HIGH RATE OF SUCCESS IN AN NIH- STUDY of hypertensive patients- highest percentage - remained on itial therapy 83% with NORVASC#{174}(amlodipi besylate) after 4 years; nearly all pati were on the 5-mg starting dose’ LOW RATE DISCONTINUATION ONLY 1.5%of patients in placebo studies (n= 1730) discontinued due to adverse effects2 PROVEN No negative inotropic effects clinical doses in hemodyna m ic stud 2* No clinically significant effect on cardiac conduction or heart rate2 *S1IflH,jr fiernodynamic findings, hcvever fiave been agents possessing significant neqafive notropic ebecto and 10-mg tablets Once-Daily NORV (ambdipine EFFICACY AND SAFETY THAT’S EASY TO WITH Br$e(Summary NORVASC(amlodlpine besylate) Tablets For Oral Use CONTRAINDICATIONS: NORVASC is contraindicated in patients with known sensitivity to arniodipirre. In hypertension WARNINGS: Increased Angina and/or MyOcardIal Infarction: Rarely, patients, particulady those with severe obstruc5ve coronary artery disease, have developed documented increased frequency,durationand/or severity of angina or acute myocardial infarction on starhng cafrium channel blocker therapy or attire time of dosage increase. The mechanism of this effect has not been elucidated. PRECAUTIONS: General: Since the vasoditation induced by NORVASC is gradual in onset, acute hypotension has rarely been reported after oraladministrationof NORVASC. Nonethetuss, caution should be exercised when admin- or angina, convenient istering NORVASC as with any other penpherio vasodilator particularly in pahentswithsevere aortic stenoros. Usein Patients with CongestIve Heart Failure: In general, csicium channelbiockersshouldbe used with caution in patients with heart failure. NORVASC (5-10 mg per day) has been studied in a placebo-cnotrolledtrialof 1153 pabents with NYHA Class Ill or IV hearifailure on stable doses oIACE inhibitor,dtgooin,and diuretics.Follow-upwas at least 6 months, with a mean of about 14 months.There was nooveralladverse effecton survivalor cardiac morbidity as once-daily dosing defined by life-threateningarrhythmia,acute myocardialinfarction,or hospitalizationfor worsened heart failure). NORVASC has been compared to placebo in four 8-12 week studiesof patientswith NYHA Class llll heart failure, involving a totalof697 pahents.In these studies,there was no evidence ofworsened heart failurebased on measuresof eoercisetolerance,NY1IAclassification,symptoms,or LVEF. Beta#{149}BlockerWithdrawal: NORVASC is not a beta-blocker and thereforegives no protection against the dangers of abrupt beta-blocker withdrawal, any such withdrawal should be by gradual reduction of the dose ofthe beta-blocker. #{149}The usual starting dose is5 mg in hypertension Patients wIth Hepatic Failure: Since NORVASC is extensively metabolized by theliverand the plasma elimination hail- Ide 1J) is 56 hoursinpatients with impaired hepatic function, caution should be enercised when administering or angina NORVASC to patientswithsevere hepatic impairment Drug kiteractions: In vitro data in human plasma indicate that NORVASC has no effect on the proteinbinding of drugs tested )digooin, phenytoin, warfarin, and indomethacin) Special studies have indicated thatthe co-administrationof - In hypertension, small, fragile, or elderly individuals NORVASC with digooindid not change serum digooinlevelsor digooinrenal clearance in normal volunteers; thatco- or patients with hepatic insufficiency may be started on administrationwithcimetidinedid not abet the pharmacokinetics of amlodipine,and that co-administrationwithwarfarin did not change the warfarmnprothrornbtn response time. 2.5 mg once daily2 In clinicaltrials,NORVASChas been safely administered with thiazide diuretics,beta-blockers,angiotensin converting enzyme inhibitors,long-actingnitrates,sublingualnitroglycerin,digooin,warfarin,non-steroidalanti- inflammatory drugs,antibiotics,and oralhypoglycemicdrugs. #{149}litration can proceed to 10 mg DruglLaborator.j Test Interactions: None known. Carcinogenesis, NUtagSnesIs,ImpSIrm.M of Fertility: Rats and mice treated with amlodipine in the dietfor two years, at concentrationscalculatedto providedaily dosage levels of0.5, 1.25, and 2 5 mg/kg/day showedno evidenceof - Most angina patients will require 10 mg carcinogen-city. The highesr dose for mice, similarto,and forratstwice the maximum recommended clinicaldose of 10 mg on a mg/mi basis), was close to the maximum tolerated dose for mice but notfor rats. Mutagenicdy studws revealed no drug related effects ateIther the gene or chromosome levels. #{149}Can be taken with or without food There was no effecton the fertilityof ratstreated with amlodipine males for64 days and females 14 days prior to mating) at dosesup to 10 mg/kg/day )8 times the maximumrecommended humandose of 10 mg on a mg/m2 basis) Pregnancy Category C: No evidence ofteratogenicity or otherembryo/fetal toxicitywasfound whenpregnant ratsor #{149}The most common side effects are headache rabbits were treated orally with up to 10 mg/kg amlodipine respectively8 times’ and 23 tirnes the maximum recom- mended human dose of 10 mg on a mgJm basis)duringtheir respective periods of major organogenesis However, litter size was signiticantlydecreased by about 50%) and the number of intrauterinedeaths was significantly increased about 5-fold)in rats administered10 mg/kg amlodipinefor 14 days before matingand throughoutmetingand and edema gestation. Amlodipine has been shown to prolongboth the gestationperiod and the durationof labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Arniodipine should be used during pregnancy only it the potential benefitjustihes the potentialrisk to the fetus. Nursing Mothers: Itis not known whether amlodipine is excreted inhuman milk.In the absence of thisinformation,it is recommended thatnursingbe disconbnued WhileNORVASC is administered Pediatric Use: Safety and effectiveness of NORVASCin childrenhave not been established. ADVERSE REACTIONS: NORVASC has been evaluated for safety inmore than 11,000 pahentsin U S. and foreign clinical trials. In general,treatmentwithNORVASC was well-tolerated at doses up to 10 mg daily Most adverse reactions reported duringtherapywithNORVASC were of mildor moderate severity.In controlledclinicaltrials directly comparing NORVASC )N =1730)in doses up to 10 rn9to placebo)N =1250), discontinuation of NORVASC due to adverse reactions was requiredin onlyabout 1 5% of patientsand was notsignificantlydifferentfromplacebo )about 1%). The most common side effects are headache and edema. The incidence)%) ofside effects which occurred in a dose related manner are as follows:edema )1.8% at 2.5 mg, 3.0% at 5.0 mg, and 10.8% at 10.0 mg, compared with 0.6% placebo); dizziness 1.1% at 2.5 mg, 3.4% at 5.0 mg, and 3.4% at 10.0 mg, compared with 1.5% placebo); flushing 0.7% at 2.5 mg, 1.4% at 5.0 mg, and 2.6% at 10.0 mg, compared with0.0% placebo); and palpitation 0.7% at 2.5 mg, 1.4% at 5 0 mg, and 4 5% at 10.0 mg, compared with0.6% placebo) Other adverse experiences which were notclearlydose relatedbut whichwere reportedwithan incidence greater fl9/tct.,. than 10% in placebo-controlled clinical tnals include the following headache 7.3%, compared with 7.8% placebo); fatigue 4.5%, compared with 2.8% placebo); nausea 2.9%, compared with 1.9% placebo); abdominal pain )1.6%, compared with 0.3% placebo);and sornnolence)1.4%, compared with0.6% placebo). For severaladverseexperiences that appear to be drug and dose related, there was a greater incidence inwomen than men associated with amlodipine treatment as follows: edema 5.6% in men, 14.6% in women,compared with a placebo incidence inmen of 1.4% and 5.1% in women);flushing 1.5% in men, 4.5% in women,compared with a placebo incidence of 0.3% in men and 0.9% in women),palpitations 1.4% in men, 3.3% in women,compared witha placebo incidenceof 0.9% in men and 0.9% in women);and somnolence)1.3% in men, 1.6% inwomen, compared with a placebo incidenceof0.8% in men and 0.3% in women). The followingevents occurredin l% but >0.1% of patientsin controlledclinicaltrialsorunder conditionsof open Once-Daily 5-mg and 10-mg tablets trialsor marketingeoperiencewhere a causal relationshipis uncertain;they are listedtoalart thephysicianto a possible relationship:cardiovascular: arrhythmia includingventriculartachycardia and atrialfibrillation),bradycardia, chest pain, hypotensiori, peripheral ischemia, syncope, tachycardla, posturaldizziness, postural hypotension; central and psrthsral nervous system: hypoestfiesia, paresthesia, fremor, vertigo; gastrointestinal: anorexia, constipation, dyspepsla, dysphagia, diarrhea, flatulence, vomiting, gingival hyperplasla; general: asthenia,’ back pain, hotfiushes. malaise, pain, rigors, weight gain;musculo-skeletal system: arthralgia, arthrosis. muscle cramps, rnyalgla; psychiatric: sexual dysfunction )male and female), msomnla,nervousness,depression, abnormal dreams, anmety,depersonalization; respIratory systim: dyoprea,’ epistaxis;skIn and appendages: pruritus, rash, rasherythematous, rash maculopapular;specIal senses: abnormalviolas,conlunctivitis, diplopia, eye pam, tinnitus;urinary system: micturthon frequency, micturitiondisorder,nocturia;autonomic nsrvous system: dry mouth, sweating increased; mitabolic and nutrttlon: thirst; hemopoletic: purpura. The following events occurredin O.1% of patients:cardiac failure,pulse irregularity,extrasystoles,skin discoloration, NORVASC#{174}urticaria, skindryness,alopecia, dermatitis,muscleweakness,twitching,ataxia, hypertonia, migraine,