PDW
`54
`2000
`
`EDITION
`
`YSICIANS’
`
`RRNOfi
`
`Senior Vice President, Directory Services: Paul Walsh
`
`Director of Product Management: Mark A. Friedman
`Associate Product Manager: Bill Shaughnessy
`Senior Business Manager: Mark S. Ritchin
`Financial Analyst: Wayne M. Soltis
`Director of Sales: Dikran N. Barsamian
`National Sales Manager, Pharmaceutical Sales: Anthony Sorce
`National Account Manager: Don Bruccoleri
`Senior Account Manager: Frank Karkowsky
`Account Managers:
`Marion Gray, RPh
`Lawrence C. Keary
`Jeffrey F. Pfohl
`Suzanne E. Yarrow, RN
`Electronic Sales Account Manager: Stephen M. Silverberg
`National Sales Manager, Medical Economics Trade Sales: Bill Gaffney
`Director of Direct Marketing: Michael Bennett
`List and Production Manager: Lorraine M. Loening
`Senior Marketing Analyst: Dina A. Maeder
`
`Director, New Business Development and
`Professional Support Services: Mukesh Mehta, RPh
`Manager, Drug Information Services: Thomas Fleming, RPh
`Drug Information Specialist: Maria Deutsch, MS, RPh, CDE
`Editor, Directory Services: David W. Sifton
`Senior Associate Editor: Lori Murray
`Director of Production: Carrie Williams
`Manager of Production: Kimberly H. Vivas
`Senior Production Coordinator: Amy B. Brooks
`Production Coordinators: Gianna Caradonna, Maria Volpati
`Data Manager: Jeffrey D. Schaefer
`Senior Format Editor: Gregory J. Westley
`Index Editors: Johanna M. Mazur, Robert N. Woerner
`Art Associate: Joan K. Akerlind
`Senior Digital Imaging Coordinator: Shawn W. Cahill
`Digital Imaging Coordinator: Frank J. McElroy, Ill
`Electronic Publishing Designer: Livio Udina
`FuiIIment Manager: Stephanie DeNardi
`
`Copyright ' 2000 and published by Medical Economics Company, Inc. at Montvale, NJ 07645-1742. All rights reserved. None of the content of this publication may
`be reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or
`otherwise) without the prior written permission of the publisher. PHYSICIANS’ DESK REFERENCE, PDR, PDR For Ophthalmology, Pocket PDR’, and The PDRI Family
`Guide to Prescription Druge are registered trademarks used herein under license. PDR For Nonprescription Drugs and Dietary Supplement'M, PDIR Companion Guide",
`PDRI for Herbal MedicinesrM, PDRI Medical Dictionary lM, PDRfi Nurse’s Drug HandbookTM, PDRI Nurse’s Dictionary 1M, The PDRT Family Guide Encyclopedia of Medical
`CareTM, The PDR Family Guide to Natural Medicines and Healing TherapiesTM, The PDRT Family Guide to Common AilmentSTM, The PDRI Family Guide to Over-the-
`Counter DrugsTM, and PDRT Electronic Library 1M are trademarks used herein under license.
`
`Officers of Medical Economics company: President and Chief Executive Officer: Curtis B. Allen; Vice President, New Media: L. Suzanne BeDell; Vice President, Corporate Human
`Resources: Pamela M. Bilash; Vice President and Chief Information Officer: Steven M. Bressler; Chief Financial Officer: Christopher Caridi; Vice President and Controller: Barry
`Gray; Vice President, New Business Planning: Linda G. Hope; Vice President, Business Integration: David A. Pitler; Vice President, Finance: Don ira Santarpia; Senior Vice President,
`Directory Services: Paul Walsh; Senior Vice President, Operations: John R. Ware; Senior Vice President, Internet Strategies: Raymond Zoeller
`OQ
`Printed on recycled paper (cid:9)
`
`ISBN: 1-56363-330-2
`
`Metrics EX1031, Page 1
`
`

`
`486/AGOU RD N
`
`Viracept(cid:151)Cont.
`
`Pediatric Use
`Nelfinavir was studied in one open-label, uncontrolled trial
`in 38 pediatric patients ranging in age from 2 to 13 years. In
`order to achieve plasma concentrations in pediatric patients
`which approximate those observed in adults, the recom-
`mended pediatric dose is 20-30 mg/kg given three times
`daily with a meal or snack, not to exceed 750 mg three times
`a day. (See DOSAGE AND ADMINISTRATION)
`A similar adverse event profile was seen during the pediat-
`ric clinical trial as in adult patients. The evaluation of the
`antiviral activity of nelfinavir in pediatric patients is ongo-
`ing.
`The safety, effectiveness and pharmacokinetics of nelfinavir
`have not been evaluated in pediatric patients below the age
`of 2 years.
`ADVERSE REACTIONS
`The safety of VIRACEPT was studied in over 1500 patients
`who received drug either alone or in combination with nu-
`cleoside analogues (d4T or ZDV/3TC). The majority of ad-
`verse events were of mild intensity. The most frequently re-
`ported adverse event among patients receiving VIRACEPT
`was diarrhea, which was generally of mild to moderate in-
`tensity.
`Drug-related clinical adverse experiences of moderate or se-
`vere intensity in ~!2% of patients treated with VIRACEPT
`coadministered with ZDV plus 3TC (Study 511) or in com-
`bination with d4T (Study 508) for up to 24 weeks are pres-
`ented in Table 3.
`[See table 3 at top of previous page]
`Adverse events occurring in less than 2% of patients receiv-
`ing VIRACEPT in all phase Il/Ill clinical trials and consid-
`ered at least possibly related or of unknown relationship to
`treatment and of at least moderate severity are listed below.
`Body as a Whole: accidental injury, allergic reaction, back
`pain, fever, headache, malaise, and pain.
`anorexia, dyspepsia, epigastric pain,
`Digestive System:
`gastrointestinal bleeding, hepatitis, mouth ulceration, pan-
`creatitis and vomiting.
`Hemic/Lymphotic System:
`thrombocytopenia.
`Metabolic /Nutritional System:
`increases in alkaline phos-
`phate, amylase, creatine phosphokinase, lactic dehydroge-
`nase, SCOT, SGPT and gamma glutamyl transpeptidase;
`hyperlipemia, hyperuricemia, hyperglycemia, hypoglyce-
`mia, dehydration, and liver function tests abnormal.
`arthralgia, arthritis, cramps, my-
`Musculosheletal System:
`algia, myasthenia and myopathy.
`anxiety, depression, dizziness, emotional
`Nervous System:
`lability, hyperkinesia, insomnia, migraine, paresthesia, sei-
`zures, sleep disorder, somnolence and suicide ideation.
`Respiratory System: dyspnea, pharyngitis, rhinitis, and si-
`nusitis.
`Skin /Appendages: dermatitis, folliculitis, fungal dermati-
`tis, maculopapular rash, pruritus, sweating, and urticaria.
`Special Senses: acute iritis and eye disorder.
`Urogenital System: kidney calculus, sexual dysfunction
`and urine abnormality.
`Laboratory Abnormalities
`Few patients experienced significant laboratory abnormali-
`ties while receiving VIRACEPT. The percentage of patients
`with marked laboratory abnormalities in Studies 511 and
`506 are presented in Table 4. Marked laboratory abnormal-
`ities are defined as a Grade 3 or 4 abnormality in a patient
`with a normal baseline value or a Grade 4 abnormality in a
`patient with a Grade 1 abnormality at baseline.
`ISee table 4 on previous page]
`
`anemia, leukopenia and
`
`OVERDOSAGE
`Human experience of acute overdose with
`VIRACEPT is limited. There is no specific antidote for over-
`dose with VIRACEPT. If indicated, elimination of unab-
`sorbed drug should be achieved by emesis or gastric lavage.
`Administration of activated charcoal may also be used to aid
`removal of unabsorbed drug. Since nelfinavir is highly pro-
`tein bound, dialysis is unlikely to significantly remove drug
`from blood.
`DOSAGE AND ADMINISTRATION
`Adults: The recommended dose is 750 mg (three 250 mg
`tablets) three times daily. VIRACEPT should be taken with
`a meal or light snack. Antiviral activity is enhanced when
`VIRACEPT is administered in combination with nucleoside
`analogues. Therefore, it is recommended that VTRACEPT
`be used in combination with nucleoside analogues.
`Pediatric patients (2-13 years): The recommended oral
`dose of VIRACEPT for pediatric patients 2 to 13 years of age
`is 20-30 mg/kg per dose, three times daily with a meal or a
`light snack. For children unable to take tablets, VIRACEPT
`Oral Powder may be administered. The oral powder maybe
`mixed with a small amount of water, milk, formula, soy for-
`mula, soy milk or dietary supplements; once mixed, the en-
`tire contents must be consumed in order to obtain the full
`dose. The recommended use period for storage of the prod-
`uct in these media is 6 hours. Acidic food or juice (e.g.,
`orange juice, apple juice or apple sauce) are not recom-
`mended to be used in combination with VIRACEPT, because
`the combination may result in a bitter taste. VIRACEPT
`Oral Powder should not be reconstituted with water in its
`original container. The recommended pediatric dose of
`VIRACEPT to be administered three times daily is de-
`scribed in Table 5:
`[See table 5 on previous page]
`
`HOW SUPPLIED
`VIRACEPT (nelfinavir mesylate) Tablets, 250 mg are light
`blue, capsule-shaped tablets engraved with "VIRACEPT" on
`one side and "250 mg’ on the other.
`Available as:
`NDC 63010-010-27, bottle containing 270 tablets
`VIRACEPT (nelfinavir mesylate) Oral Powder, 50 mg/g is
`an off-white powder containing 50 mg (as nelfinavir free
`base) in each level scoopful (1 gram).
`Available as:
`NDC 63010-011-90, multiple use bottle containing 144
`grams of powder with scoop.
`VIRACEPT Tablets and Oral Powder should be stored at
`15 to 30CC (59 to 86’F).
`Issued 10/29/97
`VIRACEPT is a registered trademark of Agouron Pharma-
`ceuticals, Inc.
`Shown in Product Identification Guide, page 303
`
`Alcon Laboratories, Inc.
`and its affiliates
`CORPORATE HEADQUARTERS
`6201 SOUTH FREEWAY
`FORT WORTH, TX 76134
`
`Direct Inquiries to:
`Pharmaceutical/Consumer: (800) 451-3937
`(Therapeutic Drugs/Lens Care)
`Surgical: (800) 862-5266
`(Instrumentation/Surgical Meds)
`Systems: (800) 289-1991
`(Medical Management Information Systems)
`6201 South Freeway
`Fort Worth, TX 76134
`(817) 293-0450
`
`OPHTHALMIC PRODUCTS
`
`For information on Alcon ophthalmic products, consult the
`PilE For Ophthalmology. See a complete listing of products
`in the Manufacturers’ Index section of this book. For infor-
`mation, literature, samples or service items contact Alcon at
`the phone numbers listed above.
`
`AZOPTrM
`(brinzolamide ophthalmic suspension) 1%
`
`DESCRIPTION
`AZOPTTM (brinzolamide ophthalmic suspension) 1% con-
`tains a carbonic arihydrase inhibitor formulated for multi-
`dose topical ophthalmic use. Brinzolamide is described
`chemically as: (R)-(+)-4-Ethylamino-2-(3-methoxypropyl)-
`3,4-dihydro-2H-thieno 13,2-el -1,2-thiazine-6-sulfonamide-
`1,1-doxide. Its empirical formula is C 12H21N3O5S3.
`Brinzolamide has a molecular weight of 383.5 and a melting
`point of about 131’C. It is a white powder, which is insoluble
`in water, very soluble in methanol and soluble in ethanol.
`AZOPT 1% is supplied as a sterile, aqueous suspension of
`brinzolamide which has been formulated to be readily sus-
`pended and slow settling, following shaking. It has a pH of
`approximately 7.5 and an osmolality of 300 mOsm/kg. Each
`mL of AZOP’F 1% contains 10 mg brinzolamide. Inactive in-
`gredients are mannitol, carbomer 974P, tyloxapol, edetate
`disodium, sodium chloride, hydrochloric acid and/or sodium
`hydroxide (to adjust pH), and purified water. Benzalkonium
`chloride 0.01% is added as a preservative.
`CLINICAL PHARMACOLOGY
`Carbonic anhydrase (CA) is an enzyme found in many tis-
`sues of the body including the eye. It catalyzes the revers-
`ible reaction involving the hydration of carbon dioxide and
`the dehydration of carbonic acid. In humans, carbonic an-
`hydrase exists as a number of isoenzymes, the most active
`being carbonic anhydrase II (CA-II), found primarily in red
`blood cells (RBCs), but also in other tissues. Inhibition of
`carbonic anhydrase in the ciliary processes of the eye de-
`creases aqueous humor secretion, presumably by slowing
`the formation of bicarbonate ions with subsequent reduc-
`tion in sodium and fluid transport.
`The result is a reduction in intraocular pressure (lOP).
`AZOPT 1% contains brinzolamide, an inhibitor of carbonic
`anhydrase II (CA-11). Following topical ocular administra-
`tion, brinzolamide inhibits aqueous humor formation and
`reduces elevated intraocular pressure. Elevated intraocular
`pressure is a major risk factor in the pathogenesis of optic
`nerve damage and glaucomatous visual field loss.
`Following topical ocular administration, brinzolamide is ab-
`sorbed into the systemic circulation. Due to its affinity for
`CA-II, brinzolamide distributes extensively into the RBC5
`and exhibits a long half-life in whole blood (approximately
`111 days). In humans, the metabolite N-desethyl brinzola-
`mide is formed, which also binds to CA and accumulates in
`RBCs. This metabolite binds mainly to CA-I in the presence
`of brinzolamide. In plasma, both parent brinzolamide and
`N-desethyl brinzolamide concentrations are low and gener-
`ally below assay quantitation limits (<10 ng/mL). Binding
`to plasma proteins is approximately 60%. Brinzolamide is
`eliminated predominantly in the urine as unchanged drug.
`
`Information will be superseded by supplements and subsequent editions
`
`PHYSICIANS’ DESK REFERENCEfi
`
`N-Desethyl brinzolamide is also found in the urine along
`with lower concentrations of the N-desmethoxypropyl and
`0-desmethyl metabolites.
`An oral pharmacokinetic study was conducted in which
`healthy volunteers received 1 mg capsules of brinzolamide
`twice per day for up to 32 weeks. This regimen approxi-
`mates the amount of drug delivered by topical ocular ad-
`ministration of AZOPTTM (brinzolamide ophthalmic suspen-
`sion) 1% dosed to both eyes three times per day and simu-
`lates systemic drug and metabolite concentrations similar
`to these achieved with long-term topical dosing. BBC CA ac-
`tivity was measured to assess the degree to svrtemic CA in-
`hibition. Brinzolamide saturation of RBC CA-11 was
`achieved within 4 weeks (RBC concentrations of approxi-
`mately 20 pM). N-Desethyl brinzolamide accumulated in
`RBCs to steady-state within 20-28 weeks reaching concen-
`trations ranging from 6-30 pM. The inhibition of CA-II ac-
`tivity at steady-state was approximately 70-75%, which is
`below the degree of inhibition expected to have a pharma-
`cological effect on renal function or respiration in healthy
`subjects.
`In two, three-month clinical studies, AZOPT (brinzolamide
`ophthalmic suspension) 1% dosed three times per day (TID)
`in patients with elevated intraocular pressure (lOP), pro-
`duced significant reductions in lOPs (4-5 mmHg). These
`TOP reductions are equivalent to the reductions observed
`with TRUSOPT* (dorzolamide hydrochloride ophthalmic so-
`lution) 2% dosed TID in the same studies.
`In two clinical studies in patients with elevated intraocular
`pressure, AZOPT 1% was associated with less stinging and
`burning upon instillation than TRUSOPT(cid:176) 2%.
`INDICATIONS AND USAGE
`AZOPTT14 Ophthalmic Suspension 1% is indicated in the
`treatment of elevated intraocular pressure in patients with
`ocular hypertension or open-angle glaucoma.
`CONTRAINDICATIONS
`AZOPTTM is contraindicated in patients who are hypersen-
`sitive to any component of this product.
`
`WARNINGS
`AZOPT is a sulfonamide and although administered top-
`ically it is absorbed systemically. Therefore, the same types
`of adverse reactions that are attributable to sulfonamides
`may occur with topical administration of AZOPT. Fatalities
`have occurred, although rarely, due to severe reactions to
`sulfonamides including Stevens-Johnson syndrome, toxic
`epidermal necrolysis, fialminant hepatic necrosis, agranulo-
`cytosis, aplastic anemia, and other blood dyscrasias. Sensi-
`tization may recur when a sulfonamide is re-administered
`irrespective of the route of administration. If signs of seri-
`ous reactions or hypersensitivity occur, discontinue the use
`of this preparation.
`PRECAUTIONS
`General:
`Carbonic anhydrase activity has been observed in both the
`cytoplasm and around the plasma membranes of the corneal
`endothelium. The effect of continued administration of
`AZOPT on the corneal endothelium has not been fully eval-
`uated. The management of patients with acute angle-clo-
`sure glaucoma requires therapeutic interventions in addi-
`tion to ocular hypotensive agents. AZOPT has not been
`studied in patients with acute angle-closure glaucoma.
`AZOPT has not been studied in patients with severe renal
`impairment (CrCl <30 mLfmin). Because AZOPT and its
`metabolite are excreted predominantly by the kidney,
`AZOPT is not recommended in such patients.
`AZOPTTM has not been studied in patients with hepatic im-
`pairment and should be used with caution in such patients.
`There is a potential for an additive effect on the known sys-
`temic effects of carbonic anhydrase inhibition in patients re-
`ceiving an oral carbonic anhydrase inhibitor and AZOPT.
`The concomitant administration of AZOPT and oral car-
`bonic anhydrase inhibitors is not recommended.
`Information For Patients:
`AZOPTTM is a sulfonamide and although administered top-
`ically, it is absorbed systemically; therefore, the same type
`of adverse reactions attributable to sulfonamides may occur
`with topical administration. Patients should be advised that
`if serious or unusual ocular or systemic reactions or signs of
`hypersensitivity occur, they should discontinue the use of
`the product and consult their physician (see Warnings).
`Vision may be temporarily blurred following dosing with
`AZOPT. Care should be exercised in operating machinery or
`driving a motor vehicle.
`Patients should be instructed to avoid allowing the tip of the
`dispensing container to contact the eye or surrounding
`structures or other surfaces, since the product can become
`contaminated by common bacteria known to cause ocular
`infections. Serious damage to the eye and subsequent loss of
`vision may result from using contaminated solutions.
`Patients should also be advised that if they have ocular sur-
`gery or develop an intercurrent ocular condition (e.g.,
`trauma or infection), they should immediately seek their
`physician’s advice concerning the continued use of the pre-
`sent multidose container.
`If more than one topical ophthalmic drug is being used, the
`drugs should be administered at least ten minutes apart.
`The preservative in AZOPTT’ 5 Ophthalmic Suspension,
`benzalkonium chloride, may be absorbed by soft contact
`lenses. Contact lenses should be removed during instillation
`of AZOPT, but may be reinserted 15 minutes after instilla-
`tion.
`Drug Interactions:
`AZOPTSM Ophthalmic Suspension 1% contains a carbonic
`anhydrase inhibitor. Acid-base and electrolyte alterations
`were not reported in the clinical trials with brinzolamide.
`
`Metrics EX1031, Page 2
`
`

`
`PRODUCT INFORMATION
`
`However, in patients treated with oral carbonic arihydrase
`inhibitors, rare instances of drug interactions have occurred
`with high-dose salicylate therapy. Therefore, the potential
`for such drug interaction should be considered in patients
`receiving AZOPT.
`Carcinogenesis, Mutagenesis, Impairment of Fertility:
`Carcinogenicity data on brinzolamide are not available. The
`following tests for mutagenic potential were negative: (1) in
`viva mouse micronucleus assay; (2) in vivo sister chromatid
`exchange assay; and (3) Ames H. co/i test. The in vitro
`mouse lymphoma forward mutation assay was negative in
`the absence of activation, but positive in the presence of mi-
`crosomal activation.
`In reproduction studies of brinzolamide in rats, there were
`no adverse effects on the fertility or reproductive capacity of
`moles or females at doses up to 18 mg/kg/day (375 times the
`recommended human ophthalmic dose).
`Pregnancy:
`Teratogenic Effects: Pregnancy Category C. Developmental
`toxicity studies with brinzolamide in rabbits at oral doses of
`1, 3, and 6 mg/kg/day (20, 62, and 125 times the recom-
`mended human ophthalmic dose) produced maternal toxic-
`ity at 6 mg/kg/day and a significant increase in the number
`of fetal variations, such as accessory skull bones, which was
`only slightly higher than the historic value at 1 and 6 mg/
`kg. In rats, statistically decreased body weights of fetuses
`from dame receiving oral doses of 18 mg/kg/day (375 times
`the recommended human ophthalmic dose) during gestation
`were proportional to the reduced maternal weight gain,
`with no statistically significant effects on organ or tissue de-
`velopment. Increases in unossified sternebrae, reduced os-
`sification of the skull, and unossified hyoid that occurred at
`6 and 18 mg/kg were not statistically significant. No treat-
`ment-related malformations were seen. Following oral ad-
`ministration of i4C.brinzolamide to pregnant rate, radioac-
`tivity was found to cross the placenta and was present in
`the fetal tissues and blood.
`There are no adequate and well-controlled studies in preg-
`nant women. AZOPTiC should be used during pregnancy
`only if the potential benefit justifies the potential risk to the
`fetus.
`Nursing Mothers:
`In a study of brinzolamide in lactating rats, decreases in
`body weight gain in offspring at an oral dose of 15 mg/kg/
`day (312 times the recommended human ophthalmic dose)
`were seen during lactation. No other effects were observed.
`However, following oral administration of i 4Cbrinzolamide
`to lactating rats, radioactivity was found in milk at concen-
`trations below those in the blood and plasma.
`It is not known whether this drug is excreted in human
`milk. Because many drugs are excreted in human milk and
`because of the potential for serious adverse reactions in
`nursing infants from AZOPT, a decision should be made
`whether to discontinue nursing or to discontinue the drug,
`taking into account the importance of the drug to the
`mother.
`Pediatric Use:
`Safety and effectiveness in pediatric patients have not been
`established.
`ADVERSE REACTIONS
`In clinical studies of AZOPT (brinzolamide ophthalmic sus-
`pension) 1%, the most frequently reported adverse events
`associated with AZOPT 1% were blurred vision and bitter,
`sour or unusual taste. These events occurred in approxi-
`mately 5-10% of patients. Blepharitis, dermatitis, dry eye,
`foreign body sensation, headache, hyperemia, ocular dis-
`charge, ocular discomfort, ocular keratitis, ocular pain, ocu-
`lar pruritus and rhinitis were reported at an incidence of
`1-5%.
`The following adverse reactions were reported at an inci-
`dence below 1%: allergic reactions, alopecia, chest pain, con-
`junctivitis, diarrhea, diplopia, dizziness, dry mouth, dys-
`pnea, dyspepsia, eye fatigue, hypertonia, keratoconjunctivi-
`tis, keratopathy, kidney pain, lid margin crusting or sticky
`sensation, nausea, pharyngitis, tearing and urticaria.
`OVERDOSAGE
`Although no human data are available, electrolyte imbal-
`ance, development of an acidotic state, and possible nervous
`system effects may occur following oral administration of an
`overdose. Serum electrolyte levels (particularly potassium)
`and blood pH levels should be monitored.
`DOSAGE AND ADMINISTRATION
`Shake well before use. The recommended dose is 1 drop of
`AZOPTtm Ophthalmic Suspension in the affected eye(s)
`three times daily.
`AZOPT may be used concomitantly with other topical oph-
`thalmic drug products to lower intraocular pressure.
`If more than one topical ophthalmic drug is being used, the
`drugs should be administered at least ten minutes apart.
`HOW SUPPLIED
`AZOPTO5i Ophthalmic Suspension 1% is supplied in plastic
`DROP-TAINERfi dispensers with a controlled dispensing-
`tip as follows:
`
`NDC 0065-0275-24 (cid:9)
`NDC 0065-0275-05 (cid:9)
`NDC 0065-0275-10 (cid:9)
`NDC 0065-0275-15 (cid:9)
`
`2.5 mL
`5 ml,
`10 mL
`15 ml,
`
`Storage: Store AZOPT Ophthalmic Suspension 1% at
`4-30’C (39-86F).
`Rx Only
`U.S. Patent Numbers: 5,240,923; 5,378,703; 5,461,081; pat-
`ents pending.
`(cid:176)TRUSOPT is a registered trademark of Merck & Co., Inc.
`
`BETOPTIC S
`(betaxolol HCI)
`0.25% as base
`Sterile Ophthalmic Suspension
`
`DESCRIPTION
`BETOPTIC S Ophthalmic Suspension 0.25% contains be-
`taxolol hydrochloride, a cardioselective beta-adrenergic re-
`ceptor blocking agent, in a sterile resin suspension formu-
`lation. Betaxolol hydrochloride is a white, crystalline pow-
`der, with a molecular weight of 343.89.
`Chemical Name:
`(– )-1-lp-l2-(cyclopropylmethoxy)ethyl]
`phenoxyl-3-(isopropylamino)-2-propanol hydrochloride.
`Each ml, of BETOPTIC S Ophthalmic Suspension contains:
`Active: betaxolol HC1 2.8 mg equivalent to 2.5 mg of betax-
`olol base. Preservative: benzalkonium chloride 0.01%. Inac-
`tive: Mannitel, Poly(Styrene-Divinyl Benzene) sulfonic acid,
`Carbomer 934P, edetate disodium, hydrochloric acid or so-
`dium hydroxide (to adjust pH) and purified water.
`CLINICAL PHARMACOLOGY
`Betaxolol HC1, a cardioselective (beta-1-adrenergic) recep-
`tor blocking agent, does not have significant membrane-
`stabilizing (local anesthetic) activity and is devoid of intrin-
`sic sympathomimetic action. Orally administered beta-ad-
`renergic blocking agents reduce cardiac output in healthy
`subjects and patients with heart disease. In patients with
`severe impairment of myocardial function, beta-adrenergic
`receptor antagonists may inhibit the sympathetic stimula-
`tory effect necessary to maintain adequate cardiac function.
`When instilled in the eye, BETOPTIC S Ophthalmic Sus-
`pension 0.25% has the action of reducing elevated intraocu-
`lar pressure, whether or not accompanied by glaucoma.
`Ophthalmic betaxolol has minimal effect on pulmonary and
`cardiovascular parameters.
`Elevated TOP presents a major risk factor in glaucomatous
`field loss. The higher the level of TOP, the greater the like-
`lihood of optic nerve damage and visual field loss. Betaxolol
`has the action of reducing elevated as well as normal intra-
`ocular pressure and the mechanism of ocular hypotensive
`action appears to be a reduction of aqueous production as
`demonstrated by tonograpby and aqueous fluorophotom-
`etry. The onset of action with betaxolol can generally be
`noted within 30 minutes and the maximal effect can usually
`be detected 2 hours after topical administration. A single
`dose provides a 12-hour reduction in intraocular pressure.
`In controlled, double-masked studies, the magnitude and
`duration of the ocular hypotensive effect of BETOPTIC S
`Ophthalmic Suspension 0.25% and BETOPTIC Ophthalmic
`Solution 0.5% were clinically equivalent. BETOPTIC S
`Suspension was significantly more comfortable than
`BETOPTIC Solution.
`Ophthalmic betaxolol solution at 1% (one drop in each eye)
`was compared to placebo in a crossover study challenging
`nine patients with reactive airway disease. Betaxolol HC1
`had no significant effect on pulmonary function as measured
`by FEV, Forced Vital Capacity (FVC), FEV 1/FVC and was
`not significantly different from placebo. The action of isopro-
`torenol, a beta stimulant, administered at the end of the
`study was not inhibited by ophthalmic betaxolol.
`No evidence of cardiovascular beta adrenergic-blockade dur-
`ing exercise was observed with betaxolol in a double-
`masked, crossover study in 24 normal subjects comparing
`ophthalmic betaxolol and placebo for effects on blood pres-
`sure and heart rate.
`INDICATIONS AND USAGE
`BETOPTIC S Ophthalmic Suspension 0.25% has been
`shown to be effective in lowering intraocular pressure and
`may be used in patients with chronic open-angle glaucoma
`and ocular hypertension. It may be used alone or in combi-
`nation with other intraocular pressure lowering medica-
`tions.
`CONTRAINDICATIONS
`Hypersensitivity to any component of this product.
`BETOPTIC S Ophthalmic Suspension 0.25% is contraindi-
`cated in patients with sinus bradycardia, greater than a
`first degree atrioventricular block, cardiogenic shock, or pa-
`tients with overt cardiac failure.
`WARNING
`Topically applied beta-odrenergic blocking agents may be
`absorbed systemically. The same adverse reactions found
`with systemic administration of beta-adrenergic blocking
`agents may occur with topical administration. For example,
`severe respiratory reactions and cardiac reactions, includ-
`ing death due to bronchospasm in patients with asthma,
`and rarely death in association with cardiac failure, have
`been reported with topical application of beta-adrenergic
`blocking agents.
`BETOPTIC S Ophthalmic Suspension 0.25% has been
`shown to have a minor effect on heart rate and blood pres-
`sure in clinical studies. Caution should be used in treating
`patients with a history of cardiac failure or heart block.
`Treatment with BETOPTIC S Ophthalmic Suspension
`0.25% should be discontinued at the first signs of cardiac
`failure.
`PRECAUTIONS
`General:
`Diabetes Mellitus. Beta-adrenergic blocking agents should
`be administered with caution in patients subject to sponta-
`neous hypoglycemia or to diabetic patients (especially those
`with labile diabetes) who are receiving insulin or oral hypo-
`
`ALCON/487
`
`glycemic agents. Beta-adrenergic receptor blocking agents
`may mask the signs and symptoms of acute hypoglycemia.
`Thyrotoxicosis. Beta-adrenergic blocking agents may
`mask certain clinical signs (e.g., tachycardia) of hyperthy-
`roidism. Patients suspected of developing thyrotoxicosis
`should be managed carefully to avoid abrupt withdrawal of
`beta-adrenergic blocking agents, which might precipitate a
`thyroid storm.
`Muscle Weakness. Beta-adrenergic blockade has been re-
`ported to potentiate muscle weakness consistent with cer-
`tain myasthenic symptoms (e.g., diplopia, ptosis and gener-
`alized weakness).
`Major Surgery. Consideration should be given to the grad-
`ual withdrawal of beta-adrenei-gic blocking agents prior to
`general anesthesia because of the reduced ability of the
`heart to respond to beta-adrenergically mediated sympathe-
`tic reflex stimuli.
`Pulmonary. Caution should be exercised in the treatment
`of glaucoma patients with excessive restriction of pulmo-
`nary function. There have been reports of asthmatic attacks
`and pulmonary distress during betaxolol treatment. Al-
`though rechallenges of some such patients with ophthalmic
`betaxolol has not adversely affected pulmonary function test
`results, the possibility of adverse pulmonary effects in pa-
`tients sensitive to beta blockers cannot be ruled out.
`Information for Patients: Do not touch dropper tip to any
`surface, as this may contaminate the contents. Do not use
`with contact lenses in eyes.
`Drug Interactions: Patients who are receiving a beta-ad-
`renergic blocking agent orally and BETOPTIC S Ophthal-
`mic Suspension 0.25% should be observed for a potential ad-
`ditive effect either on the intraocular pressure or on the
`known systemic effects of beta blockade.
`Close observation of the patient is recommended when a
`beta blocker is administered to patients receiving catechol-
`amine-depleting drugs such as reserpine, because of possi-
`ble additive effects and the production of hypotension and/or
`bradycardia.
`Betaxolol is an adrenergic blocking agent; therefore, caution
`should be exercised in patients using concomitant adrener-
`gic psychotropic drugs.
`Risk from anaphylactic reaction: While taking beta -block-
`ers, patients with a history of atopy or a history of severe
`anaphylactic reaction to a variety of allergens may be more
`reactive to repeated accidental, diagnostic, or therapeutic
`challenge with such allergens. Such patients may be unre-
`sponsive to the usual doses of epinephrine used to treat an-
`aphylactic reactions.
`Ocular: In patients with angle-closure glaucoma, the im-
`mediate treatment objective is to reopen the angle by con-
`striction of the pupil with a miotic agent. Betaxolol has little
`or no effect on the pupil. When BETOPTIC S Ophthalmic
`Suspension 0.25% is used to reduce elevated intraocular
`pressure in angle-closure glaucoma, it should be used with a
`miotic and not alone.
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Life-
`time studies with betaxolol HCT have been completed in
`mice at oral doses of 6, 20 or 60 mg/kg/day and in rats at 3,
`12 or 48 mg/kg/day; betaxolol HC1 demonstrated no carcino-
`genic effect. Higher dose levels were not tested.
`In a variety of in vitro and in vivo bacterial and mammalian
`cell assays, betaxolol HCI was nonmutagenic.
`Pregnancy: Pregnancy Category C. Reproduction, tera-
`tology, and pen- and postnatal studies have been conducted
`with orally administered betaxolol HCI in rats and rabbits.
`There was evidence of drug related postimplantation loss in
`rabbits and rats at dose levels above 12 mg/kg and 128 mg/
`kg, respectively. Betaxolol HC1 was not shown to be terato-
`genic, however, and there were no other adverse effects on
`reproduction at subtoxic dose levels. There are no adequate
`and well-controlled studies in pregnant women. BETOPTIC
`S should be used during pregnancy only if the potential ben-
`efit justifies the potential risk to the fetus.
`Nursing Mothers:
`It is not known whether betaxolol HC1
`is excreted in human milk. Because many