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LeeChuy, Katherine Lee, Sidney Abert Lerma, Daniel Joseph Legaspi, Roberto Jose Li, Henry Winston Li, Kingbherly Lichauco, Rafael Lim, Imee Loren Lim,

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Presentation on theme: "LeeChuy, Katherine Lee, Sidney Abert Lerma, Daniel Joseph Legaspi, Roberto Jose Li, Henry Winston Li, Kingbherly Lichauco, Rafael Lim, Imee Loren Lim,"— Presentation transcript:

1 LeeChuy, Katherine Lee, Sidney Abert Lerma, Daniel Joseph Legaspi, Roberto Jose Li, Henry Winston Li, Kingbherly Lichauco, Rafael Lim, Imee Loren Lim, Jason Morven Lim, John Harold Lim, Mary Lim, Phoebe Ruth Lim, Syndel Raina Lipana, Kirk Andrew Liu, Johanna Llamas, Camilla Alay

2 Name: T. R. Age: 60 Sex: M Status: Married Nationality: Filipino Date of Birth: 12/10/1949 Place of Birth: Leyte Religion: Roman Catholic Educational attainment: High School Graduate Occupation: retired; Grass cutter of Military Shrines Service Cu rrent Address: Bataan Informant: Patient, Wife, Niece, Nephew Reliability: 70%

3 “Namamaga ang mga kasukasuan sa kamay, tuhod, at bukong-bukong hanggang paa(swelling of the hands, knees and ankle to feet)”

4 10 years history of recurrent monoarthritis -No proper consult was done; self-medicated with paracetamol 500mg + ibuprofen 200mg (Alaxan) & paracetamol (Biogesic) 500mg -denied steroid intake and aspirin -pain free interval: 3 weeks initially, progressive shorter pain free intervals -frequency of drug intake 3 tabs/day: taken as needed, initially TID -efficacy: slight relief of pain 10 years PTA 4 months PTA patient slipped and sustained an injury to the both hands and wrist in an attempt to break his fall admitted at a local hospital in Bataan confined and was given unrecalled medications relieved from the pain

5 -patient accidentally stepped on a sharp object and cleaned the wound site with guava leaves and betadine and then applied 500mg penicillin powder -recurrence of joint pain and swelling of both hands, knees, and feet; self-medicated with Mefenamic acid 500 mg and amoxicillin 500 mg which provided relief, taken as needed 2 weeks PTA1 week PTA -progression of joint pain and swelling of both wrist and hands, knees, ankles and feet, graded 10/10 with limitation of movement these joints ADMISSION (August 24, 2010)

6 No major hospitalization, unrecalled immunizations No allergy, no previous transfusion (-) DM, PTB, Asthma, Cancer Family History not clear to the patient Personal and Social History Non-smoker Alcoholic beverage drinker ( 2 bottles beer; 3x a week and occasional gin drinker 2-3 bottles/week) Diet: mixed diet Denies illicit drug use

7 General: no fever, no weight loss, (-) anorexia, (-) weakness, (-) insomnia HEENT: no blurring of vision, no eye redness, pain, itchiness, no excessive lacrimation, no ear pain nor tinnitus, no ear discharge, no epistaxis, no nose discharge, no anosmia, no obstruction nor sinusitis, no mouth sores, fissures, bleeding, no dental carries, no throat irritation, Pulmonary: no hemoptysis, no coughing, no dyspnea, no chest wall abnormality Gastrointestinal: no abdominal pain, no melena nor hematochezia, no changes in bowel habits Genitourinary: no hematuria, no dysuria, no urinary frequency, no hesitancy, no incomplete voiding Endocrine: no heat or cold intolerance, no polyphagia, no polydipsia, no polyuria, no thyroid enlargement Musculoskeletal: see HPI Hematologic: no abnormal bleeding,easy bruising

8 PHYSICAL EXAMINATION Admission (August 24, 2010) General survey: Conscious, Coherent, stretcher-borne not in respiratory distress Vital signs: BP: 120/70 PR:88 regular RR:22 cpm Temp: 36.5 C Anthropometric mesaurement -Ht: cm Wt: 65 kgs BMI: 23.9 August General survey: conscious, coherent, ambulatory, not in cardiorespiratory distress, normal speech, appropriate thought process and content and well-oriented as to time, place and date. Vital Signs – BP: (RUE) 170/100 (LUE) 170/100 – PR: 74 beats/minute – RR: 17 cycles/minute – Temperature (axillary): 37.2 o C Anthropometric measurement -Ht: cm Wt: 65 kgs BMI: 23.9

9 PHYSICAL EXAMINATION Admission (August 24, 2010) Skin Warm, dry skin, (+) scaling on the right foot and ulcers on the sole of the left foot August 27, 2010 Skin: Warm, moist skin, no jaundice, no skin discoloration, (+) tophi on the right wrist, right dorsum of the hand, right elbow, both feet, (+) ruptured tophi on dorsum on the right foot and sole of the left foot. (+)desquamation and non-healing wound on the medial calcaneal area of the left foot No rashes, petechiae, No palmar erythema, no spider angioma Nails without clubbing or cyanosis.

10 PHYSICAL EXAMINATION Admission (August 24, 2010) HEENT Pale palpebral conjunctiva, slightly icteric sclera, 3-4 mm ERTL No tragal tenderness, No nasoaural discharge, nasal septum midline, no hoarseness Supple neck, no palpable cervical lymph nodes, trachea is midline thyroid not enlarged August 27, 2010 HEENT Pale palpebral conjunctivae, anicteric sclera, pupils ERTL 2- 3mm, no exophthalmos, no tragal tenderness, no aural discharge, supple neck, no distended neck veins, no palpable cervical lymph nodes, thyroid gland not enlarged

11 PHYSICAL EXAMINATION Admission (August 24, 2010) Respiratory Symmetrical chest expansion No retractions Equal vocal and tactile fremiti Resonant on percussion (+) crackles on both lower lung fields August 27,2010 Respiratory Symmetrical chest expansion, no subcostal retractions, unimpaired tactile and vocal fremiti, resonant upon percussion,(-) crackles on both lower lung bases, no wheezes, no rhonchi

12 PHYSICAL EXAMINATION Admission (August 24, 2010) Cardiovascular Adynamic precordium Apex beat at 5 th LICS MCS No heaves and thrills S1 > S2 at the apex, S2> S1 at the base No murmurs August 27,2010 Cardiovascular Adynamic precordium, AB at 5 th LICS MCL, no heaves, no lifts, no thrills, S1>S2 apex,S2>S1 base; Pulses were full and equal in all extremities, no cyanosis and clubbing

13 PHYSICAL EXAMINATION Admission (August 24, 2010) Gastrointestinal Flabby abdomen, Abdominal circumference: 98 cm, (+) shifting dullness, (+) venous collaterals, normoactive bowel sounds, no palpable mass, no tenderness, tympanitic all over, liver span 10 cm MCL, Traubes space not obliterated, (-) Murphy’s sign, DRE: smooth rectal vault, no perianal tenderness, tight sphincteric tone, no masses, prostate not enlarge and greenish brown on examining finger Genitourinary (-) CVA tenderness DRE: greenish brown on examining finger August 27, 2010 Gastrointestinal Inspection: Globular and symmetrical abdomen, No caput medusae, inverted umbilicus, no visible peristalsis, pulsation or mass Auscultation: Normoactive bowel sound, No bruits Percussion: tympanitic, Liver span 10 cm along the Right MCL, Traube’s space not obliterated, (-) shifting dullness Palpation: Liver edge not palpable. No mass, (-) succusion splash, (-) fluid wave Genitourinary (-) CVA tenderness, kidneys not palpable

14 PHYSICAL EXAMINATION Admission (August 24, 2010) Musculoskeletal Pulses full and equal, no cyanosis, (+) bipedal edema, (+) swelling on wrist to hands and ankle to foot, warm to touch, (+) draining abscess measuring 1 X 1 cm on the sole of the left foot August 27, 2010 Musculoskeletal (+) swelling on both wrists and hands, ankles and feet, warm to touch Cervical spine, L&R shoulder, left elbow, and L&R knee joints with full ROM R elbow, L& R wrists, L&R MCPs, L&R PIPs, L&R DIPs has limited ROM No tenderness upon palpation.

15 PHYSICAL EXAMINATION Admission (August 24,2010) Neurologic Exam GCS 15 (E4V5M6) Alert, oriented in three spheres Intact cranial nerves Cerebellar – can do FTNT and APST with ease MMT- 5/5 on all extremities No sensory deficits Refelexes: ++ on all extremities, (-) Babinsky, nuchal rigidity, Brudzinki’s and Kernig’s August 27, 2010 Neurologic Exam Mental status: Conscious, awake, alert GCS 15 Pupils 2-3mm, isocoric ERTL, EOMs full and equal, no ptosis, no nystagmus No facial asymmetry, can shrug shoulders, can turn head against resistance MMT: cannot be assessed No sensory deficits Reflexes: Superficial: (+) Gag and corneal reflex Deep Tendon: not done

16 Physical Examination

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22 SUBJECTIVE DATAOBJECTIVE DATA Age: 60 Sex: M Swelling of joints of hands, feet and legs Recurrent monoarthritis Limitation of movements on the hands and feet Alcoholic beverage drinker BP 170/100 (+) tophi on the right wrist, right dorsum of the hand, right elbow, both feet, (+) ruptured tophi on dorsum on the right foot and sole of the left foot. (+) desquamation and non-healing wound on the medial calcaneal area of the left foot (+) swelling on the wrists and hands, ankles and feet, which are warm to touch (+) pale palpebral conjunctiva DRE: greenish brown on examining finger SALIENT FEATURES

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25 Upon admission Given Clindamycin 300mg q 6h Cold compress on affected areas, colchicine (0.5 mg bid) Send wound discharge for Gram’s stain and culture

26 COMPLETE BLOOD COUNT *8/238/25, after transfusion of 5 ‘U’ PRBC Hemoglobin4868 RBC HCT MCV MCH MCHC RDW MPV PLATELET WBC DIFFERENTIAL COUNT NEUTROPHILS METAMYELOCYTES0.01- BANDS0.01 SEGMENTED0.89 LYMPHOCYTES MONOCYTES-- EOSINOPHILS BASOPHILS-- Reticulocyte count33 UNITREFERENCE RANGE G/L X 10^12/L U^ Pg g/dl – 14.6 fL7.4 – 10.4 x 10^9 / L150 – 450 x 10^9 / L4.5 – – – – – – – – 0.01 x 10^-3 / L5 - 15

27 8/238/258/268/289/01Reference Creatinine mg/dl BUN mg/dL Sodium mmol/L Potassium mmol/L iPO mg/dL Ionized Calcium mmol/L Fasting Blood Sugar mg/dL SGPT - ALT U/L Uric Acid mg/dl HbA1c %

28 8/268/28Reference Total Cholesterol mg/dL Triglycerides mg/dL HDL22.03 LDL68.20 Total Protein g/dL Albumin g/dL Globulin g/dL VG Ratio Intact PTH pg/ml ESR MM After 1 Hr

29 COMPLETE BLOOD COUNT 8/289/01UNITREFERENCE RANGE Hemoglobin117105G/L RBC X 10^12/L HCT MCV79.80 U^ MCH Pg MCHC g/dl RDW – 14.6 MPV fL7.4 – 10.4 PLATELET450268x 10^9 / L150 – 450 WBC x 10^9 / L4.5 – 10.0 DIFFERENTIAL COUNT NEUTROPHILS – 0.70 METAMYELOCYTES-- BANDS – 0.05 SEGMENTED – 0.70 LYMPHOCYTES – 0.40 MONOCYTES – 0.07 EOSINOPHILS – 0.05 BASOPHILS – 0.01 Reticulocyte countx 10^-3 / L5 - 15

30 Other Ancillary procedures: Fecal occult blood test – (+) ECG – Sinus rhythm with left ventricular hypertrophy Urinalysis: albumin- negative, sugar – negative, RBC-0-2/hpf, Pus cell-1-4/hpf

31 X-ray of the left foot September 1, 2010

32 X-ray of the right foot September 1, 2010

33 X-ray of the left foot September 1, 2010

34 Official X-ray findings Both feet Multiple erosive and lytic changes involving the tarsal, metatarsal, and phalangeal bones in both sides, with evidence of narrowing of the joint spaces. Calcaneal spurs are noted. One notes evidence of soft tissue swelling, with soft tissue lucencies, which may be due to abscess formation.. Sclerotic changes are also noted involving the tarsocalcaneal articulating surfaces on the right side. One notes of decreased bone density. Impression: Above findings consider the possibility of Osteomyelitis. The possibility of Gouty arthritis is not entirely ruled out.

35 Chest X-ray

36 Official X-ray findings Lung fields are clear. There is increase in the transverse diameter of the heart. Aorta is calcified. Diaphragm & sinuses are intact. Impression: Cardiomegaly Atheromatous aorta

37 Anemia due to: Patient NSAID Gastropathy Chronic Kidney Disease Hypochromic microcytic anemia Hypochromic and microcytic anemia (↓ iron) Normocytic and normochromic anemia (↓EPO) (+) FECAL OCCULT BLOOD TEST +- Chronic NSAID use (Alaxan-paracetamol+ibuprofen; Mefenamic acid) +- Hct 16%<20-25%20 to 30% Hawkey CJ. Non-steroidal anti-inflammatory drug gastropathy: causes and treatment. Scand J Gastroenterol Suppl. 1996;220: CATHERINE S. SNIVELY, M.D.,et.al. Chronic Kidney Disease: Prevention and Treatment of Common Complications. Am Fam Physician Nov 15;70(10):

38 ADA Criteria for the diagnosis of diabetes Table 3—Criteria for the diagnosis of diabetes 1. A1C ≥ 6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.* OR 2. FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.* OR 3. 2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.* OR 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dl (11.1 mmol/l). *In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing. American Diabetes Association Diagnosis and Classification of Diabetes Mellitus, DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010

39 Patient8/238/258/268/289/01Reference Fasting Blood Sugar mg/dL HbA1c % In the setting of an elevated Hba1C but “nondiabetic” FPG, the likelihood of greater postprandial glucose levels or increased glycation rates for a given degree of hyperglycemia may be present. American Diabetes Association Diagnosis and Classification of Diabetes Mellitus, DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010

40 Pending procedures Wound CS -to determine etiology of the lesion as well as the sensitivity or susceptibility of the pathogen to antibiotics

41 Polarized light microscopy of specimen collected September 2, 2010

42 Final Diagnosis Ruptured tophi on the right foot with secondary bacterial infection with osteomyelitis Acute gouty arthritis on top of chronic tophaceous gout Anemia secondary to occult GI bleeding probably due to NSAID gastropathy Chronic kidney disease secondary to gouty nephropathy and hypertensive nephrosclerosis

43 Management

44 DateMedications/ TreatmentsFrequency 8/24/10 Clindamycin 300 mg/ capQ6h 8/24/10 – 9/1/10 Cold compress on affected areaTID 8/25/10 Mupirocin ointment on affected areaTID 8/26/10 – 8/29/10 Ciprofloxacin 250 mg/tabBID 8/29/10 -9/3/10 Amlodipine 10 mg/tabOD 8/29/10 Omeprazole 40 mg/ tabOD 8/29/10 Paracetamol 500 mg/tab T >38.5Q4h 8/29/10 Bisoprolol 2.5 mg/ tabOD 8/29/10 Aminoleban 1 sachet in 1 glass waterBID 8/29/10 Sultamicillin 350 mg/ tabOD 9/1/10 Colchicine 0.5 mg/ tabOD 9/1/10 Apply ice compress min over affected jointsQ1h 9/3/10 Amlodipine 10 mg tab in amBID 9/3/10 Amlodipine 5 mg tab in pm

45 Clindamycin reversibly binds to the 50S ribosomal subunits preventing peptide bond formation thus inhibiting protein synthesis 600 mg-1.8g/d q6-8h PO Indicated for streptococci, S. aureus, and Bacteroides spp. GIT: diarrhea, pseudomembranous colitis, nausea, vomiting; HEPATIC: elevation of liver enzymes; CVS: hypotension; HEMATOLOGIC: eosinophilia; neutropenia, granulocytopenia, thrombocytopenia; LOCAL: sterile abscess at injection site; RENAL: renal dysfunction; MUSCULOSKELETAL: polyarthritis; OTHERS: hypersensitivity reactions Diarrhea and any inflammatory bowel disease, hypersensitivity to clindamycin or any component

46 Mupirocin ointment inhibits bacterial protein synthesis by reversibly and specifically binding to bacterial isoleucyl transfer RNA synthetase Apply 3x/d for 10 d Skin infection DERMATOLOGIC: polyethylene glycol {PEG} vehicle may irritate broken skin or mucous membranes. Less frequent incidence: skin burning, stinging, pain, itching, rash and dry skin Hypersensitivity to mupirocin or any component, e.g., PEG

47 Amlodipine acts primarily on peripheral vascular beds and have little effect on cardiac muscle contraction or AV conduction block the voltage dependent calcium channel inhibiting the availability of intracellular calcium to interact with the myosin complex of smooth muscles. This action leads to relaxation of the smooth muscle allowing a decrease in peripheral resistance which leads to BP lowering 5-10 mg daily Hypertension, angina CNS: headaches; CVS: postural dizziness, palpitation, tachycardia, ankle edema; DERMATOLOGIC: rash; OTHERS: flushing and fatigue hypotensive and hypersensitive to the drug and in instances of MI with heart failure or poor LV function.

48 Omeprazole Irreversibly inhibits gastric parietal cell proton pump (H+-K+ ATPase, inhibit gastric acid secretion, both basal and stimulated mg/d as single dose after breakfast for 4-8 wk PO Reflux esophagiti, acid-peptic ulcer disease, Zollinger-Ellison syndrome CNS: reversible confusional states, agitation, depression, hallucination; GIT: nausea, diarrhea, abdominal colic; Hematologic: agranulocytosis, pancytopenia, thrombocytopenia; Dermatologic : erythematous skin rashes, erythema multiforme, exfoliative dermatitis; Renal: interstitial nephritis, hematuria, glycosuria; Others: hypoglycemia, alopecia, blurred vision, arthralgia. Hypersensitivity to the drug, gastric malignancy

49 Paracetamol It is a para-aminophenol derivative with analgesic and antipyretic properties mg (6-12 mg/kg) q4h, PO; max dose 4g/d Symptomatic treatment of mild to moderate pain and/or fever CNS: stupor, coma, euphoria; CVS: hypotension; DERMATOLOGIC: pruritus, urticaria; GIT: hepatic dysfunction, jaundice; GIT disturbances, nausea, vomiting; HEMATOLOGIC: leukopenia, thrombocytopenia, pancytopenia, methemogobinemia; RESPIRATORY: dyspnea, asthma; GUT: dysuria, interstitial nephritis and renal papillary necrosis Prolonged administration is contraindicated in patients with anemia or cardiac, pulmonary, hepatic or renal disease. Hypersensitivity to paracetamol or any of its component

50 Bisoprolol Bisoprolol produces negative chronotropic effect and minimal change in stroke volume 5-10 mg PO once daily up to a max of 20 mg daily Hypertension, angina, heart failure CVS: bradycardia, AV block, sinus arrest, peripheral vasoconstriction, heart failure; RESPIRATORY: bronchospasm; OPHTHALMOLOGIC: decreased tearproduction; OTHERS: fatigue Asthma and obstructive airway disease, Heart failure, second or third degree heart block, cardiogenic shock

51 Aminoleban 150 g/day (3 sachets/day) Dietary supplement esp for patient w/ liver impairment. Nutritional support to patients w/ chronic liver disease esp those w/ hepatic encephalopathy Diarrhea & nausea Hypersensitivity

52 Sultamicillin inhibits β-lactamases in penicillin-resistant microorganisms and it acts against sensitive organisms during the stage of active multiplication by inhibiting biosynthesis of cell wall mucopeptide mg bid Respiratory tract infections, otitis media, UTI Diarrhea, nausea, vomiting, rashes, pruritus, blood dyscrasias, superinfections, dizziness, dyspnoea. Potentially Fatal: Anaphylaxis Hypersensitivity

53 Colchicine mild anti-inflammatory drug with no analgesic effects. inhibiting microtubule polymerization by binding microtubule protein subunits and preventing their aggregation, thus disrupting membrane- dependent functions as chemotaxis and phagocytosis, which are cardinal events in the inflammatory response to precipitated crystals. It has no effect on the serum uric acid levels orits renal excretion 500 mcg tab taken orally hourly until pain and inflammation subside, to a maximum cumulative dose of 6.0 mg Acute attacks of gout and other crystal induced arthritis GIT: nausea, vomiting, diarrhea and abdominal pain in up to 80% of patients undergoing rapid colchinization; hepatotoxicity, hemorrhagic colitis with overdose or with liver or renal disease; HEMATOLOGIC: aplastic anemia, bone marrow suppression; CNS: peripheral neuritis; colchicine induced-myopathy and polyneuropathy with prolonged use; DERMATOLOGIC: alopecia, rash; OTHERS: anorexia, azoospermia, renal dysfunction with overdose or with liver or renal disease. Hypersensitivity to colchicine or any components Serious renal, gastrointestinal, hepatic or cardiac disorders Blood dyscrasia

54 Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout Angelo L Gaffo Kenneth G Saag Core Evidence 2009:4;25–36

55 Objective Review the clinical evidence of effectiveness of febuxostat (TEI-3420, or TMX-67) on outcomes and its potential for clinical management of hyperuricemia and gout.

56 Methods Phases II and III evidence Literature searches – PubMed – Cochrane database – American College of Rheumatology – European League Against Rheumatism (?) Inclusion exclusion criteria not mentioned

57 Febuxostat Orally administered, nonpurine selective inhibitor of xanthine oxidase. Binds to a channel in the molybdenum center of the enzyme, leading to a very stable and long-lived enzyme-inhibitor interactions with both oxidized and reduced forms of the enzyme

58 Phase II data 28-day, multicenter, double-blind, placebo- controlled, dose response clinical trial Determine safety and efficacy of once daily febuxostat – 40, 80, 120 mg Inclusion: patients with American College of Rheumatology criteria-defined gout aged 23-80y/o Exclusion: absence of kidney dysfunction or taking drugs known to affect serum urate (aspirin or diuretics)

59 Phase II data Cases of reduction seen in as early as 7 days after start of treatment Dose-dependent effect Incidence of gout flares, due to sudden removal and mobilization of uric acid crystals from the tissues – Despite pretreatment with colchicine Diarrhea, abdominal pain Abnormal liver function tests – 40mg (14%), 80mg (8%), 120mg (8%)

60 Other Phase II data Reductions on tophi volume (by MRI) Good tolerance in allopurinol-intolerant patient 3 month colchicine prophylaxis in patients starting with febuxostat Diarrhea, GI motility disorders, headache, abnormal liver function tests, hyperlipidemia Japan (128 patients) – reduced SUA regardless of underexcretors or overproducers – Safe and well tolerated – Abnormal liver function tests and gout flares

61 Phase III data FACT APEX EXCEL CONFIRMS

62 Phase III data - FACT Febuxostat versus Allopurinol Controlled Trial (FACT) Randomized, double-blind, 52-week, multicenter – Febuxostat 80 and 120 mg/day dose – Allopurinol 300 mg/day fixed dose Inclusion: adult patients with American College of Rheumatology-defined gout and SUA at least 8.0 mg/dL Exclusion: kidney dysfunction, concomitant drugs known to affect serum urate, BMI >50, active liver disease, pregnancy, use of prednisone >10 mg/d, or alcohol abuse

63 Phase III data - FACT Primary endpoint – SUA of 6.0 mg/dL Clinical endpoint – reduction in tophus area, change in number of tophi, and proportion of patients requiring treatment for acute gout flares Prophylaxis with colchicine or naproxen during a 2-week washout period

64 Phase III data - FACT 762 patients 254 Febuxostat 80 mg/d Discontinued 88 (34%) 254 Febuxostat 120 mg/d Discontinued 98 (39%) 254 Allopurinol 80 mg/d Discontinued 66 (26%) Losses to follow-up, adverse events, and gout flares

65 Phase III data - FACT Primary endpoint Febuxostat 80 mg/d 53% Febuxostat 120 mg/d 62% Allopurinol 300 mg/d 21%

66 Phase III data - FACT Rates of total advers events and serious adverse events were similar Liver function test abnormalitis (4-5%), diarrhea (3%), headaches (1-3%) 4 patients in febuxostat group died – Cardiovascular events – Considered unrelated to administration of study medications

67 Phase III data - APEX Allopurinol and Placebo-Controlled, Efficacy Study of Febuxostat (APEX) Additional patients with mild to moderate renal dysfunction (creatinine 2.0 mg/dL) – Febuxostat at 80, 120, 240 mg/d – Allopurinol 300 mg/d (crea 1.5mg/dL), 100 mg/d (crea mg/dL) Inclusion: y/o, American College of Rheumatology-defined gout, SUA ≥8.0 mg/dL, creatinine up to 2.0 mg/dL Exclusion: intolerances to allopurinol, colchicine, naproxen, history of renal calculi, heavy alcohol intake, baseline transaminases ≥1.5 upper limit of normal

68 Phase III data - APEX More gout flares in febuxostat 120 and 240 mg/d arm in first 8 weeks Similar rates in 8-28 weeks Diarrhea, liver function test abnormalities 1072 patients Febuxostat 80 mg/d Febuxostat 120 mg/d Febuxostat 240 mg/d Allopurinol 300 mg/d or 100 mg/d Placebo

69 Phase III - EXCEL Open-label phase III extension of FACT Continue evaluation response to treatment Allopurinol compared to febuxostat failed to achieve continuous reduction of SUA 6.0 mg/dL 735 patients 294 Febuxostat 80 mg/d 294 Febuxostat 120 mg/d 147 Allopurinol 80 mg/d

70 Phase III - CONFIRMS Randomized, controlled, multicenter, double- blind 2269 patients Febuxostat 40 mg/d SUA <6mg/dL 45% Febuxostat 80 mg/d SUA <6mg/dL 67% Allopurinol 200 or 300 mg/d SUA <6mg/dL 42%

71 Summary of evidence

72 Thank You!


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