The Salina Journal from Salina, Kansas on October 6, 1996 · Page 48
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The Salina Journal from Salina, Kansas · Page 48

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Sunday, October 6, 1996
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PRAVACHOL® PransMM Sodium Tablets CONTRMWNCATKWS: Hypersensib'vity to any component of this medication. Active liver disease or unexplained, persistent elevations in liver function tests (sea WARNINGS). Pregnancy and lactation. Atherosclerosis is a chronic process and discontinuation of llpld-lowering drugs during pregnancy should have little Impact on the outcome of long-term therapy of primary rrvpercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase Inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase Inhibitors are contraindkated during pregnancy and In nursing mothers. ftavatatjnsiio^ to administered to wmen of childoetring^Mty when such prtenti are ro^unfi^ of th* potential hazards. If the patient becomes pregnant while taWna this dass of drug, therapy should be dlsconfmued and the patient apprised of the potential hazard to the fete. WARNINGS: Urn Ernmi— HMG-CoA reductase Inhibitors, like some other lipid-lovrering therapies, have been associated with biochemical abnormalities of liver function. Increases of serum transamlnase (ALT, AST) values to more than 3 times the upper limit of normal occurring on 2 or more (not necessarily sequential) occasions have been reported In 1.3% of patients treated with pravastatln In the US over an average period of 18 months. These abnormalities were not associated with cnolestasls and did not appear to be related to treatment duration. In those patients in whom these abnormalities were believed to be related to pravastatln and who were discontinued from therapy, the transaminase levels usually fell slowly to pretreatment levels. These biochemical findings are usually asymptomatic although worldwide experience Indicates that anorexia, weakness, and/or abdominal pain may also be present in rare patients. It It recommend** that Dmr ftmctton testa beperton^ before fa InWat^ therapy or elevation Ml dote, and periodically Ifeareifler (e.g, temiamuuy). Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormalityfies) return to normal. Should an Increase in AST or ALT of three times the upper limit of normal or greater persist, withdrawal of pravastaUn therapy Is recommended. Active liver disease or unexplained tonsamlnase elevators are contraindications to the use of pravastatln (see CfltnwUNDICATMMii). Caution should be exercised when Pjravastatlnis administered to patients with a history of liver disease or heavy alcohol ingestton (see CUMCAL PHARMACOLOGY: PtUOTUCOlOneticirtlttaboutm). Such patients should be doseiyrnordtored, started at the lower end of the recommended dosing range, and titrated to the desired therapeutic effect Skeletal Muscle — Ran cant o( rhtbdomyolyilt with acute mul failure stcomluy to myoglobinuria haw been report*! with pmrastatin and other drugs In this class. Uncomplicated myalgia has also been reported in pravastaun-lraated patients (see ADVERSE REACTIONS). Myopathy, defined as muscle acting or muscle weakness in conjunctionwith Increases In creattupf»sphoUnase(CPig values to greater than 10 times the upper normal limit, was rare (< 0.1%) In pravastann clinical trials Myopathy should be considered in any patient with diffuse myalgias, muscle terriemess or weakness, and/or marked elevation of CPU Patients should be advised to report promptly unexplained muscle pain, tenderness ywealyie^patic^yilaccorrjHraedfr It markedly etovated CMC knralt occur or myopithy It dtagaoied or tutpecW PravMtatta therepy should also be temporarily withheld In any patient experiencing, an acute or atriou condition to the development of renal taMurt lacondary to rhaodomyolytls, to, tensfe; : major surgery: trauma; amn metabolic, endocrine, or ttocirofyte ditordereTor uncontrolled epilepsy. The risk of myopathy during treatment with another HMG-CoA reductase Inhibitor Is Increased with concurrent therapy with either erythromycin, cydosporine, niatin, or flbrates. However, neither myopathy nor significant Increases In CPK levels have been observed In three reports Involving a total of 100 post-transplant patients (24 renal and 76 cardiac) treated for up to two years concurrently with pravastatln 10-40 mg and cydosportne. Some of these patients also received other concomitant Immunosuppressive therapies. In one single-dose study, pravastatln levels were found to be Increased in cardiac transplant patients receiving cydosporine. Further, In clinical trials Involving small numbers of patients who were treated rancurrently with prayasbjUn and niadn. there were no reports of myopalhy. Also, rnyopalhy was not reported in a trial of combination pravastatln 140 mo/day) and gemnbroil (1200 mg/day). although 4 of 75 patients on the combination showed marked CPK elevations versus one ot>3 patients receiving placebo. Therewas a trend toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared with the groups receiving placebo, gemflbrozll, or pravastafin, ™™merabyj8ee WKCAuTWM&Jrao; MtijetloiarTria us« of fuwtet aim rney c«catto^tau«ociit«h£thniyo|>*trK avoidedlurieutha'benefit of further alteration* In llpid tovda to Wury to outweigh DM tocrMMdrttk of this drug combination. PRECAUTIONS: General — Pravastatin may elevate creaUnine pnoaphoklnase and transamtoase teveMsee ADVERSE REACTIONS). This should l» corWred In trS cKenSaTdlsS ofchest pain In a patient on therapy with pravastatln. Huimmus Familial HyperctulesSSemia. Pravasttttn has no been evaluated in patients with rare homoiygous^mlllal nypercretestaroiemla. In this group of patients, it has been reportedthat HMG-CoA reductaseinhibitors are less effective because the glwglj* b" 1 *™* J£L I8C JP OT - 5"«! ***"«* A single 20 mg oral dose ofpmSrfvS administered to 24 patients with varying degrees of renal Impairment (as determined by creatinlne d ?£!!Xf ) - & f?£L*¥ oba S ( !!? d m "" Ptannacokinetics of pravastatin or Its 3a-hydroxy isomeric metabolite SO 31,906. A small inaease was seen In mean ADC values and half-Hie (t'ft) for the Inactive erizymatte nng hydroxyiatioci metabolite (SO 31,945). Given this small sample size, the dosagertmUstered and me degree of Individual variability, patients with renal impairment whoare receMngpra^tin should be dosely monitored. Informrton for PatJants - Patients should be advised fe report prompSy unexplained muscto pain, tenderness or weakness, particularly If accompanied by malaise or fever. Drug *"*«-•,/mmurxisuMress/m Oruos, GtmtOxoa. /ten IHtcoMc AcU). fiyf/iromycfo: See 1 ^ MM "*L^2ffi?-'S 08 ewwIUrt administration of pmrastatjn had no effect on f antipynne, interactions with other drugs metabolized via the same hepatic cytochrome are not MpK^-OwltitymnlneXoletllpol: Concomitant admlrtstratlonreaulfed In an approxmaiely 40 to 50% decrease m the mean AUC of pravastatln. However, when pravastatin was administered 1 hour beforew '4 hours alter cholestyramlne or 1 hour before colesttpol and a standard meal, $?.!.J(£. I !?,,S?2"» "SnJKantiDecrease m bfaavaJtabllrty or therapeutic effect (See DOSAGE ANd MMINBTRATJOft Concomitant Therapy.) Warfarin: In a study Involving 10 healthy mate subjects given pravastatin and warfarin concomitantly tor 6 days, bioavallabilrtypararr^ at stea« state ior^ara&tin toarent compound) were not altered. Pravastatln did not attar The plasma proMrHjhdirKj of warfarin Cwcomitant ooslng dk) Increase the AUC and Cmax of warfarin but (SfrSt produce^y crSgeiK ., no increaa waaseen In mean prothrombln time after 6 days'of concomitant *. ••-• HJ- "j- - t SS? in i and VS*"* Pgtonaatai of prothrombln time haa'been reported wioTanother ^"^^I^'ISS^'K^^J" 1 ' 0 ^'^ ***** "a* ttairprothrombln times closely monitored when pravastalin is initiated or the dosage of oravastatin Is changed Cmi&iirw The AIK> 11 * for pravastatin when riven with timetjdlne was not significantly different from the AUC for pravastatin vvrKsn^enalorw.Ai^fatdrflerwcew^ dmetBne compared b when administered with antacid. Olgoon: In a crossover Wallrevolving T8 hlialthy male subjects given pravastatin and dlgoxin concurrently for 9 days the otoavailabilitv oaramatera of diooxln mraixitafleiM.Tr«AUCofj>rava3laBn£nM^ Its metabolites SO 31,906 andSQ 31,945 wasnot alteredttSiwo^lr^nve^lorahaverr^^ cvdosporlne levels In patients on pravastatin. and to date. Iheseresuibi IndkatenocSnlcaliv meanSwiul S^^^^s^s&s ^w^^™**^*^^ volunteers given concomitant single dosesoTpravasL in urinary excretion and protein binding of pnwaatatinJh addition, there was as Cmax, and Tmax for the pnvastttjn metabolite SO 31,906. Cornokian ' gemtlbrozii is generalty not recommended, m interaction studies with i PRAVACHCi), rtmoMw. n/cotac add, or onoucal no s Soffi y\>a ff ^^^-^yy^s-f^ n ' l ^- > - uTMKSffJ}h : J£LS^ t S. steroid hormone 'H were inconstont with reoard to of21 males, the mean testosSone., 0.004) after 16 weeks of treatment „.. ^ JW^ta pta^^tMtortsrona i males and poet-menopaual females were effects of the drug on basal steroid hormone knell. In a ' effects of HMG-CA reductaseJnhltxtors on sporratogmetls andi I I. The eflectt, » any. c* JBL - •" numbers of , . femalM are unknown, dvsfunction should be. or other agent . _.,, ot mnMtm on the pttultary-jonaoal ttda In pre- treaied wii oravaataon who display finical evidence of ^^^opf^Ca^shaildaisobee»rclsedaan to lower choiesti seen with the 60 mg/kg/day dose. Carclnogenetls, Mutagenetlt, knpakiMnt of fertility—In a 2-year study In rats fed pravastatln at doses of 10,30. or 100 mo/ta body weight there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p < 0.01). Although rats were given up to 125 times the human dose (HD) on a rag/kg body weight basis, serum drug levels were only 6 to 10 times higher than those measured to humans given 40 mg pravastatin as measured by AUC. The oral admWstratWionO, 30, or 100 mo/kg (producing plasma drug levels approximately 0.5 to 5.0 times the human drug levels at 40 mg) of pravastafin to mice for 22 months resulted In a statistically significant Increase In the incidence of malignant lymphomas in treated females when all treatment groups were pooled and compared to controls (p < 0.05). The Incidence was not dose-related and male mice were not affected. A chemically similar drug in this dass was administered to mice for 72 weeks at 25,100, and 400 mg/ta body weight which resutted In mean serum drug levels approximately 3,15, and 33 times higher than the mean human serum drug concentration (as total kihibtory activity) after a 40 mg oral dose. Liver carcinomas were significantly Increased in high-dose females and mid- and high-dose males, with a maximum Incidence of 90 percent In males. The Incidence of adenomas of the liver was signfficantfy Increased to mid- and high-dose females. Drug treatment also significantly Increased the Incidence of lung adenomas In mid-and high-dose males and females. Adenomas ofthe eye Harterlan gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of mujjgenidty was (ibserwd ft »flro, with or without rat-liver metabolic activation, hi the following studies rnicrotxal muogen tests, using mutant strains of Sa/monHla /vpMmunbm or Escherichla colt, a forward mutation assay to L5178V TK +/- mouse lymphoma cells; a chromosomal aberration test to hamster cells; and a gene conversion assay using Saccrurornrcescerevbfe*. In addition, there was no evidence of mutagenlcity to either a dominant lethal test in mice or a mtaonudeus test In mice. In a study in rats, with dairy doses up to 500 mg/kg, pravastatln did not produce any adverse effects on ferffllty or general reproductive performance. However.ln a study with another HM6-CoA reductase Inhibitor, there was decreased fertHHv in mate rats treated for 34 weeks at 25 mg^ body weight altnougri this effect was not observed in a subsequent fertility study when this same dose was administered forTl weeks (the entire cycle of spermatogenesis, toduding epMfdymal rnaturatton). In rats treated with ttiIs same reductase Inhibitor at 160 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatooertc epithelium) was observed. Although not seen with pravastattt, tw simliar drugs In tills dass caused drug- related testlcular atrophy, decreased spermatogenesis, sparmatocybc degeneration, and giant cell formation In dogs. The dMcal significance of these findings is undear. hwiMKTrpregnancy C»l»gory X. — See raNTRAHOKATIONS. Safety to pregnant women ha not been established. PravastaOn wan* taraogenlc inratsatdosesuptoirxWmg/kgdallyorinraljbibatoteesofuptoWmg to 20x (rabbit) or 240x (rat) the human exposure based on surface area (mgymeterl. However, to studies with another HM&CoA reductase Inhibitor, skeletal malformations were observed In rate and mice. There has been one report of severe congenital bony deformity, tracteo-esophageal fistula, and anal atresla (Vater association) to a baby bom to a woman who took another HMG-CoA reductase inhibitor with dextroamphetimlne sulfata during the first trimester of pregrarx?. PfWVACHOL (pravastatin sodium) should be administered to women of chad-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potsntiat hazards. If the woman becomes pregnant while taking PRAVACHOL (pravastatin sodium). It should be discontinued and the patient advised amln as to the potential hazards to the fetus, (taring Moiriin—A small amount of pravastatln Is excreted human breast milk. Because of the potential for serious adverse reactions In nursing Infants, women taking PRAVACHOL should not nurse (see CONTRAINOICATIOItS). PedMric Ute—Safety and effectiveness to Individuals less than 18 years old have not been established. Hence, treatment to patients less than 18 yean old is not recommended at this time. ADVERSE REACTIONS: Pravastatin 19 generally weU tolerated: adverse reactions have usually been mild and transient In 4-month long placebo-controlled trials, 1.7% of pravastatin-Ueated patients and 1.2% of placebo-treated patients were dteoonUnued from treatment because of adverse experiences attributed to study drug therapy; this difference was not statistically significant to long-term studies, the most common reasons for discontinuation were asymptomatic serum transamlnase Increases and mild, non-specific gastrointestinal complaints. During clinical trials the overall Incidence of adverse events to the elderly was not different from the Incidence observed to younger patients. Advene Clinical Ewnb—All adverse clinical events (regardless of attribution) reported to more than 2% of pravastatto-treated patients to the placebc-controlledWals are Identified m the table below; also shown are the percentages of patients to whom these medical evenla were believed to be related or possibly related to the drug: AIIEv«rt» Body System/Event Cardiovascular Cardiac Chest Pain Dermatologlc Rash Gastrointestinal Nausea/Vomiting Diarrhea Abdominal Pain Constipation Flatulence Heartburn General Fatigue Chest Pain Influenza MuscukBketetal NmrnSsS Headache 1 Dizziness ReraWjenltourinary Urinary Abnormality Respiratory Common Cold Rhinitis Cough Prwwtatin 4.0 4.0' 7.3 6.2 5.4 4.0 3.3 2.9 3.8 3.7 2.4' 10.0 2.7 8.2 3.3 2.4 7.0 4.0 2.6 Placebo 3.4 1.1 7.1 5.6 6.B 7.1 3.6 1.9 3.4 1.9 0.7 9.0 1.0 3.9 32 2.9 6.3 4.1 1.7 Event* Attributed to Study Drug Prawttrtn 0.1 1.3 2.9 2.0 2.0 2.4 2.7 2.0 1.9 0.3 0.0 1.4 0.6 1.7' t.O 0.7 0.0 0.1 0.1 Placebo (N a 411) 0.0 0.9 3.4 1.9 3.9 5.1 3.4 0.7 1.0 0.2 0.0 1.5 0.0 02 0.5 1.2 0.0 0.0 0.0 •Statistically significantly different from placebo. In the Pravastatln Primary Prevention Study (West of Scotland Coronary Prevention Study) («M CUWCAL PHARMACOLOGY: CIMcal SMlM) Involving 6595 oatlemi treaW wW HWV/Maia (pravastalln sodium) (N = 3302) or placebo (n = 3293) the adverse event profile m the pravastatin oroup was comparable to thai .... ._>??"?"M__.,__< J • of the placebo group over the median 4.8 m IhWdasc i/; myopathy, ^— pravastatin group was comparable to that pming effects have been reported with .__ certain cranial nerves (including paretis), tremor, vertgo, memory Ion, deprenlon. Hmetserottnity ch hu"incluoea one or more syndrome, wral neuropathy, peripheral nerve palsy, 9 has been Kent hypersensltMty syndrome has ti features: anaphytais, anoioedema. ^ J4-538D REGIMEN OF REST ^ How best to relax This week your coach Is Geonp Foreman. Q: I walk 3S miles early in the morning. Afterward, I relax for an hour before work. Recently I was told I've been cheating myself — that once I've exercised I must stay active to reap the benefit True? Iris Jenkins Mount Kisco, N.Y. Foreman: Three- and-a-half miles before work is a wonderful idea, and so is your rest afterward. For me, it's not how hard I work out, but how well I can relax later. There's definitely a big place for rest and relaxation in health and fitness. Don't work out vigorously and then lie down. Instead, cool down, do some stretching, then sit and rest. As long as you do 30 minutes of aerobic activity as many days a week as possible, you get the benefit of your activity. Rest is even more important for elite athletes, because the body needs that time to recover. Probably the thing that I have going for me more than most athletes is I'm able to rest. After cooling down, I'll sit and try to read a book or close my eyes or listen to music (classical is the best music for relaxation). If you don't wear yourself out, you can exercise more later on. Resting is as important as the exercise, d MY PRE-FIGHT ROUTINE Graft Tonmtn and FtoraoM Qrtmtli Joymr take turns answering questions on sitting and staying In 1000 Wilson Blvd., Arlington, \fe. 8229-QOJ2 (e-mail: fflness@usaweetvjnd.com; tax: 703-276-5518). «9 ONUNi: Stretch your potential in the Body Smart* area of USA WEEKEND. America Online keyword; USA WEEKEND. 10 USA WEEKEND • Oct. 4-6, 1996

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