Mier SIUUUIY, Accourm nWcti ra« FUU Husammc iwowunow. Sit PKOfllSIONAl INFORMATION ACCOLATE twice a day helps me control my asthma. ACCOLATE® (zafirlwkast) isn't just another medication, it's a new type of asthma therapy. ACCOLATE is an oral tablet available only by prescription, for the prevention and chronic treatment of asthma in adults and children 12 years of age and older. ACCOLAFE doesn't just treat your symptoms; it targets a cause - leukotrienes. ACCOLATE isn't a steroid or a theophylline. The way ACCOLATE works is simple, in people with asthma, the body produces natural chemicals known as leukotrienes. These lewkotrienes cause the muscles in the airways to contract and lung tissue to swell, resulting in difficulty breathing. Taken regularly, ACCOLATE can actually block the effects of these chemicals. The result? Improvement in your asthma condition reflected in fewer daytime symptoms and less frequent nighttime awakenings. ACCOLATE should not be used to treat an acute asthma attack. With ACCOLATE, you simply take one tablet in the morning, another in the evening - an hour before or two hours after eating. Improvement in symptoms usually occurs within one week of starting treatment fe Ask your doctor if ACCOLATE is right for you. As with all medicines, talk to your doctor before stopping or decreasing other medications. in over 4,000 people studied, ACCOLATE was generally well tolerated. 1 The most common side effects include headache, infection, 2 and nausea. Women who are breast-feeding should not take ACCOLATE, as the drug may be excreted through breast milk. Patients on oral warfarin therapy and ACCOLATE should have their pro- thrombin times monitored and anticoagulant dose adjusted accordingly. ACCOLATE is a simple, convenient way to help control asthma. So talk to your doctor. Please see important information on the right. ORAL, Att. ORAL, COLATE* ZAFIRLUKASTffi! For more information, calf toll free 1800 262-8472. 'ACCOLATE full prescribing information, Zeneca Pharmaceuticals, Wilmington, Delaware. 2 ln clinical trials, an increased proportion of patients on ACCOLATE over ttoe age of 55 years reported infections as compared to placebo-treated patients; infections were generally mild to moderate, predominantly of the respiratory tract, and dose proportional to ACCOLATE. Infections were associated with coadministration of inhaled corticosteroids. The clinical significance of this finding is unknown. ACCOLATE Is Indicated for the prophylaxis and chronic treatment of asthma In adults and children 12 years of aaeandolder. coNrUMnomaa ACCOLATE fs awtra/ndlcaterf in patients who ore rryptrsensrove to zafriukost or any cf to irwctiw Ingredients. ACCOLATE is not Indicated for use in the revmal ofbronchospasm In acute asthma attack], Including status asthmatlcus. Therapy wift ACCOLATE can be continued during acute exacerbations of asthma. Coadministration of zoflrtukast with warfarin results In a clinically significant Increase in pratrrrombin time (PT). Patients on oral warfarin anticoagulant therapy and ACCOLATE should have their prothrombln times monitored closely and anticoagulant dose adjusted accordingly. (See PRECAUTIONS, Drug Interactions.) MKMmOM >»iinjsUlll *r KsUnHJ ACCOLATE Is Indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods. ACCOLATE Is not a bronchodilator and should not be used to treat acute episodes of asthma, patients receiving ACCOLATE should be Instructed not to decrease the dose or stop taking ory other antiasthma medication unless Instructed by a physician, women who are breastfeeding should be instructed not to take ACCOLATE (see PRECAUTIONS. Nursing Mothers). Alternative antiosthma medication should be considered In such patients. The UcmatlaUHty of ACCOLATE may be decreased when taken with food. Patients should be instructed to take ACCOLATE at least l hour before or 2 hours after meals. OHM MncttoK In a drug Interaction study m 16 healthy male volunteers, coadministration of multiple doses of zafWukast (160 mg/day) to steady state with a single 25-mg dose of warfarin resulted In a significant Increase In the mean AUC (* 63\) and halHife (»36!»l of S-warfarin. The mean protnrombln time (PT) increased by approjjmatery 35>s. This Interaction is probably due to an Inhibition by zaflrlukast of the cytochrome P4SO 209 Isoenzyme system. Patients on oral warfarin anticoagulant therapy and ACCOLATE should have their pmtirombln times morutmd closely and anticoagulant -•—-"——- "wryfrwlSSSSs). l Interaction studies her drugs known to be metabolized by the cytochrome P450 2C9 Isoenzyme (eg, tofbulamlde, phenytoln, aufcarmueplnej haw been conducted; however, care should be exercised when Accaurc is coadmin- Isteredwrtti these drugs. in a drug Interaction study In 16 neartny male volunteers, coadministration of (Mmgroice zojrlukast (320 rrya ----- idaiMtu st at In the mean c ma » (•«'•) u steady state resulted and AUC (-54*) of ACOXAIE. NO efbt of zafirlukast on terfenadlne plasma concentrations or ECC parameters (ie. OT C interval) mis seen. No formal drug-drug interaction studies between ACCOLATE and other drugs known to be metabolized by the P4SO 3A4 (OP 3A1) Isoenzyme (eg, dihydropyrfdine calcium-channel btocken, cyclosporin, clsapride, astemizole) have been conducted. AS ACCOLATE Is known to be an inhibitor of OP 3*4 in vitro. It is reasonable to employ appropriate dinical monitoring when these drugs are coodminlstered with ACCOLATE. In a drug interaction study in n asthmatic patients, coadmlrwtrauon of a single dose of zafirlukast (40 mg) with erythromycfn (500 mg three times aairy |br 5 days) to steady state resulted in decreased mean plasma levels of zafirlukast by approximately 40S due to a decrease In zafiriukast btovaikibilrly Coadministration of zafirlukast (80 jnolQofl at steady stale with a single (6 mg/kg) in 13 asthmatic patients resulted In decreased mean plasma levels of zajlnukast by approximately 30*. but no eject on plasma theopnytlne levels was observed. coadministration of zaflrlukast (40 mo/doy) with aspirin (6SO mg four times dairy) resulted In mean Increased plasma levels of zafirlukast by appraximatery4S!«. in a sinoitMnd, ponniekiroup, 3-wet* study in gheartby (em* subjects taking, oral contraceptive, 40 mg twice dairy of jorlrluluut had no slanifl- ' - ' ethlrr/l estrvdiol plasma r ccncweiitlut e|kacy: c«rcl»f»Mli, MvcMtmiii, mtulriiieirT sjf ftitWty: inlwo-year cartJnogenlcity studies, zufiriukast was aoMnrsund at oral dairy doses of K), 100. and 300 maM to mice arid 40, 400, aru 2000 mg/kg to rats. Male mice given 300 mg7kgjday of zaflrlukast had a greater Incidence of hepatocellular adenomas as compared to concurrent controls; ferrule mice at this dose shaved a greater Incidence of whole body lutocyac sarcatus. mle and ferrule roo given 2000 rria/kg/auy of zafirlukast had a greater Incidence of urinary bladder vunsltloruii cell papillomas as compared to concurrent controls, pharmacoklnetic In mice at nontumorlacnlc (100 mg/kg) and tumon'genfc (joo mg/kg) doses of zaflrtukast were approximate 70 times and 220 times, respectively, the plasma concentrations at the maximum narnrnenacd' human dairy oral due. for rats, plasma concentrations at the nontumorlgenlc (400 mg/kg) and tumorlgenic (2000 mg/kg] doses of zofHuknst were approximately 170 times and ice times, respectncry, fte plasma concentrations in humans at the maximum recommended human daily oral dose. The clinical significance of these findings for the long-term use of ACCOLATE is unknown. In mutaaenicity studies, there was no evidence of mutogenkT potential In reverse (5. typhlmurium and E. coll) or forward point mutation (CHO-HCPRT ana! mouse lymphonw) assays or in two assays for chromosomal aberrations (human peripheral blood rymphocyte clastogenlc assay and the rat bone marrow mkronucleus assay). rleproducdon and fertility studies In mB showed no effect on fertility due to zafirfukost at doses up to 2000 ma/kg (approximately 400 times the maximum recommended human dairy oral dose on mj/m'basis), in tne one-year toxicity studies In dogs, zafirlukast produced on increase In absolute and relative uterine and ovarian weights at an oral dose of ISO mg/kg. resultingTn appmfmatery is times the systemic exposure (AUC o.,ji.) in humans at the maximum recommended human oral dairy dose, frtf rwncy cnuory I: NO terato- genicity was observed at oral doses up n 1«B mo/kg/doy in mice (approximately 160 times the maximum recommended human dairy oral dose on a majnf basis), 2000 mg/kg/day in rats (approximately 400 times the maximum recommended human dairy oral dose on a mg/m 1 basis) and 2000 mg/kj/day In cynomolgus monkeys (opproumotely «oo times the maximum recommended human dally oral dose on a mg/m' basis). At 2000 mg/kg/doy in rats, maternal toncity and deaths were seen with Increased incidence of early fetal resorptlon. Spontaneous abortions occurred In cvnomolau) monkeys ot a maternally toxic dose of 2000 mg/kg/day orally. There are no adequate and weil-controiled trials In pregnant women. Because animal reproduction studies are not always predictive of human response. Account should be used during pregnancy only If dearfyneeaed. ^ ' " Mtf*« Modm: zaflriukost Is excreted In breast milk. Following repeated 40mg twlce-o-doy dosing In healthy women, average steady-state concentrations of zaflriuusst In breast milk were so ng/ml compared to 255 no/ml In plasma, lecause of the potential for (umorigenlcity shown for zaflrlukast in mouse and rat studies and the enhanced sensitivity of neonatal rats and dogs to the adverse effects of zaflrlukast, ACCOLATE should not be administered to mothers who are breast-ttedlng. fedlatrlc use: The safety and effectiveness of ACCOLATE in pedlatrlc patients below the age of 12 yean hax not been established. The safety database for ACCOLATE consists of more than 4000 healthy volunteers and patients who received ACCOLATE, of which 172] were asthmatics enrolled In trials of 13 weeks duration or longer. A total of 671 patients received ACCOLATE for l year or longer. The majority of the patient! were 18 years of age or older; however. 222 patients between the age of 12 and 18 years received ACCOLATE. A comparison of adverse events reported by i 1% of zafiriukast-treated patients, and at rates numerkalry greater than in placebo-treated patients, 5 shown for all trials In the following table. Adverse Event ACCOLATE PLACEBO JMCSS Heodoche Infection Nausea Diarrhea Pain (generalized) Asthenia Abdominal win Accidental injury Dizziness Myolgla fever lack Win vomiting SOT Elevation dyspepsia 12.9% 3.5S, 3.1ft 2.8% 1.SA, 1.8«. 1.8% 16'o 1.6*. 1.6% 1.6S 1.SX 1.5*. 15". 1.3X 11.7% 3.4H iM 2.1 <« 1.7H 1.6!» MS 1.5% t.5>» 1.5* 1.1% 1JS MS 1.1* IJ* The frequency of leu common advene event! was comparable between ACCOLATE and placebo. Although the frequency of hepatic funsamuuse elevations was comparable between zafblukast and placebo-treated patients, a tingle case of symptomatic nepatias and rrjtXTWiruwnernia, without other attributable cause, occurred In a patient who had received 40 ma/day at zapttukastfw 100 days, in this paGait; the liver eruymes returned to normal within 3 months cflttpping ACCOWTC. in clinical Mais, an Increased proportion of zafirlukast patients over the age of 5! years reported Inflection as compared to placebo-treated patients. A similar putting wot not observed in other aae groups studied, ihese Infections were mosoy mild or mxtaau In Intensity ant predominantly affected the respiratory tract Infections occurred equally In botfi sexes, were dose-proportional to total milligrams of zaffrlukast exposure, and were associated with coadmwi&oupn of inhaled corticoslerolds. The clinical significance ofttiis Uniting is unknown. Manufactured |br: ZENECA A BiwJntM Unit ot Z*n»e» inc. Wilmington. 0«Uwir« 1IM0 (4J7 by. IP* ftwrnacjeuticaii inc.
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