CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICA TI0N NUMBER:
`
`19-386/8010
`
`Trade Name:
`
`' Brevibloc lOOmg/lOrnL and 2.5g/10ml ampule
`Injection
`
`‘ Generic Name: EsmolOl Hydrochloride
`
`Sponsor:
`
`Anaquest Inc. ‘
`
`Approval Date:
`
`July 1, 1993'
`
`' Indications:
`V
`
`.
`
`'
`
`Short-Term control of heart rate in patients
`with abnormally fast heart rhythms such as
`artrial fibrillation, atrial flutter or sinus
`' tachycardia.
`'
`'
`
`‘
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`19-386/S010
`
`-. CONTENTS
`
`
`
`.
`
`I Reviews / Information Included in this NDA Review.
`
`
`
`
`
`'
`
`
`
`
`
`
`
`
`A: roval Letter
`A rovable Letter
`
`Labelin_
`
`Medical Review s
`
`Chemist" "Review s
`
`Pharmacolo Review s)
`Statistical Review s
`'
`
`
`
`
`
`
`‘ -Microbiolo' Review 8
`
`
`
`, Clinical Pharmac010_ '
`harmaceutics Review s ‘
`
`
`
`Administrative/Corns 7
`ondence Document s)
`
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`-
`RESEARCH .
`
`APPLICA TI0N NUMBER:
`19#386/S010
`
`APPROVAL LETTER
`
`

`

`
`
`‘
`
`Public Health Service
`i DEPARTMENT OF HEALTH 8?. HUMAN SERVICES
`
`
`Food and Drug Administration
`Rockville MD 20857
`
`NDA '19-386/8-010
`
`Anaquestlnc.
`Attention: Ms. Brenda Marczi
`110 Allen Road
`
`Liberty Corner, NJ 07938-0804
`
`Dear Ms. Marczi:
`
`'
`
`'
`
`JUL
`
`-
`‘993
`
`l
`
`We acknowledge the receipt on June 2,- 1993 of your June 1. 1993 supplemental-new drug
`application submitted under section 505(b)(1) of the Federal Food. Drug, and Cosmetic Act for
`Brevibloc (esmolol H01) 100 mg/10 ml vial and 2.5 g/10 ml ampule Injection.
`
`.The supplemental application provides for final printed labeling revised as follows:
`
`Under the PRECAUTIONS/Pregnancy Category C subsection the first
`1.
`sentence of the second paragraph has been revised to read as follows:
`
`Although there are no adequate and well controlled studiesvin
`pregnant women, use of esmolol in the last trimester of pregnancy
`or during labor or delivery has been reported to cause fetal
`bradycardia, which continued after termination of drug infusion.
`Brevibloc should be used during pregnancy only if the potential
`benefit justifies the potential risk to the fetus.
`
`2.
`
`The name and address of the sponsor has been changed to:
`
`Anaquest Inc.
`110 Allen Road
`
`PO Box 804
`,Liberty Corner, NJ
`
`.
`
`_
`07938-0804
`
`.
`
`A subsidiary of 800 Health Care Inc
`800 Health Care
`
`We have completed the review of this supplemental application and it is approved.
`
`‘
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 314.81.
`_
`
`

`

`Page 2 - NDA 19-386/8-010
`
`Should you have any questions, please contact:
`
`Ms. Zelda McDonald
`Consumer Safety Officer
`Telephone:
`(301) 443-4730
`
`Sincerely yours.
`
`a x 71w;
`
`Raymond J. Lipicky, MD.
`Director
`'
`
`Division of Cardio-Renal Drug Products
`Office of Drug Evaluation |
`Center for Drug Evaluation and Research
`
`C: Original NDA
`HFD-110
`HFD—110/CSO
`
`3
`
`HFD-80/DDl-R
`HFD-232 (with labeling)
`.
`HFD-t10/ZMcDonald/6/t-5/93:6/16/93 3,," 9/30 Mg,
`sb/6/15/93:6/30/93
`‘
`_
`RID:
`.RWolt'ers/6/21/93
`CResnick/6/21l93.
`.SChen/‘6/21/93
`
`.
`
`.
`
`NMorgenstern/6/30/93
`
`Approval Date:- December 31‘. 1986
`
`APPROVAL
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`19-386/8010
`
`LABELING
`
`

`

`BREVIBLOC® INJECTION (esmolol hydroChloride)
`:IIATTOAgflngg?INTRAVENOUS INJECTTON. AMPULMUST BE DILUTEDPRIOR TOITS INFUSION -SEE DOSAGEANDADMINISTRATION.
`10 mL Single Dose Vial—100 nlg
`
`-
`.
`:-.
`»
`,
`.
`DESCRIPTION
`BHEVIBLOC (esmolol HCI) is a betarselective (cardioselecllve) adrenergic receptor blocking agent with a very short duration 01 action
`(elimination hall-lite is approximately 9 minutes). Esmolol Hells:
`.
`.
`».
`'
`'
`
`(it-Methyl p[2—hydroxy-a-Gsopropylamino) propoxy] hydrocinnamate hydrochloride and has the following structure:
`CHJOzCCIIzCHz'ocuzcllollcnzllllcmcrlg2-HCI
`Esmolol HCI has the empirical-lormula ClstsNdfil and a molecular weight-cl 331.8. It has one asymmetric center and-'exists-a‘s an
`'
`.-
`'.
`.
`.
`-
`7
`enantiomeric pair.
`.
`
`It is a relatively hydrophilic compound which is very soluble in water and 'Ireely
`Esmolol HCI is a white to oil-white crystalline powder.
`soluble in alcohol. Its partition coellicient (octanolMater) at pH 7.0 is 0.42 compared to 17.0 for propranolot.
`BREVIBLOCJNJECNdN is a clear, colorless to light yellow, sterile, nonpyrogenic solution.
`2.5 g, 10 mL Ampul—Each mL contains 250 mg esmolol HCI in 25% Propylene Glycol, USP, 25% Alcohol, use and Water lor Injection,
`USP: buttered with 17.0 mg Sodium Acetate, USP, and 0.00715 mL Glacial Acetic Acid, USP. Sodium hydroxide and/or hydrochloric acid
`added, as necessary, to adjust pH to 3.5-5.5.
`.
`
`100 mg, 10 mL Single Doselfial—Each mL contains 10 mg esmolol HCI and Water lor- Injection, USP; buffered with 2.8 mg Sodium Acetate,
`USP and 0.546 mg Glacial Acetic Acid, USP. Sodium hydroxide and/or hydrochloric acid added ,-as necessary to adjust pH to 4.55.5:
`-
`CLINICAL PHARMACOLOGY
`'
`EHEVIBLOCis a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a very short duration of action, and
`no significant intrinsic sympathomimetic or membrane stabilizing activity at therapeutic dosages. Its elimination halt-lite after intravenous
`infusion is approximately 9 minutes. BHEVIBLOC inhibits the beta1 receptors located chiefly in carrfiac muscle. but this preferential effect is
`not absolute and at higherdoses it begins to inhibit betaz receptors located chiefly in the bronchial and vascular musculature.
`.
`Pharmacoklnetlcsand Metabolism
`
`Using an appropriateloalfing dose, steady-state bloodlevels ot BREVIBLOC lor dosages from 5&300 mog/kglmin (.0503 mglkg/min) are
`obtained within five minutes. (Steady-state is reached'in about 30 minutes without the loading dose.) Steady-state blood levels of
`
`Consistem with’the high rate at bloodbased metabolism ol 'BFIEVIBIDC, less than 12% of the drug is excreted unchanged in the mine.
`Wlthin 24 hours of tlle end at intusion, approximately 734387. of the dosage has been amounted lor in the urine as the acid metabolite oi
`BREVIBLOC.
`.
`-
`.
`7
`._
`Metabofism ol BHEVIBLOC results in the lonnatl'on at the corresponding free acid and methanol-The acid metabolite has been shown in
`animals to have about1l1500th the activity of esmclol and in normal volunteers its blood levels do not correspond to the level ol beta
`
`Methanol blood Ieliel‘s, monitored in subjects receiving BREVIBLOC for up to 6 hours at 300_mcglkglmin (0.3 mg/kg/min) and 24 hours at
`150 mcglltglmin (0.15 mglkglmin), approximated endogenous levels and were less than 2% ol levels usually associated with methanol
`toxicity.
`'
`.
`'
`'
`'
`
`BHEVIBLOC has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.
`.
`Pharmacodynamtcs’
`.
`.
`Cfiniml pharrnacolcgy studies in normal volunteers have confirmed the beta blocking activity at BREVIBLOC, showing reduction in heart
`rate at rest and during exercise, and attenuation ol isoproterenol—irlduced increases in heart rate. Blood levels of BREVIBLOC have been
`shown to correlate with extent at beta blockade. Alter termination of inlusion, substantial recovery from beta blockade is observed in 10-20
`minutes.
`,
`-
`,
`'
`-
`_
`
`In patients undergoing radionuclide angiography, BREVIBLOC, at do ges at 200 moglkglmin (0.2 mg/kglmin), produced reductions in heart
`rate, systolic blood pressure, rate pressure product, left and right ventricular ejection traction and cardiac index at rest, which were similar in
`magnitude to those produced by intravenous propranotol (4 mg). During exercise, BREVIBLOC produced reductions in heart rate rate
`pressureproduct and cardiac index whichwere also similar to those produced by propranolot, but produced a significantly larger (all in
`
`
`
`
`
`

`

`.
`‘
`Supraventricular Tachycardia
`In two multicenter. randomized. double-blind, controlled comparisons of BREVIBLOC with placebo and propranolol, maintenance doses of
`50 to 300 mcglkg/min (0.05 to 0.3 mglkglmin) of BREVIBLOC were found to be more eltective than placebo and about as effective as
`propranolol. 345 mg given by bolus iniections. in the treatment of supraventricular tachycardia. principally atrial fibrillation and atrial tlutter.
`The majority of these patients developed their arrhythmias postoperatively. About 60-70% at the patients treated with BREVIBLOC had a
`desired therapeutic ettect (either a 20% reduction in heart rate. a decrease in heart rate to less than 100 bpm. or. rarely. conversion to NSR)
`and about 95% of those who responded did so at a dosage at 200 moglkglmin (0.2 mg/kg/min) or less. The average effective dosage of
`BREVIBLOC was approximately 100415 mcglkg/min (0.1-0.1l5 mglkg/min) in the two studies. Other multicenter baselinecontrolled
`studies gave essentially similar results. In the comparison with propranolol, about 50% of patients in both the BREVIBLOC and propranolol
`groups were on concomitant digoxin. Response rates were slightly higher with both beta blockers in the digoxin-treated patients.
`In all studies significant decreases of blood pressure occurred in 20-50% of patients, identified either as adverse reaction reports by
`investigators. or by observation of systolic pressure less than 90 mmHg or diastolic pressure less than 50 mmHg. The hypotension was
`symptomatic (mainly diaphoresis or dizziness) in about 12% of patients. and therapy was discontinued in about 11% of patients. about half
`of whom were symptomatic. In comparison to propra'nolol. hypotension was about three times as frequent with BREVIBLOC. 53% vs. 17%.
`The hypotension was rapidly reversible with decreased infusion rate or alter discontinuation ot therapy with BREVIBLOC. For both
`BREVIBLQC and propranolol, hypotension was reported less frequently in patients receiving concomitant digoxin.
`-
`INDICATIONS AND USAGE
`Supraventrlcular Tachycardia
`BREVIBLOC is indicated for the rapid control at ventricular rate in patients with atrial librillation or atrial flutter in perioperative.
`postoperative. or other emergent circumstances where short term control at ventricular rate with a short-acting agent is desirable.
`BREVIBLOC is also indicated in noncompensatory sinus tachycardia where. in the physician's judgment. the rapid heart rate requires
`specific intervention. BREVIBLOC is not intended tor use in chronic settings where transler to another agent is anticipated.
`lntraoperative and Postoperative Tachycardia and/or Hypertension
`BREVIBLOC (esmolol HCI) is indicated lor the treatment of tachycardia and hypertension that occur during induction and tracheal
`intubation, during surgery. on emergence from anesthesia, and in the postoperative period. when in the physician's judgment such specific
`intervention is considered indicated.
`.
`
`Use of BREVIBLOC to prevent such events is not recommended.
`_
`CONTRAINDICATIONS
`BREVIBLOC is contraindicated in patients with sinus bradycaro'la. hean block greater than first degree. cardiogenic shock or oven heart
`failure (see WARNINGS).
`'
`WARNINGS
`Hypotenslon: In clinical trials 20-50% at patients treated with BREVIBLOC have experienced hypotension. generally defined as systolic
`pressure less than 90 mmHg and/or diastolic pressure less than 50 mmHg. About 12% of the patients have been symptomatic (mainly
`diaphoresis or'dizziness). Hypotension can occur at any dose but is dose-related so that doses beyond 200 mcglkglmin (0.2 mg/kglmin) are
`not recommended. Patients should be closely monitored. especially if pretreatment blood pressure is low. Decrease of dose or termination of,
`infusion reverses hypotension. usually within 30 minutes.
`Cardiac Failure: Sympathetic stimulation is necessary in supporting circulatory tunction in congestive heart failure. and beta blockade
`carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. Continued depression at the
`myocardium with beta blocking agents over a period of time can. in some cases, lead to cardiac failure. At the first sign or symptom of
`impending cardiac failure. BREVIBLOC should be withdrawn. Although withdrawal may be sufficient because of the short elimination hall-
`lite ct BREVIBLOC, specific treatment may also be considered (see OVERDOSAGE). The use of BREVIBLOC for control of ventricular
`response in patients with supraventricular arrhythmias should be undertaken with caution when the patient is compromised
`hemodynamicatly or is taking other drugs that decrease any or all of the following: peripheral resistance. myocardial filling. myocardial
`contractility. or electrical impulse propagation in the myocardium. Despite the rapid onset and otfset of the effects of BREVIBLOC, several
`cases of death have been reported in complex clinical states where BREVIBLOC was presumably being used to control ventricular rate.
`
`lntraoperative and Postoperative Tachycardia and/or Hypertension: BREVIBLOC should not be used as the treatment for hypertension
`inpatientsinwhomtheMeasedbboduessweispnnarfiydnmfiewsommmaionassodatedmmhymmma.
`Bronchospastlc Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL. NOT RECEIVE BETA
`BLOCKERS. Because of its relative beta1 selectivity and titratabilitv. BREVIBLOC may be used with caution in patients with bronchospastic
`diseases. However. since betai selectivity is not absolute. BRE\ .. '.00 should be carefully titrated to obtain the lowest possible effective
`dose. In the event of bronchospasm. the intusion should be terminated immediately; a betaz stimulafing agent may be administered if
`conditions warrant but should be used with particular caution as patients already have rapid ventricular rates.
`
`Diabetes Mellitus and Hypoglycemia: BREVIBLOC should be used with caution in diabetic patients requiring a beta blocking agent. Beta
`blockers may mask tachycardia occurring with hypoglycemia. but other manifestations such as dizziness and sweating may not be
`significantly affected.
`PRECAUTIONS
`General
`Inlusion concentrations of 20 mglmL were associated with more serious venous irritation, including thrombophlebitis. than concentrations of
`to mglmL Extravasation of 20 mglmL may lead to a serious local reaction and possible skin necrosis. Concentrations greater than 10
`mglmL or infusion into small veins or through a butterfly catheter should be avoided.
`-
`
`Because the acid metabolite of BREVIBLOC is primarily excreted unchanged by the kidney. BREVIBLOC should be administered with
`caution to patients with impaired renal tunclion. The elimination half-life of the acid metabolite was prolonged ten-fold and the plasma level
`was considerably elevated in patients with end-stage renal disease.
`Care should be taken in the intravenous administration of BREVIBLOC as sloughing oi the skin and necrosis have been reported in
`association with infiltration and extravasation of intravenous infusions.
`
`‘
`Drugtnteractlons
`Catecholaminedepleting drugs. e.g.. reserpine. may have an additive etfect when given with beta blocking agents. Patients treated
`concurrently with BREVIBLOC anda wtecholamine depletor should therefore be closely observed for evidence of hypotension or marked
`bradycardia. which may result in vertigo. syncope. or postural hypotension.
`
`A study at interaction'between BREVIBLOC and wartarin showed that concomitant administration of BREVIBLOC and warlarin does not
`alter wartarin plasma levels: BREVIBLOC concentrations were equivocally higher when given with wartarin. but this is not likely to be
`clinically important.
`When digoxin and BREVIBLOC were concomitantly administered intravenously to normal volunteers. there was a 10-20% increase in
`digoxin blood levels at some time points. Digoxin did not affect BREVlBLOC pharmacokinetics. When intravenous morphine and
`BREVIBLOC were concomitantly administered in normal subjects. no effect on morphine blood levels was seen, but BREVIBLOC steady-
`state blood levels were increased by 46% in the presence at morphine. No other phannacckinetic parameters were changed.
`The etiect'of BREVIBLOC on the duration of succinylcholine-induced neuromuscular blockade was studied in patients undergoing surgery.
`The onset of neuromuscular blockade by succinylcholine was unafiected by BREVIBLOC. but the duration of neuromuscular blockade was
`prolonged from 5 minutes to 8 minutes.
`'
`
`
`
`
`Although the interactions observed in these stmfies do not appear to be of major cfinical importance. BREVIBLOC should be titrated with
`caution in patients being treated concurrently with digoxin. morphine. succinylcholine or wartarin.
`
`While taking beta blockers. patients with a history of severe anaphylactic reacfion to a variety of allergens may be more reactive to repeated
`'challenge. either accidental, diagnostic. or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat
`allergic reaction.
`.
`Caution should be exercised when considering the use of BREVIBLOC and verapamil in patients with depressed myocardial function. Fatal
`cardiac arrests have occurred in patients receiving both drugs. Additionally. BREVIBLOC should not be used to control supraventricular
`
`_,.__
`
`/..\
`
`
`
`

`

`tachycardia in the presence of agents which are vasoconstriclive and inotropic such as dopamine, epinephrine. and norepinephrine
`because of the danger of blocking cardiac contractility when systemic vascular resistance is high.
`.
`Carcinogenesis, Mutagenesis. impairment of Fertility
`Because of its short term usage no carcinogenicity. mutagenicity or reproductive performance studies have been conducted with
`BREVIBLOC (esmolol HCI).
`Pregnancy Category C
`Teratogenicity studies in rats at intravenous dosages of BREVIBLOC up to 3000 mog/kglmin (3 mglkglmin) (ten times the maximum human
`maintenance dosage) for 30 minutes daily produced no evidence of maternal toxicity. embryotoxicity or teratogenicity. while a dosage of
`f0.000 mcglkglmin (10 mg/kglmin) produced maternal toxicity and lethality.
`In rabbits. intravenous dosages up to 1000 mcg/kglmin (1
`mg/kglmin) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity. while 2500 mcg/kglmin (2.5
`mg/kg/min) produced. minimal maternal'toxicity and increased fetal resorptions.
`
`Although there are no adequate and wellcontrolled studies in pregnant women. use of esmolol in the last trimester of pregnancy or during
`labor or delivery has been reponed to cause fetal bradycardia, which continued after termination of drug infusion. BREVIBLOC should be
`used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`Nursing Mothers
`It is not known whether BREVIBLOC is excreted in human milk; however. caution should be exercised when‘BREVIBLOC is administered to
`a nursing woman.
`'
`Pediatric Use
`The safety and effectiveness of BREVIBLOC in children have not been established.
`ADVERSE REAC‘I10NS
`The following adverse reaction rates are based on use of BREVIBLOC in clinical trials involving 369 patients with supraventricular
`tachycardia and over 600 inlraoperative and postoperative patients enrolled in clinical trials. Most adverse effects observed in controlled
`clinical trial settings have been mild and transient. The most important adverse effect has been hypotension (see WARNINGS).VDeaths
`have been reported in post-marketing experience occurring during complex ciinical states where BREVIBLOC was presumably being used
`simply to control ventricular rate (see WARNINGS/Cardiac Failure).
`
`Cardiovascular — Symptomatic hypotension (diaphoresis. dizziness) occurred in 12% of patients, and therapy was discontinued in about
`11%.'about half of whom were symptomatic. Asymptomatic hypotension occurred in about 25% of patients. Hypotension resolved during
`BREVIBLOC (esmolol HCI) infusion in 63% of these patients and within 30 minutes after discontinuation ofinfusion in 80% of the remaining
`patients. Diaphoresis accompanied hypotension in 10% of patients. Peripheral ischemia occurred in approximately 1% of patients. Pallor.
`flushing. bradycardia (heart rate less than 50 beats per minute). chest pain. syncope. pulmonary edema and heart block have each been
`reported in less than 1% of patients. In two patients without supraventricular tachycardia but with serious coronary artery disease (post
`discontinuation of treatment
`'
`inferior myocanfial infarction or unstable angina). severe bradycardia/sinus pause/asystole has developed. reversible in both cases with
`
`Central Nervous System —- Dizziness has occurred in 3% of patients; somnolence in 3%; confusion. headache. and agitation in about 2%;
`and fatigue in about 1% of patients. Paresthesia. asthenia, depression. abnormal thinking. anxiety. anorexia. and lightheadedness were
`reported in less than 1%-of patients. Seizures were also reported in less than 1% of patients, with one death.
`
`Respiratory — Bronchospasm. 'wheezing. dyspnea. nasal congestion. rhonchi. and rates have each been reported in less than 1% of
`patients.
`
`Gastrointestinal — Nauseawas reported in 7% of patients. Vomiting has occurred in about 1% of patients. Dyspepsia. constipation. dry
`mouth, and abdominal discomfort-have each occurred in less than 1% of patients. Taste perversion has also been reported.
`Skin (Infusion Site) -— Infusion site reactions including inflammation and induration were reported in about 8% of patients.~Edema.»
`erythema. skin discoloration. burning at the infusion site. thrombophlebitis. and local skin necrosis from extravasation have each occurred in
`less than 1% of patients.
`.
`'
`
`Miscellaneous — Each of the following has been reported in less than 1% of patients: Urinary retention, speech disorder. abnormal vision.
`midscapular pain. rigors. and fever.
`OVERDOSAGE
`>
`.
`Acute Toxicity
`A few cases of massive accidental overdosage of BREVIBLOC (esmolol HCI) have occurred due to errors in dilution. These intravenous
`bolus doses BREVIBLOC of 500045250 meg/kg (5-6.25 mglkg) over 1-2 minutes have produced hypotension. bradycardia. drowsiness and
`loss of consciousness. The effects have resolved within 10 minutes. in some uses with administration of a pressor agent.
`Because of its approximately 9-minute elimination half-life. the first step in the management of toxicity should be- to discontinue the
`BREVIBLOC/infusion. Then, based on the observed clinical effects. the following general measures should also be considered.
`Eradycardia: Intravenous administration of atropine or another anficholinergic dnrg.
`
`I
`
`Bronchospasm: Intravenous administration of a betaz stimulating agent and/or a theophylline derivative.
`7 Cardiac Failure: Intravenous administration of a diuretic and/or digitalis glycoside. In shock resulting from inadequate cardiac contractilityg-
`intravenous administration of dopamine. dobutamine. isoproterenol. or amrinone may be considered.
`‘
`
`Symptomatic Hypotenslon: Intravenous administration of fluids and/or pressor agents.
`DOSAGE AND ADMINISTRATION
`.
`-.
`.
`2.5 g AMPUL
`THE 2.5 g AMPUL IS NOT FOR DIRECT INTRAVENOUS INJECTION. THIS DOSAGE FORM IS A CONCENTRATED. POTENT DRUG
`WHICH MUST BE DILUTED PRIOR TO ITS INFUSION. BREVIBLOC SHOULD NOT BE ADMIXED WITH SODIUM BICARBONATE.
`BREVIBLOC SHOULD NOT BE MIXED WITHOTHER DRUGS PRIOR TO DILUTION IN A SUITABLE INTRAVENOUS FLUID. (See
`Compatibility Section below.)
`
`Dilution: Asepticaily prepare a 10 mg/mL infusion by adding two 2.5 g arnpuls to a 500 mL container or one 2.5 g ampul to a 250 mL
`container of a compatible intravenous solution listed below. (Remove overage prior to dilution as appropriate.) This yields a final
`concentration of 10 mglmL The diluted solution is stable for at least 24 hours at room temperature. Note: Concentrations of BREVIBLOC
`greater than 10 mglmL are likely to produce irritation on continued inhrsion (see PRECAUTIONS). BREVIBLOC has. however. been well
`tolerated when administered via a central vein.
`-
`.
`'
`.
`.
`100 mg VIAL
`This dosage form is prediluted to provide a ready-to—use 10 mgme concentration recommended for BREVIBLOC intravenous
`administration. It may be used to administer the appropriate BREVIBLOC loading dosage infusions by hand—held syringe while the
`maintenance infusion is being prepared.
`.
`
`When using the 100 mg vial, a loading dose of 0.5 mglkglmin for a 70 kg patient would be 3.5 mL
`,
`_.
`.
`Supraventricular Tachycardia
`.
`,
`,
`In the treatment of supraventricular tachycardia. responses to BREVIBLOC usually (over 95%) occur within the range of 50 to 200
`mog/kglmin (0.05 to 0.2 mg/kglmin). The average effective dosage is approximately 100 moglkg/min (0.1 mg/kglmin) although dosages as
`low as 25 mog/kglmin (0.025 mglkglmin) have been adequate in some patients. Dosages as high as 300 mcglkglmin'(0.3 mglkglmin) have
`been used. but these provide little added effect and an- increased rate of adverse effects. and are not recommended. Dosagevof
`BREVIBLOC in supraventricular tachycardia must be individualized by titration in which each step consists of a loading dosage followed by
`a maintenance dosage.
`»
`-
`.
`.
`
`To initiate treatment of a patient with supraventricular tachycardia, administer a loading infusion of 500 mcglkglmin (0.5 mglkg/min) over
`one minute followed by a four-minute maintenance infusion of 50 mcglkg/min (0.05 mg/kg/min).
`If an adequate therapeutic effect is
`observed over the five minutes of drug administration, maintain the maintenance infusion dosage with periodic adjustments up or down as
`needed. if an adequate therapeutic effect is not observed. the same Ioacfing dosage is repeated over one minute followed byran increased
`maintenance infusion rate of 100 mogfkglmin (0.1 mg/kglmin).
`‘
`»
`'
`.
`
`
`
`
`
`

`

`Continue titration procedure as above, repeating the original loading infusion 01 500 mcglkglmin (0.5 mglkg/min) over 1 minute, but
`increasing the-maintenance inlusion rate over the subsequent lour minutes by 50'mcglkg/min (0.05 mglkglmin) increments. As the desired
`heart rate or blood pressure is approached, omit subsequent loading doses and titrate the maintenance dosage up or down to endpoint.
`Also, it desired, increase the interval between steps from 5 to 10 minutes.
`Loading Dose
`Maintenance Dosage
`"
`(over 1 minute)
`(over 4 minutes)
`mgjlgglmin m mg/kglmin ,
`0.5
`'
`0.5
`0.5
`'
`
`50
`100
`
`0.05
`0.1
`
`_
`
`'[aka
`
`Time
`minutes mg/kglmin
`0-1
`500
`1—5
`5-6
`500
`6-10
`~l0-1l
`500
`
`11-1515-16
`'
`16-20
`20-(24 hrs)
`
`
`
`0.15
`150
`'02
`.
`'200
`Maintenance dose titrated
`to heart rate or other
`clinical endpoint.
`_
`' As the desired'heart rate or endpoint is approached. the loading inlusion may be omitted and the maintenance infusion titrated to 300
`mog/kglmin (0.3 mg/kglmin) or downward as appropriate. Maintenance dosages above 200 moglkg/min (0.2 mg/kglmin) have not been
`shown to have significantly increased benefits. The interval between titration steps may be increased.
`.
`
`
`intracperative use.
`This specific dosage regimen has not been studied intraoperatively and, because 01 the time required ior titration, may not be optimal lor
`
`The salety oi dosages above 300 mcg/kg/min (0.3 mg/kglmin) has not been studied.
`
`in the event 01 an adverse reaction, the dosage oi BREVlBLOC may be reduced or discontinued. ii a local inlusion site reaction develops,
`an alternate inlusion site should be used and caution should be taken to prevent extravasation. The use 01 butterfly needles should be
`avoided.
`'
`
`Abrupt cessation ol BREVIBLOC in patients has not been reported to produce the withdrawal ellects which may occur with abrupt
`withdrawal cl beta blockers lollowing chronic use in coronary artery disease (CAD) patients. However, caution should still be used in
`abruptly discontinuing inlusions oi BREVIBLOC in CAD patients.
`
`After achieving an adequate control 01 the heart rate and a stable clinical status in patients with supraventricular tachycardia, transition to
`alternative antiarrhythmic agents such as propranolol, digoxin, or verapamil, may be accomplished. A recommended guideline tor such a
`transition is given below but the physician should carehrlly consider the labeling instructions lor the alternative agent selected.
`Alternative Agent
`Dosage
`Propranoloi hydrochloride
`10—20 mg q 4-6 h
`Digcxin
`0.12505 mg q 6 h (p.o. or iv.)
`Verapamil
`80 mg q 6 h
`'
`The dosage oi BREVIBLOC (esmolol HCl) should be reduced as iotlows:
`
`l. Thirty minutes lollowing the first dose at the alternative agent, reduce'the inlusion rate 01 BREVlBLOC by onehall (50%).
`2. Following the second dose oi the alternative agent, monitor the patient's response and ii satislactory control is maintained lor the first
`hour, discontinue BREVlBLOC.
`
`The use oi iniusions oi BREVIBLOC up to 24 hours has been well documented; in addition, limited data from 24-48 hrs (N=48) indicate that
`BREVIBLOC is well tolerated 'up to 48 hours.
`»
`-
`
`‘
`.
`lntraoperative and Postoperative Tachycardia and/or Hypertension
`In the intraoperative and postoperative settings it is not always advisable to 'slowly titrate the dose at BREVIBLOC to a therapeutic ellect.
`therefore, two dosing options are presented: immediate control dosing and a gradual control when the physician has time to titrate.
`1. Malamute
`For intraoperative treatment at tachymrdia andlor hypertension give an 80 mg (approximately 1 mg/kg) bolus dose over 30 seconds
`lollowed by a 150 meg/kglmin inlusion, it necessary. Adjust the inlusion rate as required up to 300 moglkglmin to maintain desired heart
`rate and/or blood pressure.
`_
`2. Grad La (antral
`-
`For postoperative tachycardia and hypertension, the dosing schedule is the same as that used in supraventricular tachycardia.
`To initiatetreatment administera loading dosage inlusion 01500 mog/kglmin oi BREVlBLOC lor one minute lollowed by a tour-minute
`maintenance infusion at 50 mcglkglmin. ii an adequate therapeutic eitect is not observed within live minutes, repeat the same
`loading dosage and lollow with a maintenance inlusion increased to 100 mog/kglmin (see above Supraventricular Tachycardia).
`Note: Higher dosages (250-300 mog/kglmin) may be required ior adequate control 01 blobd pressure than those required for the treatment
`oi atrial fibrillation, flutter and sinus tachycardia. One third 01 the postoperative hypertensive patients required these higher'doses.
`Compatibility with Commonly Used intravenous Fluids
`'
`‘
`-
`BREVlBLOC lNJECTlON was tested for compatibility with ten commonly used intravenous lluids at a final concentration oi 10 mg esmolol
`HCl per mL BREVIBLOC lNJECTlON was lound to be compatible with the lollowing solutions and was stable tor at least 24 hours at
`controlled room temperature or under refrigeration:
`,
`'
`‘
`.
`Dextrose (5%) injection, USP
`Dextrose (5%) in Lactated Ringer's injection
`' Dextrose (5%) in Ftinger's injection
`Dextrose (5%) and Sodium Chloridev(0.45%) injection, USP
`Dextrose (5%) and Sotfium Chloride (0.9%) injection, USP
`.Lactated Ringer's injection, USP
`j
`Potassium Chloride (40 mquliter) in Dextrose (5%) injection, USP
`Sodium Chloride (0.45%) injection, USP
`'
`Sodium Chloride (0.9%) injection, USP
`
`BREViBLOC tNJECTION was NOT compatible with Sodium Bicarbonate (5%) injection, USP.
`
`Note: Parenteral drug products should be inspected visually tor particulate matter and discoloration prior to administration, whenever
`solution and container permit
`HOW SUPPUED
`.
`NDC 10019-0l5-71, 100 mg — t0 mL vial, Box 0120
`NBC 100l9-025-18 , 2.5 g — 10 mL ampui, Box 0110
`
`
`
`
`
`a elevated temperatures should be avoided.
`.
`STORE AT CONTROLLED ROOM TEMPERATURE (59°- 86° F, 15° - 30° C). Freezing does not adversely atlect the product, but exposure
`Anaquest inc= 110 Allen Road
`PO Box 804
`Lbaty Corner, NJ 079380804
`A Subsidiary ei BOC Health Care Inc
`
`BOCHeaJthCare
`
`'400-277—00
`
`-
`
`5-53
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TI0N NUMBER:
`
`_ 19-386/8010
`
`CHEMISTRY REVIEWfS) '
`
`

`

`5,10.
`
`,
`
`JUN
`
`71993
`
`ORGANIZATION
`HFD-llO
`
`'
`
`Name and Address of Applicant (City & State)
`Anaquest Inc.
`110 Allen Road
`P. 0. Box 804
`Liberty Corner, NJ 07938--O804
`Drug Name
`6. Nonproprietary Name
`Brevihlocr
`Esmolol h drochloride
`Suppl-ement Provides For:
`Final printed labeling revised to complete the
`c-hange of ownership procedure under 21 CFR
`314. 70. Changes under PRECAUTIONS/Pregnancy
`Category C is revised.
`Pha-rmacological Category
`Anti-adrenergic (fl—receptor)
`.
`-
`
`10. How Dispensed
`E]
`‘ E]
`'
`Rx
`OTC
`
`4. Supplement(s)
`' Number(s)
`Date(s)
`S-OlO
`' 6/1/93
`(LR)
`
`8. Amendments &
`other (reports,
`etc) - Dates
`
`111 Related IND(s)/
`NDA(S)/DMF(s)'
`
`June 7'! 1993
`
`>12. Dosage Form(s)
`Intravenous injedtion
`
`’13. Potency(ies)
`100mg/mL, 250mg/mL
`10 mg/mL
`
`::14. Chemical Name and Structure
`-
`
`15. Records/Reports
`Current
`
`SPECIAL SUPPLEMENT:
`£16. Chmments:
`Following revisions are included:
`
`[:1 Yes
`Reviewed
`D Yes D L
`CHANGES-BEING EFFECTED
`
`DNo :E'
`Lg
`
`1.
`
`The name and address of sponsor was changed to:
`Anaquest Inc.
`'110 Allen Road
`P.0. Box 804
`
`Liberty Corner, NJ 079