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Study ReferenceAdverse EffectsAdverse EffectsOrlistat TrialsAcharya, 2006133Perrio, 2007134Total adverse eventsIG --CG --368 events in 315 (2.0% of cohort) patients were reported as AEsSerious adverse eventsIG --CG --Stopped treatment during the first 3 mo of treatment: 4854 (30.3%)Adverse events most frequently reported as reason for stopping treatment at any time during the study, No (% of 8093*): Diarrhea525 (6.5)Weight gain239 (2.9)Intolerance120 (1.5)Unspecified side effects110 (1.4)Pain abdomen91 (1.1)Flatulence79 (1.0)Malaise, Lassitude70 (0.9)GI unspecified63 (0.8)Fecal incontinence62 (0.8)Reported by GP; could give more than one reason per patient*No. of patients who stopped treatment at any time and for whom the reason(s) for stopping was given Events most frequently reported as adverse drug effects, No. of events (% of cohort)Unspecified side effects110 (0.7)Diarrhoea75 (0.5)GI unspecified32 (0.2)Flatulence23 (0.1)Faecal incontinence15 (0.09)Rectal Discharge12 (0.07)Malaise/lassitude9 (0.06)Distension abdominal8 (0.05)Pain abdominal8 (0.05)Nausea, vomiting8 (0.05)Selected events assessed as probably related to orlistat treatment (No.)Skin Erythema 1 Erthyema nodosum1 Lichen planus1 Pruritus1 Rash5 Urticaria2Musculoskeletal Muscle weakness1 Osteoarthritis1 Pain joint1Psychiatric Dreams abnormal 1 Hallucination 1Nervous system Amnesia 1 Demyelination 1 Dizziness 3 Tremor 1Eye Haemorrhage vitreous 1 Hemianopia 1 Retinal vein thrombosis 1Ear Labyrinthitis 1 Cardiovascular Deep vein thrombosis 1 Fibrillation atria 1 Hypertension 3 Oedema 1 Swollen ankles 3 Palpitation 1Alimentary Liver funct tests abnormal2 Pain abdomen2(continued)Acharya, 2006133Perrio, 2007134Metabolic & Endocrine Hypothyroidism2 Female reproductive Metrorrhagia1Haemopoietic Haematoma spontaneous1Incidence Densities, incidence/1000 patient months exposure Diarrhoea9.29Abdominal pain2.51Intolerance1.47Flatulence1.44Headache1.97Nausea,vomiting 1.57Rectal discharge 0.91Depression 2.76Flatulence1.44Headache1.97Nausea,vomiting1.57Rectal discharge0.91Depression2.76Deaths, n(%)33 (0.2)**no instances where GP attributed cause of death to the drugPregnancy data is available (3 babies born with congenital anomalies), but no associations between exposure and risks are reported by authorsBakris, 2002126 52 weeksTotal adverse eventsIG --CG --Participants reporting adverse events (%)IG 89*CG 71*p <0.001Possibly associated with study drugIG 0CG 0 Serious adverse events*IG 14CG 15 (calc)*IG: myocardial infarction, chest pain, atrial fibrillation, CG: accelerated hypertension, MI, worsening of atherosclerotic coronary artery disease, chest pain, and ductal carcinoma in situ. None were attributed to study medicationWithdrew due to adverse eventsIG 18* (1 due to serious AE)CG 20 (4 due to serious AE)*GI associated: IG: 15; CG: 6 52 weeksMost commonly reported: fatty/oily stool, soft stool, liquid stool, oily fecal spotting, flatus with discharge, and fecal urgency (data not reported)DeathsIG 0CG 0Gastrointestinal events (%)*IG 72.5CG 43.6p< 0.001*occurred early during therapy, frequency tended to decreased with continued treatmentCardiovascular eventsIG --CG --Other body systems (%) Infectious IG 46.1 CG 37.7 Likely NS as NR Musculoskeletal IG 22.8 CG 15.5 p < 0.05 All other systems IG 61.4 CG 50.6 p < 0.05Broom, 2002132 24 weeksTotal adverse eventsIG --CG --Reported ≥ 1 adverse event, %IG 95.5*CG 85.9*with exception of GI events, not considered to be drug related, most mild or self-limitingSerious adverse events*IG 4 (n=4)CG 10 (n=6) *IG: elective cytoscopy and hydrodistension, stroke, sleep disorder, benign fluid-filled breast cyst. CG: radiculitis in right elbow, cellulitis, limb pain, hiatus hernia, gastric ulcer, esophageal reflux, anaemia, pregnancy and cholecystectomySerious adverse events reported during open label phaseIG 6Former CG 1*IG: neuropathic toe ulcer, cellulitis, Bell's palsy, dermal bleeding & upper limb injury caused by traffic accident, suicide attempt. CG: abdominal painWithdrew due to adverse eventsIG 11CG 57 and 3 respectively for GI eventsGI events reported by 54.8% of patients who remained on drug & 75.9% of those who switched to drug during open label phase 24 weeksGastrointestinal events, %IG 86.6CG 42.3 Most transient and mild to moderateMost commonly reported (≥ 5%) (%) IG CGLiquid stools32.89.9 Increased defecation23.911.3Fatty/oily stool22.44.2Soft stool22.49.9Fecal urgency16.40.0Abdominal pain 13.45.6Flatulence7.58.5Oily spotting6.00.0Flatus with discharge6.02.8*open label phase data availableKelley, 2002127 52 weeksTotal adverse eventsIG --CG --Serious adverse eventsIG --CG --Withdrew due to adverse events, n(%)IG 35 (13)CG 22 (8) IG n analyzed: 274CG n analyzed: 276 52 weeksDeathsIG --CG --Vitamin levelsIG --CG -- Vitamin supplementationIG --CG -- Gastrointestinal events, (%)IG 80*CG 62*p <0.05 (Most with single episode and mild to moderate intensity)Cardiovascular eventsIG --CG --Hypoglycemia, (%)IG 16.9*CG 9.7p <0.054 patients (1 in CG, 3 in IG) required medical intervention for hypoglycemiaIncidence of AEs related to other organ systems was similar in both groupsMuls, 2001130 48 weeksTotal adverse eventsIG --CG --Serious adverse eventsIG --CG --% of group reporting adverse eventsIG 80 CG 67**p=0.016Incidence of GI events, (%)IG 64CG 38Withdrew due to adverse eventsIG 12CG 4 48 weeksMost frequently reported adverse events, (%)Liquid stoolIG 23CG 8Increased defecationIG 22CG 5Loose stoolsIG 16CG 3Decreased defecationIG 3CG 12BronchitisIG 11CG 6During open-label extension, AEs were more frequently reported in former CG (81%) than former IG (59%)Van Gaal, 1998129IG1: 30 mg, IG2: 60mg, IG3: 120 mg, IG4: 240 mg 6 moTotal adverse eventsIG1 --IG2 --IG3 --IG4 -- CG --% of patients with adverse events*IG1 79IG2 83IG3 84IG4 87 CG 69*similar in all treatment groups in all body systems, except for gastrointestinal systemSerious adverse eventsIG 12*CG 2 *4 were considered remotely, possibly or probably related to med (fecal incontinence, diverticulitis, and abdominal pain)Withdrew due to adverse events, n(%)*IG1 7 (6)IG2 6 (5)IG3 2 (2)IG4 3 (3) CG 3 (2)*11 due to gastrointestinal events (10 in IGs). Main AE withdrawals considered to be related to treatment: CG: abnormal GTT, UrticariaIGs: fecal incontinence, flatulence, liquid stools, abdominal pain, polymyalgia rheumatica, depression, gastritisDeathsIG1 --IG2 --IG3 --IG4 -- CG -- BL 24 weeksVitamin A, mean (?mol ·1-1)IG12.462.42IG22.502.50IG32.402.50IG42.462.57 CG2.462.49Vitamin D, mean (?mol ·1-1)IG160.0756.65IG271.1960.24IG361.2656.10IG465.2654.24*CG68.2867.01Vitamin E, mean (?mol ·1-1)IG126.8427.36*IG227.4226.51*IG326.3626.66*IG427.3425.74*CG27.4729.70 Beta-carotene, mean (?mol ·1-1)IG10.410.32*IG20.400.30*IG30.430.30*IG40.470.28*CG0.420.45 Patients with 2 or more low vitamin levels(%)IG1 4.2IG2 6.7IG3 4.2IG4 12.8CG 3.3Received vitamin supplementation, nIG1 2IG2 0IG3 4IG4 8CG 224 weeksPatients with at least 1 GI event (%) (mild to moderate, usually when first starting)IG1 60.7IG2 75.6IG3 70.8IG4 82.9 CG 46.4(continued)Van Gaal, 1998129Severe Gastrointestinal events, n*IG1 9IG2 8IG3 2IG4 10 CG 1*subjectively classified*p ≤ 0.001 compared to placeboGI event incidence of 5% or at least twice that of CGFatty/oily stoolIG1 20.5IG2 31.7IG3 37.5IG4 36.8CG 2.4Increased defecationIG1 18.9IG2 18.7IG3 19.2IG4 17.9CG 5.6Soft stoolsIG1 11.5IG2 18.7IG3 13.3IG4 20.5CG 8.1Oily spottingIG1 8.2IG2 14.6IG3 12.5IG4 22.2CG 0.0Oily evacuationIG1 6.6IG2 5.7IG3 8.3IG4 11.1CG 0.0Flatus with dischargeIG1 2.5IG2 6.5IG3 7.5IG4 6.0CG 0.0Fecal incontinenceIG1 1.6IG2 3.3IG3 5.0IG4 7.7CG 0.0Metformin TrialsTrolle, 2007131 6 moTotal adverse eventsIG --CG --Participants reporting adverse event, nIG 29*CG 2*mostly gastrointestinalSerious adverse eventsIG 0CG 0Withdrew due to adverse eventsIG 2CG 0Combination TrialsGokcel, 2002136 6 moWithdrew due to adverse eventsIG2 2 IG3 0 6 mo (n)Abdominal DiscomfortIG2 22IG3 14Abbreviations: ACE=angiotensin-converting enzyme; ADA=American Diabetes Association; adj=adjusted; AE=adverse event; BDI=Beck Depression Inventory; BL=baseline; BMI=body mass index; BP=blood pressure; bpm=beats per minute; bts=beats; C=cholesterol; CAD=coronary artery disease; calc=calculated; CG=control group; CGIQ=Caregiver Intelligence Quotient; CHF=congestive heart failure; CIC=Clinical Investigation Center; d=day; DBP=diastolic blood pressure; diff=differ/difference; ECG=electrocardiography; est=estimated; FPG=fasting plasma glucose; FSG=fasting serum glucose; GI=gastrointestinal; GP=general practitioner; HDL=high-density lipoprotein; HR=heart rate; HTN=hypertension; ID=incidence density; IG=intervention group; ITT=intention to treat; LCD=low-calorie diet; LDL=low-density lipoprotein; LOCF=last observation carried forward; LV=left ventricle; LVEF=left ventricle ejection fraction; LVH=left ventricle hypertrophy; LVM=left ventricle mass; LVMI=left ventricle mass/height; maint=maintenance; med=medication; n=number; NA=not applicable; NHS=National Health Service; NR=not reported; NS=not significant; obs=observed; PCOS=polycystic ovary syndrome; PCP=primary care physician; pt=patient; QTc=QT interval; RCT=randomized controlled trial; RMR=resting metabolic rate; Rx=prescription; SBP=systolic blood pressure; SD=standard deviation; SE=standard error; SEM=standard error of the mean; SES=socioeconomic status; TG=triglycerides; UK=United Kingdom; US=United States; WHO=World Health Organization; wt=weight; x=times. ................
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