Ukiah Daily Journal from Ukiah, California on June 14, 1998 · Page 32
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Ukiah Daily Journal from Ukiah, California · Page 32

Ukiah, California
Issue Date:
Sunday, June 14, 1998
Page 32
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ONCE-DAILY TROGLITAZONE TABLETS WAJMHKS Hepatic hn out of <mn Idioeyecntic I ... ADVERSE REACTIONS). Tie hepatic inject It Bttalfy nmilUt, M my m cans el betarfc fallen, kidJtg t» dee* or linr uimelsm, km bra repotted. Injury ta» ecwnd after boA start- and tout-Urn tncjItaoM liur uttofy ton MM npOflM otnio) mrkitefl HM (SM During ill clinitil ttudiu in North Americi, i total of M of 251011.9%] Renilin-Beated patients and 3 ol 475 I0e%l placebo-treated patens had ALT levels grester thin 3 times the upper limit of normil. Twenty of the Reiulin- treated end one of the placebo-treated pitienti were withdrawn from treetmint Two of the 20 Return-treated patients developed reversible jaundice; one of these patients had a liver biopsy which was consistent with an idiosyncratic drug reaction. An additional Reiulin-treeted patient had e liver biopsy which was also consistent with an Idiosyncratic drug million. (See ADVERSE REACTIONS. Laboratory Abnormalities.) It is recommended that serum traniaminase levels be checked at the suit of therapy, monthly for the first six months of therapy, every two months for the remainder of the first year of troglitazone therapy, and periodically thereafter. Liver function tests also should be obtained for patients at the first symptoms suggestive of hepatic dysfunction, eg, nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine. Ruulin therapy should not be initiated if the patient exhibits clinical or laboratory evidence of ective liver diseese leg, ALT>3 bmes the upper limit of normal) end should be discontinued if the patient has jaundice or laboratory measurements suggest liver injury (eg. ALT>3 times the upper limit of normal). MEFSUMMAIV Consult Peckage Insert for full Prescribing Information. MOKOTONIMO USAGE Reiufin may be used concomitendy with a sulfonylurea or insulin to improve jfycemic control. Reiulin, as monothere- py, is indicated as an adjunct to diet end eurcise to lower blood glucose in patients with type II diabetes {see DOSAGE AND ADMINISTRATION in Package Insert for full Prescribing Information). Reiulin should not be used es monothera- py in patients previously well-controlled on aulfonylutea therapy. For patients inadequately controlled with a suKony- luree alone, Reiulin should be added to, not substituted for, the sutfonyluree. Menagement of type II diabetes should include diet control Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient This is important not only in the primary treatment of type II diabetes, but in maintaining the efficacy of drug therapy. Prior to initiation of ReniBn therapy, secondary causes of poor glycemic control, eg, infection or poor injection technique, should be investigated and treated. Heailn is contraindlcated in patients with known hypersensitivity or allergy to Reiulin or any of ia components. SEE BOXED WARNING. PRECAUTIOU teenl Because of its mechanism of action, Rezulin is active only In the presence of insulin. Therefore, Reiulin should not be used in type I diabetes or for the treatment of diabetic keto-ecldosis. ll(iegl)cenie: Patients receiving Ruulin in combination with insulin or oral hypojlycemic egents may be at risk (or hwoglyeemia and e reduction in the dose of tie concomitant sgent mey be necessary. Hypogtyeemie hes not bein observed during tin administration of Retulin as roonotherapy and would not be expected based on till mechanism of action. Omlaties: In primenopiusal anovuletory patients with insulin resistance, Reiulin Keatnint may result in resumption of ovuletion. Teew iieMs em be et risk fee emu«cy. Heteenleier Across ill clinical studies, hemoglobin declined by 3 to 4% in troglituone-treatid patients compared with I to 2* in those Heeled with placebo. White Wood ceU counts also declined slightly in ttoglruuone-trealed patient] compared to those treated with placebo. These changes occurred within the list four to eight weeks of therapy. Levels stabilized and remained unchanged for up to two yean of continuing therapy. These changes nay be due to the dilutionel effects of increasedplesma volume and have not been associated wnfi any significant hemetologic clinical effecu (see ADVERSE REACTIONS, Laboratory Abnormalities). Use ia Patees Wit Heart Fefere Heart enlargement without microscopic changes has been obsened in rodents at exposures of parent compound and active metabolite exceeding ) tunes die AUC of the 400 mg human dose (see PRECAUTIONS, Carcinogenesij. Mutagenesis, Impairment of Fertility, and Animal Toxicology). Serial echocerdiographic evaluations in monkeys treated chronically at exposures at 4-9 tunea the human exposure to parent compound and active metabolite at the 400 mg dose did not reveal changes in heart siie or function. In a 2-yeer ecfiocardiographic clinical study using 600 to 800 mg/iey of Reiulin in patients with type II diabetes, no increase in left ventricular mass or decreesi In cardiac output was observed. The methodology employed was able to detect a change of about to* or more in left ventricular mass. In animal studies, trogtaone treatment was associated with increases of 6* to 15H in plasma volume. In a study of 24 normal volunteers, en increase in plasma volume of 6% to IX compared to placebo was observed following (weeks of troglitaione treatment No Increased incidence of adverse evens potentially related to volume expansion (eg, congestive heart failure) have been obsened during controlled clinical trials. However, patients with New York Heait Association (NVHA) Class III and IV cardiac status were not studied during clinical trials. Therefore, Reiulin is not indiceted unless the expected benefit is believed to outweigh the potential nsk to patients with NVHA Class III or IV cardiac atatus. Rtiulin should be taken with meals. If the dose is missed atthe usual meel, it may betaken at the next meaL Uthe dose is missed on one day, the dose should not be doubled the following day. It is important to adhere to dietary instructions and to regularly have blood glucose end glycosylated hemoglobin tested. During periods of stress such as fever, Vauma, infection, or suigery, insulin requirements may change and patients should seek the advice of their physician. . Patients who develop nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine or other symptoms suggestive of hepatic dysfunction or jaundice should immediately report these signs or symptoms to their hysician. When using combination tiierepy wM insulin or oral hypoglycemic egents, the risk and treatment, and conditions that predispose to its developme bers. , , ent should be explained to (mints and their family mem- Use of Reiulin cen ceuse resumption of ovuletion in women taking oral contraceptives and in patienla with polycystic overv disease. Therefore, e higher dose of an oral contraceptive or en alternate method of contraception should be considered. Reiulin mey effect other nwdicslions used in diabetic patients. Patients started on Reiulin should esk their physician to review their other indication! to make sure that they ere not effected by Reiulin. DneMtractiMS OwCwnceetms: Adminiatration ol Reiulin with an oral contraceptive containing ethinyl estradM end norethin- drone reduced the plasma concentrations of bom by approximately 30%, which could result in lots of contraception. Therefore, e higher dose ot oral contraceptive or an alternative method of contraception should be considered. TedHeefrr Coadministration of Reiulin with terfenadine decreases the plasma concentration of both lerfenadine end its active metabolite by 50-70% and nay result in decreased efficacy of terfenadine. faeleiiiieeeiaa Concomitant administration of choltityramina with Retulin reduces the absorption of Iroglitazone by 70%; thus, coadministretion of chotostyremine end Reiulin Is not recommended. Gtyejricfe Coedministretion of Reiulin end glyburide does not appear to alter troglrtanne or gryburide phsrmacoki- nebcs. . Oiguk Coadministration of Reiulin with digoiin does not altar the steady-state pharmacokinetics ol 4jo»a Wertane: Reiulin has no clinically significant effect on prothrombin time whan administered to patient! receiving chronic warfarin therapy. ....—,_„.... ,..j —^uujgg 0 | acetaminophen and Reiulin does not after the pharmacokinetica of either drug. E No information ii available on the use of Ruulin with madormin. Uuttt A single administration of a moderate amount ol alcohol did not increase the risk of ecutt hypoglycemia in taliiHreatad patients with type II diabetes meUitus. The above interactions witii terfuiadine and oral conneceptives suggest diet troglitaione may induce drug metabolism by CYP3A4. Studies have not been performed with older drugs metaboliied by this eiuyme such at asttmiiole, calcium channel Mockers, cisepride, corticosteroids, cyclosporine, HMG-CoA reductase inhibiton, ttcrolimus, Irian- lam, end trirutrexale. The possibility of altered safety and efficacy should be considered when Ruulin b used con- eomittntiy with these drugs. Patients stable on one or more ol these agents when Reiulin is started should be closely monitored and dwir therapy adjusted as necessery. Ci rtefFtitaity a end to female rats at 25, SO, or 200 mg/kg. No tumors ol any type were Increesed et the tow and mid dosei Plesme drug exposure beted on AUC of parent compound and total nwteboGtes et the low end mid doses was up to 24-fold higher then human exposure at 400 mg daily. The highest dose in each sex exceeded the meximum tolerated dose. In e 104-week study in mice given SO, 400, or NO mg/kg, incidence of hemangiosarcome was increeced in females et 400 mg/kg and in both aexes et BOO mg/kg; Incidence of hepetoceUer carcinoma was increesed in females et 100 mg/kg. The lowest dose associated with increesed tumor incidence 1400 mg/kg) wes associated with AUC values of parent compound end total metebo- Itoi thet were et leest 2-fold higher then the human exposure et 400 mg dejty. No tumors of any type were increesed in mice at SO mgftg at exposures up to 40% of that in humans at 400 mg daily, based on AUC of parent compound and total metabolites. Trogliteione wes neither mutagenic in bacteria nor clastogenic in bone merrow of mice. Equivocal increases in chromosome aberrations were observed In en In vim Chinese hemster lung cell assay. In mouse fymphome cell gene mutations assays, results were equivocal when conducted with e microtrler technique end negebve with an ager plate technique. A Ever unscheduled DNA synthesis essay in rets wes negetive. No edveru effecta on fertility or reproduction wen observed in mile or ft higher than the human exposure. Aetna] Tnkeloir Increesed heert weights without microscopic changes were observed in mice and rats treeted for up tol year at exposure (AUCI of parent end ective meteboite exceeding 7 times the humen AUC et 400 mg/dey. These heart weight incnases were reversible in 2- end 13-week studies, were prevented by coedministrab'on of an ACE inhibitor, and 14 deys of trogAtuone administration to red did not effect left ventricular performance. In the lifetime cerclnogenicity studies, microscopic chenges were noted in the hearts of rets but not In mice. In control end treated rata, microscopic changes included myocerdial inflammation and fibrosis and karyomegely of (trill myocytes. The incidence of these chenges in drug-treated rats was Increased compered to controls et twice the AUC of Hie 400 mg humen dose. Pregnancy Category B. Troglilaione was not tentogenic in rets given up to 2000 mg/kg or rabbits given up to 1000 mjAg dunng orgenogenesit. Compared to humen exposure of 400 mg dak estimeted exposures In rets (parent compound) and rabbits (parent compound and active metabolite) band on AUC et these dons were up to Mold end Wold higher, respectively. Body weights of fetuses and offspring of rats given 2000 mg/kg during gestation wen decreesed. Delayed postnetal development attributed to decreesed body weight wes observed in offspring of rats given 40,200, or 1000 nig/kg during lete gestation and lectition periods; no effects were observed in offspring of nts given 10 or 20 mgVkg. There are no edequate end welj-conlroUed studies in pregnant woman. Reiulin should not be used during pregnency unless the potential benefit justifies the potentiel risk to the fetus. Because current Information strongly suggests that abnormal Wood glucose levels during pngnancy are associated with a higher incidence of congenital anomalies es well as increesed neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels es close to normal as possible. ft is not known whether tnglitaione ia secreted In human milk. Troglitarani is secreted in the milk of lactating rats. Beceuse many drugs are excreted in human milk. Ruulin should not be administered to e breest-feeding woman. PttietncUse Safety and effectiveness in pediatric patients heve not been established. Geriatric Use Twenty-two percent of patients in clinical trials ol Reiulin were 65 end over. No differences in effectiveness end sele- ty were observed between these patients end younger petients. Two patients in the clinical studies developed reversible jaundice; one of these patients bed e linr biopsy which was consistent wM en Idiosyncratic drug reection. An additional patient had a liver biopsy which wes also consistent with an idiosyncratic drug reaction. Symptoms that are associated with hepatic dysfunction or hepatitis heve been reported, including: nausea, vomiting, abdominal pain, fatigue, inorexie, derk urine, ebnormal Ever function tests (including incressed All, AST, LDH, aUtaFne phosphatase, bitrubin). Also see WARNINGS. The overall incidence and types of adverse reactions reported in plecebo-controlled clnlcal trials for ReiuUn-tnated patients end plecebo-treeted patients are shown in Table I. In patients treated with Reiulin in ghjburide-controlled studies |N=SOI or uncontrolled studies (N=5IOt, the safety profile of Ruulin appeared sMer to that displayed in Table I. The incidence of wimdrawala during clinical trials was similar for patients treated with placebo or Rtiulin (4%). AfctmEreatolee^eUFreqwcy^mirfRuidU-taM Petfett SelPetieete Plecebo N.432 Reiulin N.14SO Placebo Nt4i2 Ruulin N>I450 Infection Headache Pain Accidental Injury Asthenia Dioiness BeckPein Neusee Rhinitis Diarrhea Urinary Tract Infection Periphenl Edema Pharyngitis Types of adverse evens seen when Reiulin was used concomitantiy with insulin |N=543I were similar to those during Reiulin monotherepylN>l731|, although hypoglycemia occurred on insulin combination therapy (me PRECAUTIONS]! llee»ale|it: Smell decreases in hemoglobin, hematocrit and neutroplul counts (within the normal range) were more common in Ruulin-tnuted than placebo-treeted patients and mey be related to increased plasma volume observed with Rezulin treatment. Hemoglobin decreeses to below the normal range occurred In 5% of neiulin-ireated end 4% of placebo-treated petienls. liatte Smell chenges in serum tpids have been observed (see CLINICAL PHMMACOLOGY, Pharmecodynamics and inn Traeuuuse Lntta During all clinical studies in North Americe, e totel of 49 of 2S10 H-9%1 Ruulin-treated patients and 3 of 475 10.1*1 placebo-treated patent* had ALT levels greater then 3 timea the upper tmrt of normel. During controlled clinical Dials, 13% of ReiuliMreated patiema had reversible elevations In AST or ALT greater than 3 times the upper limit of normal, compared with 0.6% of patients receiving placebo. HyperbOkubinemie \>\K upper limit of normal) was found in 0.7% of Ruulin-treated patients compared win 1.7% of paunta receiving placebo. In the population of patents treeted with Reiulin, mean end median vital for bilirubm. AST, ALT, alkaline phosphatase, and GGT were decreesed et the final visit compared with baseline, while values for LDH ware increased slightly (see Adverte events associated with Reiulin thet heve been reported since market introduction, diet ere not listed above, end for which ceusal relationship to drug has not been established include the following: congestive heart felure, weight gain, edema, fever, abnormal lab tests including increased CPK end crutinine, hyperglycemia, syncope, ane- betiy * tW.POPL February 1998 Manufactured by: r«t» to* Pknticwfcils, I* Vega Beia, PR 00634 DMiutedby: FAME-DAVIS OivofWemer-UmbettCo Morris Plains, NJ 07850 USA Marketed by: HUKE-OAMt Div of Warner-Lambert Co and SANttl) PAKE DAW Persippany,NJ 07054 USA 0352G203 FARKE-DAVIS Division of Wam«r-Urnten Cwnpany Monii Pltns, N«w Joiny 07950 SANKYO PARKE DAVIS Continued from previous page Julia Roberts: Becket made me want to be political." Madonna: To Kill a Mockingbird Marlee Matlin: The Wizard ofOz Walter Matthau: The Informer Writer-director Kevin Smith: Do the Right Thing Matthew McConaughey: Hud Chris O'Donnell: It's a Wonderful Life Tim Bobbins: Waitingfor Guffman Susan Sarandon: The Grapes of Wrath Actor Johnathon Schaech: From Here to Eternity Robin Williams: Dr. Strangelove, or How I Learned to Stop Worrying and Love the Bomb — Compiled by Jennifer Mendelsohn Rank the big movies of summer At www.usa, debate the best of Hollywood in our guestbook - and rank summer's blockbusters in the Movie Meter. 8 USA WEEKEND • June 12-14.1998

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