED TO 33% IN PLACEBO-TREATED PATIENTS (20% ESTIMATED MEDIAN DIFFERENCE BETWEEN TREATMENT GROUPS WITH 95% CONFIDENCE INTERVAL [7, 32]). THIS CORRESPONDS TO A MEDIAN DURATION OF MORNING STIFFNESS OF 46 MINUTES IN THE NP01 GROUP AND 85 MINUTES IN THE PLACEBO GROUP.