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`"““““ ‘rt
`
`- BREVIBLOU INJ
`(esmolol hydrochloride)
`III lnl Ailplil — 2.5 |: N_iIT_FIIII BIIIECT INTRAVENOUS IIIJEi2TIiIN.,AMPlll Mil
`INFUSION ISEE IIDSAEE ANII -AIIMINISNIATIBN SEBTIONI.
`in rat. Single llm ml —' llill up
`.
`DESCRIPTION
`BHEVlBLOc°'iesmoloi Hcl) is a beta,-selective (cardioselectivel adrenergic receptor blocking agent with a very
`short duration oi action (elimination hail-lite is approximately 9 minutes). Esmolol HGI is:
`i :)-Illethyl p-I2-hydroxy-3-iisopropylaminol propnxy] hydrocinnamale hydrochloride and has the lollowing struc-
`ture:
`'
`.
`'
`
`AUG l 5 1988
`
`APPROVED
`
`Ro'd- i_
`
`
`cH_.02ccii.cH,-QocH‘,cHoHcH.NHcH(cH.l..Hct
`Esmolol ticl has the empirical lormlua C15Hz5ND4CI and a molecular weight at 331 B. it has one asymmetric center
`and exists as an enantiomerlc pair.
`_
`‘
`Esmolol Hcl is-a white to ml-white crystalline powder. It is a relatively hydrophilic compound which is very soluble
`in water and lreely soluble in alcohol. its partition coellicient ioctanollwatert at pit 7.0 is 0.42 compared to 17.0 tor
`proptanolol.
`_
`-
`BHEVl8L0c° iesmoiol licll INJECTION is a clear. colorless to light yellow. sterile. nonpyrogerlic solution tor intrave-
`nousinlusion alter dilution
`‘
`2.5 g. 10 mL Ampul — Each mL contains 250 mg estnolol Hcl in 25% Propylene Glycol. USP. 25% Alcohol. USP and
`water tor injection. USP; buttered with t7.lJ mg Sodium Acetate. USP. and 0.007l5 mL Glacial Acetic Acid. USP.
`Sodium hydroxide andlor hydrochloric acid added. as necessary. to adiust pH to 3.5-5.5.
`too mg. to mL Single Dose Vial
`-— Each m‘L contains 10 mg esmoiol HCI and Water lor injection. USP; buttered
`with 2.8 mg Sodium Acetate. USP. and 0.546 mg Glacial Acetic Acid. USP. sodium hydroxide andlor hydrochloric _
`acid added. as necessary. to adjust pH to 4.5-5.5.
`-
`.
`I
`Blllllliltl PHTIIIIIAGOLIJIIV
`-
`BHEVlB[Oc° (esmolol
`lftcil is a beta.-selective lcardioseicctive) adrenergic receptor blocking agent with rapid
`onset. a very shortduratton of action. and ‘no significant intrinsic sympathorttimeiic or membrane stabilizing activity
`at therapeutic dosages. its elimination hall-lite alter intravenous inlusion is approximately 9 minutes. BHEVIBLOCO
`inhibits the beta, receptors located chielly in cardiac muscle. but this prelerential ettect is not absolute and at
`higher doses it begins to inhibit beta, receptors located cttielly in the bronchial and vascular musculature
`-
`Phlrmacoltlutlc; and liatalrellxu
`.
`.
`—
`BliEVlBLDC' Iesmolo|.HG|) is rapidly metabolized by hydrolysis oi the ester linkage. chietly by. the esterases in the
`cytosoi oi redbiood cells and not by_piasma chollnesterases or red cell membrane acetylcholinesterase Total body
`clearance in man was lound to be.about 20 Ukglhr. which is greater than cardiac output; thus the metabolism ol
`. BREVl8LOc° is not limited
`by the rate ol blood llow to metabolizing tissues such as the liver.or aliected by hepatic
`a
`ut minutes.
`-
`orbgenasl blood llow. BliEVl8LOC° has a rapid distribution hall-tile oi about 2 minutes and an eltminationhall-lite ot
`Using an appropriate loading dose. steady-state blood levels oi BliEVlBLOc° tor dosages lrom 50-300 moglkglmin
`are obtained within live minutes. (Steady-stale is reached in about 30 minutes withutt the loading dose.) Steady-
`state blood levels at BHEVlBLOc° increase linearly over this dosage range and elimination kinetics are dose-
`independenl over this range. steady-state blood levels are maintained during intusion but decrease rapidly alter
`termination of the inlusion. Because at its shirt halt-lite. blood levels at BREVlBLOC° can be rapidly altered by In-
`creasing ordecreasing the inlusion rate and_rapidly'eliminated by discontinuing the inlusion.
`_ Consistent with the high rate at blood-based metabolism ol.BRE\llBLOC', less than 2% ol the drug is excreted un-
`changed in the u'rine._within' 24 hours ofthe end oi inlusion. approximately 73-88% oi the dosage has been account-
`’
`ed lot in the urine as the acid metabolite oi BREVlBLOc'.
`Metabolism oi BHEVIBLOC5 results in the lormatlon oi the corresponding tree acid and methanol. The acid metabo-
`lite has been shown in animals to have about 1I1500th the activity ol esmolol and in normal volunteers its blood
`levels do not correspond to the level at beta-blockade. The acid metabolite has an elimination hall-lite ol about 3.7
`hours and is excreted in the urlnefwith a clearance approximately equivalent to the glomeruiar tiltrationrate. Excre-
`'tion oi the acid metabolite is slgnllicantty decreasedin patients with renal tftsease. with the elimination hall—iile in-
`creased to about ten-told that o normals; and plasma levels considerably elevated.
`.
`Methanol blood levels. monitored in sublects receiving BHEVIBLOCO lor up to 6 hours at -300 mcglkglmin and 24
`met an
`toxicity.
`-
`'
`houas atfll 50 mcglkglmin. approximated endogenous levels and were less than 2% at levels usually associated with
`BHE\_IlBL0(-)0 has bee'n'shown to be 55% bound to human plasma protein. while the acid metabolite is only 10%
`bound.
`'
`'
`'
`-
`
`_
`_
`Phatlucedyaantict
`Clinical pharmacology studies in normal volunteers have conlirmed the beta blocking activity oi BREVlBLOC' (es-
`moioi Hcli. showing reduction in heart rate at rest and during exercise. and attenuation at lsoproterenol-induced in-
`creases in heart rate. Blood levels.ol BREVlBLOc° have been shown to correlate with extent at beta blockade Alter
`termination oi inlusion. substantial recovery trom beta blocltadeis observed in 10-20 minutes
`in humanelectrophysiology studies. BREVIBLOCO produced ettccts typical ot a beta blocker: a decrease in the
`heart rate, increase in sinus cycle length. prolongation oi the sinus node recovery time. prolongation ot the AH inter-
`val during normal sinus rhythm and during atrial pacing. and an increase in antegrade Wenclrebach cycle length.
`in patients undergoing radionuclide angiogtaphy. BREVIBLOCO. at dosages at 200 mcglkglmin.
`reduced reduc-
`tions inheatt rate, systolic blood pressure. rate pressure product. tell and right ventricular election raction and car-
`diac_ index at rest, which were similar in magnitude to those produced by intravenous propranolol (4 mg). During ex-
`ercise. 8HEViBLOC° produced reductions. in heart rate. rate pressure product and cardiac index which were also
`simllarto those produced by propranoloi. but produced a significantly larger tall in systolic blood pressure. in pa-
`tients undetgoingcardiac catheterizatldn. the maximum therapeutic despot soc ltluglhglttiitr ul ont'.vtoi_.oo- plu-
`duced similar etlccts. and, in addition. there were small. ctinicallylnsignrlnztnt. increases In the Ielt ventricular and
`diastolic pressure and
`lmonary capillary wedge pressure. At thirty minutes alter the discontinuation of
`BREVlBi;0C° inlusion. at oi the hemodynamic parameters had returned to pretreatment levels.
`-
`The relative cardloselectivity oi BliEvlBLqc° was demonstrated in _10 mildly_asthm_atic pattenls._lnlustons oi
`BREVlBL_0_C° (100. 200 and 300 mcglkglmtn) produced no significant increases in specttic airway resistance com_—
`pared to placebo. At 300 mcglkglmin. BflEVl_t!L0p° produced slightly enhanced bronchomotor Sel'lSiIiVlIy to dry air
`stimulus. These ettects were not clinically significant. and BHEVlBLOc' was well tolerated by all patients. six oi
`the patients also received intravenous propratiolol. and at a dosage of 1 mg. two experienced significant. _svmo-
`tomatic bionchosliasm reoulfino I>f0iIchod_itator treatment. one other propranoiol-treated patient also experienced
`dry air-induced broncttospasm. No adverse pulmonary ettects were observed ll'llI33I'9"I5 tflilfl 305’? WI“? ’°°°'V_°d
`therapeutic dosagesol BltEVlBLOc° tor treatment ol supraventncular tachycardia (St patients) or in penoptrattve
`settings (32 patients).
`
`MYLAN ET
`
`00001
`AL. — EXHIBIT 1009
`
`MYLAN ET AL. - EXHIBIT 1009
`
`0001
`
`

`
`V
`_
`given with wartarin, but this is'not_like_iy _to b_gctinicaily__irn_port_ant.
`Whemdbexin-oIdifiGliBt!D'€
`(esmoloi HGT) were concomitantly administered intravenously to-normal volunteers.
`ere was-a 10-20% increase i digoxin blood levels at some time points. Digoxin did not aiiect BREVIBLOCO phar-
`acokir1gfi_g‘s,tV]i.fi;firj§,:;Qveno morphine and I3REVIB_LOC' were concomitantly administered in normal subjects.
`eitect ‘on morphine load I
`is was seen, _but BREVlBLOC° steady-state blood levels were‘ increased by 46% in
`presence at morfihine. goo er pharmacokinetic parameters were changed.
`_
`tjem __
`u
`_
`_ _on the duration ot succinylcholine-induced neuromuscularblockade was studied in pa-
`t ndw oitlg s_fli. cry. The onset or neuromuscular blockade byssuccinylchotine was unatlected by
`EEOC‘. but thedu ation oi neuromuscular blockade was prolonged trom Sminutes tu8 minutes.
`B
`Although the interactions observed in these studies do not appear to be or maior clinical importance. BREVIBLOCD
`W3 ar n.
`'
`'
`shorrérldlbe titrated with caution in patients being treated concurrently with oigoxin. morphine, succinylchotine or
`carcinogenesis. flute emit. lII_|IlH'lItbIl at Fertility
`Because or its shon erm usage no carcinogenicity. mutagenlcity or reproductive pertormance studies have been
`conducted with BREVIBLOC‘.
`
`mgnlcy Clllflflfl ti
`. Teratogenicity studies in rats at intravenous dosages oi BREVIBLOCO up to 3000 mcglkglmin Iten times the maxi-
`mum humanmaintenance dosage) lor 30 minutes daily produced no evidence oi maternal toxicity. embryotoxicity
`or teratogenicity. white a dosage ot i_ 0.000 meg/kg/min produced maternal toxicity and lethality. In rabbits. intrave-
`nous dosages up to 1000 rncglltg/min tor 30 minutes daily produced no evidence of maternal toxicity. ernbryotoxici-
`ty or teratogenicity. white 2500 mcg/kglmin produced minimal maternal toxicity and increased ietat resorptions
`There are no adequate and well controlled studies in pregnant women. BREVlBLOC° should be used during
`pregnancy only it the potential benefit iustities the potential risk to the lotus.
`luraien flutters
`.
`it is not known whether BREViBLOC° is excreted in human milk, however, caution should be exercised when
`BREVIBLDCO is adrninisteredrto a nursing woman.
`reliable tin
`.
`The safety and eitectiveness or BiiEViBLOC° in children have not been established.
`lt|VEflS_E_ IIEIIITIOIS
`. Supnmtrtcrriar Tachycardia
`The ioiiowing adverse reaction rates are based on use at BREVlBLOC' tesmoloi HCII In almost 400 ctinil trial pa-
`tients with supraventricuiar tachycardia in addition. over 600 patients have been‘ exposed in clinical studies at
`other conditions. The most ‘important adverse‘ etteci has been hypotension (see Warnings). Most adverse eliects
`have been mild and transient.
`-
`'
`‘
`liarrilmlcrrilr - Symptomatic hypotension (diaphoresis. dizziness) occurred in 12% or patients; and therapy was
`discontinued in about tt%. about hail of whom were.symptomatic. Asymptomatic hypotension occurred in about
`25% or patients Hypotension resolved during BREVIBLOCO infusion in 63% or these patients and within 30 minutes
`alter discontinuation oi inlusion in 80% at the remaining patients. Diaphoresis accompanied hypotension in 1076 of
`items Peripheral ischemia occurred in approximately 1% oi patients. Paiior. tlushing. bradycardia (heart rate
`ess than 50 beats per minute); chest pain. syncope. pulmonary edema and heart block have each been reported in‘
`less than 1% at patients. In two patients without supraventricular tachycardia but with serious coronary artery dis-
`ease (post interior myocardial intarction or unstable angina). severe bradycardialslnus pauselasystole has devel-
`oped. reversible in both cases with discontinuation oi treatn_rent.
`-
`-
`clntnt ttenrm 8 tut ,— Dizziness has occurred in 3% or patients; somnolence in 3%. contusion. headache. and agi-
`tation in about 2 , and tatig_ue in about 1% ct patients. Paresthesia. asthenia. depression. abnormal thinking. anxi-
`ety, anorexia. and lightheadedness were reported in less than 1% or patients One briet (30 second) episode or grand
`mat seizure has been reported.
`Iuplralory —— Bronchospasm. wheezing. dyspnea. nasal congestion. rhonchi, and rates have each been reported in
`less than 1% ct patients.
`_
`_
`_
`._
`Intrcietuttni — Nausea was reported In 7% ol patients Vomiting has occurred in about 1% or patients". Dyspepsia.
`constipation. dry mouth. and abdominal discomlort have each occurred in less than 1% at patients. Taste perversion
`has also beenlreported.
`'
`-
`Ilrie Iieiuriee Siirl — inlusion site reactions including intlammation and lnduratlon were reported In about 895 or pa-
`tients Edema. erythema. skin discoloration, and burning at the inlusion site have each occurred in lesslhan iii of
`patients.
`_
`_
`.
`Itirceilroem 7 Each oi the totiowing has been reported in less than 1% oi patients: Urinary retention. speech disor-
`der. abnormat vision, mtdscapuier pain, rigors. and-tever.
`'
`'
`IIIEBIIDSAEE
`Acute Toxicity
`A lew cases oi massive accidental overdosage oi BREVIBLOCP (esmolol .HCit have occurred-due to errors in dilution.
`. These intravenous bolus doses oi BREVIBLOCO oi 5000-6250 mcglkg over 1-2 minutes have produced hypotension.
`bradycardia, drowsiness and loss or consciousness The eilecis have resolved within to minutes, in some cases
`with administiation ot a pressor agent.
`Because of its approximately 9-minute elimination halt-lite. the first step in the management of toxicity should be
`to discontinue the'8REVtBLOC° inlusion. Then. based on the observed clinical ettects. the following general mea-
`sures should also be considered:
`lruycerllr: intravenous administration oi atropine or another anticholinergic drug.
`Ireactespunz intravenous administration or a beta, stimulating agent and/or a theophyiilne derivative.
`tlrllrc Flllm: Intravenous adrninistratian or a diuretic andlor digitalis glycoside. in shock resulling'trorn inade-.
`quate cardiac contractility, intravenous administration oi dopamine, dobutamine. isopraterenal. or amrinone may be
`considered.
`>
`-
`iyupteutie llypotmlee: intravenous administration or iluids andlor pressor agents
`,
`ogs_r%irrro ilorirrirrsrnerrorr
`I
`Ti'lE'2.5 g AMPUL IS NOT FOR DIRECT INTiiAVENOu_s INJECTION. THIS DOSAGE FORM is A CONCENTRATED.
`WI
`0_
`B A
`O ATE. BREVIB 00° SHOULD NOT BE MIXED WITH OTHER DRUGS PRIOR TO DILUTION IN
`Pogfiiy
`%lLisT BE DIL%_TEI_J PRIOR TO ITS INFUSION. BiiEVlBLOC° SHOULD NOT BE ADMIXED
`A SUITABLE INTRAVENOUS FLUID. (See compatibility Section below.)
`Ililtiu: Asepticaily prepare a 10 mgImL intusion. by adding tw_o 2.5 g ampuls to a 500 mL container. or one 2.5 g
`ampul to a 250 mL container. at a compatible intravenous solution listed below. (Remove average prior to dilution as
`appropriate). This yields a iinal concentration or to mgImt.. The diluted solution is stable tor at least 24 hours at
`room temperature. Note: concentrations at BREViBLOC° greater than 10 mgImL are likely to produce irritation on
`,ra v n.
`....— ,...-.' _,a...
`ttnorrtirgled inlusion (see Precautions). BREVlBLOc° has',’however, been welltolerated when administered‘via a cen-
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`Stiprmatrlcuiar Tachycardia
`In two multicenter, randomized, double-blind, controlled comparisons oi BREV|BLElC° (esmolol llCli with placebo
`and propranolol. maintenance doses of 50 to 300 mcg/kglmin oi flliEVl8LOC° were lound to be more ellective than
`placebo and about as eilective as propr‘anoiol.'3-G mg given by bolus injections. in the trwtmenl oi supraventricular
`tachycardia. principally atrial lihriilatlon and atrial llulter. the majority ol these patients developed their arrhyth-
`mias posloperativeiy. About 60-70% ol the patients treated with BREViBLOc° had a desired therapeutic ellect
`(either a 20% reduction in heart rate. a decrease in heart rate to less than too bpm. or. rarely. conversion to NSRI
`and about 95% at those who responded did so at a dosage oi 200 mcg/kglmin or less. The average ellective dosage
`oi BREViBLOC° was approximately 100-115 mcglkglmin in the two studies. Other multlcenter baseline-controlled
`studies pave essentially similar results in the comparison with propranoiol. about 50% oi patients in both-the
`BREVlBLOC° and propranoiol groups were on concomitant digoxin Response rates were slightly higher with both
`beta-blockers in the digoxin-treated patients.
`»
`in all studies signilicanl decreases cl blood pressure occurred in 20-50% oi patients, identilied either as adverse
`reaction reports by investigators. or by observation at s stolic pressure ias than 90 mmHg or diastolic pressure
`less than 50 mmHg. The hypotension was symptomatic erlnainiy diaphoresis or dizziness) in about 12% ct patients.
`and therapy was discontinued in about 11% ct patients, about hall oi whom were symptomatic: in comparison to
`propranolol, hypotension was about three times as lrequent with BllEVlBLOC°, 53% vs. 17%. The hypolension was
`rapidly reversible with decreased infusion rate or alter rliscontinuation oi therapy with BllEVlBLOC'. For both
`BflEvl8L0c° and propranoloi. hypotension was reponed less ireoueitly in patients receiving concomitant digoxin.
`IIDIGATIIINSAMII USAGE
`'
`_
`"
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`ventricular Tachycardia
`.
`B EViBLOC' (esmolol HCi)' is indirzted tor the rapid control oi ventricular rate in patients with atrial iibriliatton or
`atrial tlut_ter in perioperative. postoperative. or other emergent circumstances where short term control at ventricular
`rate with a shon-acting agent is desirable. BREVIELOC‘ is also indicated in noncompensatory sinus tachycardia
`where. in the physician's judgement. the rapid heart rate requires specific intervention. BliEViBLOC° is not intended
`tor use in chronic settings where transter to another agent is anticipated.
`'
`.
`.
`corrrnntrrotcartons
`_
`BHEVIBLOC“ (esmolol Hcll is contraindicated in patients with sinus bradycardia. heart block greater than lirst
`degree, cardiogenic shock or overt heart lailure (see Wamingsi:
`VRIIIIINGS
`ilypatmianz in clinical trials 20-50% oi patients treated with BREVIBLOCO (esmolol Hcli have experienced hypoten-
`sion. generally dellned as systolic pressure less than 90 mmlig and/or diastolic pressure less than 50 mmHg. About
`12% ol the patients have been symptomatic (mainly diaphoresis or dizziness). llypotension can occur at any dose"
`but is dose-related so that doses beyond 200 mcglkgimln are not recommended. Patients _should be closely moni-
`tored. especially ll_pretreatment blood pressure is low. Decrease oi dose or termination of intusion reverses hypoten-
`slon. usually within 30 minutes
`'
`Carlin Fallm: Sympathetic stimulation is necssary in supporting circulatory function in'congestiva heart lailure,
`and beta blockade carries the potential hazard oi lurther depressing myocardial contractility and precipitating more
`severe lailure. Continued depression at the myorardium with beta blocking agents over a period oi time can. in
`some cases. lead to cardiac lailure. At the first sign or symptom ol impending cardiac lailure. the dosage should be
`reduced or BHEViBLOC' should be withdrawn. Although this dosage adiustment or withdrawal may be sulticient
`aoe— -
`'
`.
`beca)use oi the short elimination hall-lite at BFl£ViBLOG°. speciiic treatment may also be considered. (See Overdos-
`lrmiinxputt: fllnuu: l'AllEliTl Willi Inlillliilltsrlstill IJISEASES slltttllll. II sEilEllAl.
`lllit
`llEt:EllE IEIA
`lltllllili. Because oi its relative beta, selectivity and tltratabiiity. Bi'tEVIBLOc° may be used ‘with motion in pa-
`tients with bronchospastic diseases. However. since beta. selectivity is not absolute, BiiEVlBLOC° should he care-
`luiiy titrated to obtain the lowest possible etleclivc dose. in the event at bronchospasm. the intusion should be ter-
`minaled immediately; a beta, stimulating agent may beadministered it conditions warrant butshould be "used with
`particular caution as patients already have rapid ventricular rates.
`limln lalliln and it aglyunla: BREVIBLOCO should be used with caution in diabetic patients requiring a beta
`blocking agent. Beta b ockers may mask tachycardia occurring with hypoglycemia. but other manilestatlcris such
`as dizliness and sweating may not he signiiicantiy aliected.
`.
`PHEGMITIIIIIS
`.
`.
`General
`intusion concentrations cl 20 rngImi._ were asociated with more venous irritation and thrombophiebltis than con-
`centrations ot 10 mglmL. Concentrations greater than 10 mgImL should, therelore. be avoided.
`.
`.
`Because the acid metabolite oi BltEVlBLOC° is primarily excreted unchanged by the kidney. BREVlBLOc' (esmolol
`HCI) should be administered with caution to patients with impaired renal lunction. The elimination hail-tile oi the
`acid metabolite was prolonged ten-told and the plasma level was considerably elevated in patients with end-stage
`renal disease
`.
`‘
`.
`'
`ling iataractlm
`catecholamine-depleting drugs, e.g., reserpine. may have an additive ellect when given with beta blocking agents
`Patients treated concurrently with BltEVlBLOc' and a catecholamine depletor should therelore be closely observed
`tor evidenm oi hypotension or marked bradycardia. which may result in vertigo. syncope. or postural hypotension.
`it study of interaction between BREWBLOC0 and wartarin showed that concomitant administration oi BHEVtBi.0cI
`and warlarln does not alter wartarin plasma levels BREVlBLOC° concentrations were equivocally higher when
`
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`This tfosage iorm is prediiuted to provide a ready-to‘-"use l0 mglmt concentration recommended for Brevibior:° in-
`travenous administration. it may be used to administer the appropriate Brevibloc' loading dosage infusions by
`hand-held syringe while the maintenance infusion is being prepared.
`’
`I
`_
`ilolrnvanlrievllr Tachycardia
`in the treatment of supraventricutar tachycardia. responses to BREVIBLOC° usually (over 9596) occur within the
`range of 50 to 200 mcglkglrliin. The average eltective dosage is approximately 100 mcglkglmin although dosages
`as low as 25 mcglkglmin have been adequate in some patients. Dosages as high as "300 mcgllrglmin have been
`used. but these provide little added effect and an increased rate oi adverse "effects. and are not recommended.
`Dosage of BREVlBLOC° in supraventricular tachycardia must be individualized by titration _in which each step _con-
`. sisis of a loading dosage followed by a maintenance dosage.
`To initiate treatment of a patient with supraventricular tachycardia, administer a loading dosage infusion of 500
`mcgikglmin oi BREVIBLOCD for one minute ioiiowed by a-4 min maintenance infusion of 50 mcglkglmin. ii an ade-
`quate therapeutic eliect is not observed within five minutes. repeat the same loading dosage and follow with a main-
`tenance inluslon increased to 100 mcglkglmin.
`Continue titration procedure as above. repeating loading infusion (500 mcgllrglmin for 1 minute}. increasing main-
`tenance intusion by increments of 50 meg/irgl min (for 4 minutes). As the desired heart rate or a salety end-point
`(e.g., lowered blood pressurei is approached. omit the loading intusion and reduce incremental dose in maintenance
`intusion from 50 mcglirglmln to 25 mcg/kglmin or lower. Also. if desired. increase interval between titration steps
`from 5 to 10 minutes.
`This specific dosage regimen has not been studied intraoperatively and. because of the time required for titration.
`may not be optimal for intraoperative use.
`7
`-
`Maintenance dosages above 200 meg/kglmin have not been shown to have signlticantiy increased benefits. and the
`safety of dosages above 300 mcglkglmin has not been studied.
`In the event of an adverse reaction, the dosage of BREVIBLOCO may be reduced or discontinued. it a focal infusion
`site reaction develops. an alternative infusion site should be used. The use of butteriiy needles should be avoided.
`Abrupt cessation of BREVlBLOC° in patients has not been reported to produce the withdrawal effects which may
`occur with abrupt withdrawal of beta blockers following chronic use in coronary artery disease (CAD) patients. How-
`ever, caution should still be used-in abruptly discontinuing infusions of BREVlBLOC° in CAD patients.
`After achieving an adequate control of the heart rate and a stable clinical status in patients with supraventricuiar
`tachycardia. transition to alternative antiarrhythmic agents such as propranoioi. digoxin. or verapamii. may beac-
`complished. A recommended guideline for such a transition is given below but the physician should carefully con-
`sider the labeling instructions for the altomative agent-selected:
`.
`.
`Altarnfln mat
`ilmgl
`,
`,
`Propranoiol hydrochloride
`10-20 mg ‘g 4-6 h
`Digoxin _
`O.l25-0.5 mg q 6 h (pp. or i.v.)
`Verapamii
`80 mg q 6 h
`The dosage of BREVIBLOCO should be reduced as follows:
`i. Thin gr’I‘r;utes following the first dose of the alternative agent. reduce the initsion rate‘of BREViBLOC' by one-
`haii 5
`.
`'
`2. Following the second dose of the alternative agent. mmitor the oatlent's response and if satisiactory control is
`maintained for the first hour. discontinue BREViBLOC°
`The use of infusions oi BREVIBLOCO up to 24 hours has been well documented; in addition. limited data irorn 24-48
`hrs iN=4D) indicate that BREViBLOC'- _is'w'eI| tolerated up to 48 hours.
`.
`.
`_
`_
`.
`-
`can ali_Illii1 will count llnl lntrumrrn Fluid:
`-
`BR
`lBLDC' (esrnoloi HCl
`lNJECTiON was tested for compatibility with ten commonly used intravenous fluids _at
`a final concentration of to mg esmolol _HCl per mL BREVIBLOCO INJECTION was found to be ccrnpatibie with the
`ioliowi_n_g solutions and was stable for at least 24 hours at controlled room temp'erature_or under refrigeration:
`’
`y
`'
`Dextrose (5%) Injection. USP
`-
`Dextrose (5%) in Lactated Ringer's injection
`Dextrose (5%) in Ringers in action
`Dextrose (5%) and Sodium hioride (0.45%) injection. USP
`Dextrose (5%)_ and Sodium Chloride (0.9%) iniection. USP
`_-
`Lactated Ringers in ectidn. USP
`"
`_
`_
`Potassium Chloride 40 mEqIlite'r) in Dextrose (5%) injection. use
`Sodium Chloride (0.45%) Injection. USP
`Sodium Chloride (0.9%) injection. USP
`8REVlBLDC' INJECTION was NOT compatible with Sodium Bicarbonate (5%) injection. USP.
`ttato: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to admin-
`istration. whenever solution and container permit.
`‘
`'
`lfflill SUPPLIED" .
`NDC 0094-0015-7i. lilo mg — 10 mL vial. Box of 20
`.
`NDC 0094-00254 8. 2.5 g -— iii mL ampui. Box of 10
`STORE AT CONTROLLED ROOM TEMPERATURE (59‘-86‘F. l5‘-30‘C). Freezing does not adversely aftect the prod-
`uct. but exposure to elevated temperatures should be avoided.
`.
`' no not Pharmaceuticals
`E. t du Pontdo Nemours and Company .
`lMlrn_ing_ton. Delaware 19898
`--—---
`Date: May. 1988
`.
`
`.
`
`_
`I M3049.
`
`0004
`
`0004