`
`PHYSICIANS’
`SaSe
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1021, p. 001
`
`

`

`
`
`PDR
`
`EDITION
`
`PHYSICIANS
`EOK
`REFERENCE
`
`
`
`
`
`
`
`
`
`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
`Managerof 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
`SeniorDigital Imaging Coordinator: Shawn W. Cahill
`Digital Imaging Coordinator: Frank J. McElroy,III
`Electronic Publishing Designer: Livio Udina
`Fulfillment Manager: Stephanie DeNardi
`
`se Copyright©2000 and published by Medical Economics Company,Inc. at Montvale, NJ 07645-1742. All rights reserved. Noneofthecontent ofthis 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 PDR® Family
`Guide to Prescription Drugs* are registered trademarks used herein underlicense. PDR For Nonprescription Drugs and Dietary Supplements™, PDR Companion Guide™,
`PDR® for Herbal Medicines™, PDR® Medical Dictionary™, PDR® Nurse's Drug Handbook™, PDR® Nurse's Dictionary™, The PDR* Family Guide Encyclopedia of Medical
`Care™, The PDR® Family Guide to Natural Medicines and Healing Therapies™, The PDR® Family Guide to Common Ailments™, The PDR® Family Guide to Over-the-
`Counter Drugs™, and PDR® Electronic Library™ are trademarks used herein underlicense.
`
`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: Donna Santarpia; Senior Vice President,
`Directory Services: Paul Walsh; Senior Vice President, Operations: John R. Ware; Senior Vice President, Internet Strategies: Raymond Zoeller
`
`& Printed on recycled paper
`
`ISBN: 1-56363-330-2
`
`

`

`VEPLTTRCINE DECLAAWY3043
`
`DOSAGE AND
`ADMINISTRATION—PSYCHOTIC
`CHILDREN
`Dosage should be adjusted to the weight of the child and
`severity of the symptoms. These dosages are for children.
`sion.
`:
`ages 6 to 12, who are hospitalized or under close supervi-
`Oral: The starting dosage is 1 mg administered once a day
`or b.i.d. Dosage may be increased gradually until symptoms
`arecontrolled or until side effects become troublesome.
`
`producing someof the dystonic reactions described above.
`Symptomsofcentral nervous system depression to the point
`ofsomnolenceor coma, Agitation andrestlessness may also
`occur. Other possible manifestations include convulsions,
`EKG changes and cardiac arrhythmias, fever and auto-
`nomic reactions such as hypotension, dry mouth and ileus.
`TREATMENT—Itis important to determine other medica-
`tions taken by the patient since multiple dose therapyis
`common in overdosage situations. Treatmentis essentially
`symptomatic and supportive. Early gastric lavage is helpful.
`Keep patient under observation and maintain an open air-
`way, since involvement of the extrapyramidal mechanism
`may produce dysphagia and respiratory difficulty in severe
`overdosage. Do not attempt to induce emesis because a
`dystonic reaction of the head or neck may develop that
`could result in aspiration of vomitus. Extrapyramidal
`ees may be treated with anti-parkinsonism drugs,
`
` Neuroleptic Malignant Syndrome (NMS)has been reported
`
`
`ADVERSE REACTIONS
`Drowsiness, dizziness, skin reactions, rash, dry mouth,in-
`in association with antipsychotic drugs. (See WARNINGS.)
`somnia, amenorrhea, fatigue, muscular weakness, anorexia,
`Notall of the following adverse reactions have been ob-
`lactation, blurred vision and neuromuscular (extrapyrami-
`dal) reactions.
`served with every phenothiazine derivative, but they have
`been reported with one or more and should be-borne in mind
`Neuromuscular (Extrapyramidal) Reactions
`when drugs of this class are administered: extrapyramidal
`These symptoms are seen in a significant number of hospi-
`symptoms: (opisthotonos, oculogyric crisis, hyperreflexia,
`talized mental patients. They may be characterized by mo-
`dystonia, akathisia, dyskinesia, parkinsonism) some of
`tor restlessness, be of the dystonic type, or they may resem-
`which have lasted months and even years—particularly in
`ble parkinsonism.
`elderly patients with previous brain damage; grand mal and
`Depending on the Severity of symptoms, dosage should be
`petit mal convulsions, particularly in patients with EEG ab-
`reducedor discontinued. Iftherapyis reinstituted,it should
`normalities or history of such disorders: altered cerebrospi-
`quire higher dosages.
`be at a lower dosage..Should these symptoms occur in chil-
`nal fluid proteins: cerebral edema;intensification and pro-
`Intramuscular: There has beenlittle experience with the
`dren or pregnant patients, the drug should be stopped and
`longation of the action of central nervous system depres-
`use of Stelazine (trifluoperazine HCl) Injection in children.
`not reinstituted. In most cases barbiturates by suitable
`However,ifit is necessary to achieve rapid control ofsevere
`sants (opiates, analgesics, antihistamines, barbiturates,
`
`route. of administration.will. (Or,-injectablesuffice.
`
`alcohol}, atropine, heat, organophosphorus insecticides; au-
`symptoms, 1 mg,('/. mL) of the drug may be administered
`Benadryl®"may be useful.) In more severe cases, the ad-
`intramuscularly once or twice a day.
`tonomic reactions (dryness of mouth, nasal congestion,
`ministration of an anti-parkinsonism agent, except
`headache, nausea, constipation, obstipation, adynamicil-
`OVERDOSAGE
`levodopa, usually produces rapid reversal.of symptoms.
`eus, ejaculatory disorders/impotence, priapism, atonic co-
`Suitable supportive measures such as maintaining a clear
`lon, urinary retention, miosis and mydriasis); reactivation
`airway and adequate hydration should be employed.
`of psychotic Processes, catatonic-like states: hypotension
`Motor Restlessness: Symptoms may include agitation or
`(sometimesfatal); cardiac arrest; blood dyscrasias (pancyto-
`Jitteriness and sometimes insomnia. These symptoms often
`penia, thrombocytopenic purpura, leukopenia, agranulocy-
`disappear spontaneously. At times these symptoms may be
`tosis, eosinophilia, hemolytic anemia, aplastic anemia):
`similar to the original neurotic or psychotic symptoms. Dos-
`liver damage (jaundice, biliary stasis); endocrine disturb-
`age should not be increased until these side effects have
`ances (hyperglycemia, hypoglycemia, glycosuria, lactation,
`subsided,
`1
`galactorrhea, gynecomastia, menstrual irregularities,false-
`If this phase becomes too troublesome, the symptoms can
`positive pregnancy tests); skin disorders (photosensitivity,
`usually be controlled by a reduction of dosage or change of
`itching, erythema, urticaria, eczema up to exfoliative der.
`drug. Treatment with anti-parkinsonian agents, benzodiaz-
`matitis); other allergic reactions (asthma, laryngeal edema,
`epines or propranolol may be helpful.
`angioneurotic edema, anaphylactoid reactions): peripheral
`Dystonias: Symptoms may include: spasm of the neck
`edema; reversed epinephrine effect; hyperpyrexia; mild fe-
`muscles,’ sometimes progressing to torticollis; extensor ri-
`ver after large I.M. doses; increased appetite; increased
`gidity of back muscles,-sometimes progressingto opisthoto-
`weight; a systemic lupus erythematosus-like syndrome;pig-
`nos; carpopedal spasm, trismus, swallowing difficulty, ocu-
`mentary retinopathy: with prolonged administration ofsub-
`logyric crisis and protrusion ofthe tongue.
`stantial doses, skin pigmentation, epithelial keratopathy,
`These usually subside within a few hours, and almost al-
`and lenticular and corneal deposits.
`wayswithin 24 to 48 hours,after the drug has been discon-
`EKG changes—particularly nonspecific, usually reversible
`tinued.
`Q and T wave distortions—have been observed in somepa-
`respiratory depression, If administration of a stimulantis
`In mild cases, reassurance or a barbiturate is often suffi-
`tients receiving phenothiazine tranquilizers. Although phe-
`desirable, amphetamine, dextroamphetamine or caffeine
`cient. In moderate cases, barbiturates will usually bring
`with sodium: benzoate ig recommended. Stimulants that
`nothiazines cause neither psychic nor physical dependence,
`rapid relief. In more severe adult cases, the administration
`sudden discontinuance in long-term psychiatric patients
`may cause convulsions(e.g., picrotoxin or pentylenetetrazol)
`should be avoided.
`of an anti-parkinsonism agent, except levodopa, usually
`May cause temporary symptoms, e.g., nausea and vomiting,
`Ifhypotension occurs, the standard measures for managing
`dizziness, tremulousness,
`produces rapid reversal ofsymptoms. Also, intravenous caf-
`circulatory shock should be initiated. Ifit is desirable to ad-
`feine with sodium benzoate seems ta be effective. In chil-
`Note: There have been occasional reports ofsudden death
`minister a vasoconstrictor, Levophed and Neo-Synephrine
`dren, reassurance and barbiturates will usually control
`in patients receiving phenothiazines. In some cases, the
`are most suitable. Other pressor agents, including epineph-
`symptoms. (Or, injectable Benadryl may be useful.) Note:
`cause appeared to be cardiac arrest or asphyxia due to fail-
`rine, are not recommended because phenothiazine deriva-
`See Benadryl prescribing information for appropriate chil-
`ure of the cough reflex,
`.
`tives may reverse the usual elevating action ofthese agents
`dren's dosage. If appropriate treatment with anti-parkin-
`DOSAGE ANDADMINISTRATION—ADULTS
`and cause a further lowering ofblood pressure.
`:
`sonism agents or Benadryl fails to reverse the signs and
`Dosage should be adjusted to the needs of the individual.
`Limited experienceindicates that phenothiazines arenotdi-
`symptoms, the diagnosis should be reevaluated.
`alyzable.
`The lowest effective dosage should always be used. Dosage
`Pseudo-parkinsonism: Symptoms may include: mask-like
`should be increased more gradually in debilitated or emaci-
`HOW SUPPLIED
`facies; drooling: tremors; pill-rolling motion; cogwheel Tigid-
`ated patients, When maximum response is achieved, dosage
`ity; and shuffling gait. Reassurance and sedation are impor-
`Tablets, 1 mg, 2 mg, 5 mg and 10 ing in bottles of 100;
`may be reduced gradually to a maintenance level. Because
`tant. In most cases these symptoms are readily controlled
`1 mg 100’s: NDC 0108-4903-20
`ofthe inherent long action ofthe drug, patients may be con-
`when an anti-parkinsonism agent is administered concomi-
`2 mg 100's: NDC 0108-4904-20
`trolled on convenient b.id. administration; some patients
`tantly. Anti-parkinsonism agents should be used only when
`5 mg 100’s: NDC 0108-4906-20
`may be maintained on once-a-day administration,
`required. Generally, therapyofa few weeks to 2 to 3 months
`10 mg 100’s: NDC 0108-4907-20
`WhenStelazine(trifluoperazine HCl)is administered by in-
`will suffice. After this time patients should be evaluated to
`Multi-Dose Vials, 10 mL (2 mg/mL), in I's:
`tramuscular injection, equivalent oral dosage may be sub-
`NDC 0108-4902-01
`determine their need for continued treatment.
`(Note:
`stituted once symptoms have been controlled.
`Levodopa has notbeen found effective in pseudo-parkinson-
`Concentrate (for institutional use), 10 mg/mL, in 2 fl oz
`Note: Althoughthere islittle likelihood of contact derma-
`ism.) Occasionally it is necessary to lowerthe dosage ofStel-
`bottles and in cartons of 12 bottles,
`titis due to the drug, persons with known sensitivity to phe-
`azine (trifluoperazine HCl)or to discontinue the drug.
`The Concentrate form is light-sensitive. For this reason,it
`nothiazine drugs should avoid direct contact.
`Tardive Dyskinesia: As with all antipsychotic agents, tar-
`should be protected from light and dispensed in amber
`Elderly Patients:
`In general, dosages in the lower range
`ive dyskinesia may appear,in some patients on long-term
`bottles. Refrigeration is not required,
`are sufficientfor most elderly patients. Since they appear to
`therapy or may appear after drug therapy has been discon-
`10 mg/mL 2 fl oz (carton of 12): NDC 0108-4901-42
`be more susceptible to hypotension and neuromuscular re-
`tinued. The syndrome can also develop, although much less
`Store all Stelazine (trifluoperazine HCl) formulations be-
`actions, such patients should be observed closely. Dosage
`frequently, after relatively brief treatment periods at low
`tween 15° and 30°C (59° and 86°F).
`shouldbe tailored to the individual, responsecarefully mon-
`doses. This syndrome appears in all age groups. Although
`itored, and dosage adjusted accordingly. Dosage should be
`its prevalence appears to be highest among elderly patients,
`*“ norepinephrine bitartrate, Sanofi Winthrop Pharmaceuti-
`increased more gradually in elderly patients.
`cals.
`especially elderly women,it is impossible to rely upon prev-
`Non-psychotic Anxiety
`alence estimates to predict at the inception of neuroleptic
`+ phenylephrine hydrochloride, Sanofi Winthrop Pharma-
`Usual dosage is 1 or 2 mg twice daily. Do not administer at
`ceuticals.
`‘
`treatment which patients are likely to develop the syn-
`doses of more than 6 mg per day or for longer than 12
`weeks,
`f
`+ phenytoin, Parke-Davis.
`drome. The symptoms are persistent and in somepatients
`§ metrizamide, Sanofi Winthrop Pharmaceuticals,
`appear to be irreversible. The syndromeis characterized by
`Psychotic Disorders
`f
`rhythmical involuntary movements of the tongue, face,
`diphenhydramine hydrochloride, Parke-Davis,
`Oral: Usual starting dosage is 2 mg to 5 mg b.i.d. (Small or
`mouth or jaw (e.g., protrusion of tongue, puffing of cheeks,
`Veterans Administration/Military/PHS—Injection, 2 meg/
`emaciated patients should always be started on the lower
`mL, 10 mL, 1’s, 6505-01-220-1479; Tablets, 1 mg, 100’s,
`puckering ofmouth, chewing movements). Sometimes these
`dosage.)
`f
`6505-00-761-5658; 2 mg, 100's, 6505-01-361-5235; 5 mng,
`may be accompanied by involuntary movements of extrem-
`Most patients will show optimum response on 15 mg or 20
`ities. In rare instances, these involuntary movements ofthe
`100’s, 6505-01-311-3784; 10 mg, 100’s, 6505-01-246-1918.
`mgdaily, although a few may require 40 mg a day or more.
`SZ:L70
`extremities are the only manifestations of tardive dyskine-
`Optimum therapeutic dosage levels should be reached
`sia, A variant of tardive dyskinesia, tardive dystonia, has
`Shown in Product Identification Guide, page 339
`within 2 or 3 weeks.
`-
`also been described.
`seepEneaeOEaee
`When the Concentrate dosage form is to be used, it should
`There is no known effective treatment for tardive dyskine-
`be added to 60 mL (2 fl oz) or more of diluentjust prior to
`sia; anti-parkinsonism agents do not alleviate the symp-
`administration to insure palatability and stability. Vehicles
`toms of this syndrome.Ifclinically feasible, it is suggested
`suggested for dilution are: tomatoorfruitjuice, milk, simple
`that all antipsychotic agents be discontinued ifthese symp-
`Syrup, orange syrup, carbonated beverages, coffee, tea or
`toms appear. Should it be necessary to reinstitute treat-
`water. Semisolid foods (soup, puddings, etc.) may also be
`used.
`ment, or increase the dosage ofthe agent, or switch to a dif-
`ferent antipsychotic agent, the syndrome may be masked.
`Intramuscular (for prompt control of severe symptoms):
`It has been reported thatfine vermicular movements of the
`Usual dosage is 1 mg to 2:mg (1/, to 1 mL) by deep intra-
`tongue maybe an early sign ofthe syndrome and ifthe med-
`muscular injection q4 to 6h, p.r.n. More than 6 mg within 24
`ication is stopped at that time the syndrome may not de-
`velop.
`hours is rarely necessary,
`Onlyin very exceptional cases should intramuscular dosage
`Adverse Reactions Reported withStelazine(trifluoperazine
`exceed 10 mg within 24 hours. Injections should not be
`HCl) or Other Phenothiazine Derivatives: Adverse effects
`given at intervals ofless than 4 hours becauseofa possible
`with different phenothiazines vary in type, frequency, and
`cumulative effect.
`mechanism of occurrence, i.e., some are dose-related, while
`Note: Stelazine (trifluoperazine HCl) Injection has been
`others involve individual patient sensitivity. Some adverse
`usually well tolerated and there is little, if any, pain and
`effects may be more likely to occur, or occur with greater
`irritation at the site of injection.
`:
`intensity, in patients with special medical problems, eg.,
`This solution should be protected from light. This is a clear,
`patients with mitral insufficiency or pheochromocytoma
`colorless to pale yellow solution; a slight yellowish discolor.
`have experienced severe hypotension following recom-
`ation will not alter potency, Ifmarkedly discolored, solution
`ghanld hea Atansel3
`mended doses of certain
`iazines,
`—
`
`RE
`
`TAGAMET®
`[tag ‘ah-met |
`brand of cimetidine tablets
`cimetidine hydrochloride liquid and
`cimetidine hydrochloride injection
`DESCRIPTION
`Tagamet(cimetidine) is a histamine H,-receptor antagonist.
`Chemically it is N "-cyano- N -methyl-N '-[2-[[(5-methyl-1
`H-imidazol-4-yl) methyl] thio]-ethy]]-guanidine.
`
`Continued on next page
`
`Information on the SmithKline Beecham Pharmaceuticals
`Products appearing here is based on the labeling in effect on
`June 15, 1999. Further information on these and other
`products may be obtained from the Medical Department,
`Dhiladtelehkt«. PA “Bane
`SmithKline Beecham Pharmaceuticals, One Franklin Plaza,
`
`

`

`Tagamet—Cont.
`
`The empirical formulafor cimetidine is C,)H,,N,S and for
`cimetidine hydrochloride, C,>H,,N,SHCI; these represent
`molecular weights of 252.34 and 288.80, respectively.
`
`CH;
`
`—
`
`a
`H,5CH,CHjNHCNHCH,
`N-CaN
`
`‘
`7
`HN V2 N
`Cimetidine
`
`= = least 50%. During the subsequent 2 hours Taga-
`
`FC.
`Duodenal Ulcer Healing Rates’
`with Various Tagamet Dosage Regimens*
`
`300 mg
`400 mg
`800 mg
`1600 mg
`Regimen
`gid,
`b.i.d.
`hs,
`hs.
`
`week 4
`68%
`73%
`80%
`86%
`week 6
`80%
`80%
`89%
`=
`week 8
`_
`92%
`94%
`_—
`
`* Averages from controlled clinical trials.
`
`met inhibited gastric acid secretion by at least 75%.
`The effect of a 300 mg breakfast dose of Tagamet con-
`tinued for at least 4 hours and there was partial sup-
`pression of the rise in gastric acid secretion following
`the luncheon meal in duodenal ulcer patients. This
`suppression of gastric acid output was enhanced and
`could be maintained by another 300 mg dose of Taga-
`met given with lunch.
`In another study, Tagamet 300 mg given with the meal
`increased gastric pH as compared with placebo.
`
`1 hour
`2 hours
`3 hours
`4 hours
`
`Mean Gastric pH
`Tagamet
`Placebo
`3.6
`2.6
`8.1
`1.6
`3.8
`19
`6.1
`2.2
`
`Stimulant
`Betazole
`
`Pentagastrin
`
`Stimulant
`% Inhibition
`Tagamet
`Dose
`85% at 24/5
`300mg
`1.5mg/kg
`hours
`(po)
`(sc)
`60% at 1
`100mg/hr
`6mceg/kg/
`hour
`(iv)
`hr (iv)
`100%at 1
`300mg
`5:
`hour
`(po)
`hr (iv)
`82% at 1
`100mg/hr
`0.03 units/
`Insulin
`
`
`(iv)kg/hr(iv) hour
`
`Caffeine
`
`
`
`AU.S., double-blind, placebo-controlled, dose-ranging
`study demonstrated that all once-daily at bedtime (h.s.)
`Cimetidine contains an imidazole ring, and is chemically re-
`Tagamet regimens were superior to placebo in ulcer heal-
`lated to histamine.
`ing and that Tagamet 800 mgh.s. healed 75% of patients
`(Theliquid and injection dosage forms contain cimetidine as
`at 4 weeks. The healing rate with 800 mg h.s. was signif-
`the hydrochloride.)
`icantly superior to 400 mg h.s. (66%) andnot significantly
`Cimetidine hasabitter taste and characteristic odor.
`24-Hour Mean H* Activity: Tagamet 800 mg h.s., 400
`different from 1600 mg h.s. (81%).
`mg bid. and 300 mg q.i.d. all provide a similar, moderate
`Solubility Characteristics: Cimetidine is soluble in alcohol,
`In the U.S. dose-ranging trial, over 80% of patients re-
`{less that 60%) level of 24-hour acid suppression. However,
`slightly soluble in water, very slightly soluble in chloroform
`ceiving Tagamet 800 mg h.s. experienced nocturnal pain
`the 800 mg h.s, regimen exerts its entire effect on nocturnal
`and insoluble in ether. Cimetidine hydrochloride is freely
`relief after 1 day. Relief from daytime pain was reported
`acid, and does not affect daytime gastric physiology.
`soluble in water, soluble in alcohol, very slightly soluble in
`in approximately 70% of patients after 2 days. As with
`Chemically Stimulated: Oral Tagamet (cimetidine) sig-
`chloroform and practically insoluble in ether.
`ulcer healing, the 800 mg h.s. dose was superior to 400
`nificantly inhibited gastric acid secretion stimulated by be-
`Tablets for Oral Administration: Each light green, film-
`mgh.s. and not different from 1600 mg h.s.
`tazole (an isomer of histamine), pentagastrin, caffeine and
`coated tablet contains cimetidine as follows: 200 mg—
`insulin as follows:
`In foreign, double-blind studies with Tagamet 800 mg
`round, imprinted with the product name TAGAMET, SKF
`h.s., 79% to 85% of patients were healed at 4 weeks,
`and 200; 300 mg—round, debossed with the product name
`While short-term treatment with Tagamet (cimetidine)
`TAGAMET,SB and 300; 400 mg—oval Tiltab® tablets, de-
`ean result in complete healing of the duodenal ulcer,
`bossed with the product name TAGAMET,SB and 400; 800
`acute therapy will not prevent ulcer recurrence after
`mg—oval Tiltab® tablets, debossed with the product name
`Tagamet has been discontinued. Some follow-up studies
`TAGAMET,SBE and 800. Inactive ingredients consist of cel-
`have reported that the rate of recurrence once therapy
`lulose, D&C Yellow No. 10, FD&C Blue No. 2, FD&C Red
`was discontinued was slightly higher for patients healed
`No. 40, FD&C Yellow No. 6, hydroxypropyl methylcellulose,
`on Tagamet than for patients healed on other formsof
`iron oxides, magnesium stearate, povidone, propylene gly-
`therapy; however, the Tagamet-treated patients generally
`had more severe disease.
`col, sodium lauryl sulfate, sodium starch glycolate, starch,
`titanium dioxide and trace amounts ofother inactive ingre-
`Maintenance Therapy in Duodenal Ulcer: Treatment
`dients.
`with a reduced dose of Tagamet has been proven effective
`Liquid for Oral Administration: Each 5 mL (1 teaspoonful)
`as maintenance therapy following healing of active duo-
`denal ulcers.
`of clear, light orange, mint-peach flavored liquid contains ci-
`metidine hydrochloride equivalent to cimetidine, 300 mg;
`In numerousplacebo-controlled studies conducted world-
`alcohol, 2.8%. Inactive ingredients consist of FD&C Yellow
`wide, the percent of patients with observed ulcers at the
`No. 6, flavors, methylparaben, polyoxyethylene polyoxypro-
`end of 1 year’s therapy with Tagamet 400 mg h.s, was sig-
`pylene glycol, propylene glycol, propylparaben, saccharin
`nificantly lower (10% to 45%) than in patients receiving
`sodium, sodium chloride, sodium phosphate, sorbitol and
`water.
`placebo (44% to 70%). Thus, from 55% to 90% of patients
`were maintained free of observed ulcers at the end of 1
`Injection:
`year with Tagamet 400 mg h.s.
`»
`:
`Single-Dose Vials for Intramuscular or Intravenous Admin-
`Factors such as smoking, duration and severity of dis-
`istration: Each 2 mL contains,in sterile aqueous solution
`ease, gender, and genetic traits may contribute to varia-
`(pH range 3.8 to 6), cimetidine hydrochloride equivalent to
`tions in actual percentages.
`cimetidine, 300 mg; phenol, 10 mg.
`Trials of other anti-ulcer therapy, whether placebo-con-
`Multi-Dose Vials for Intramuscularor Intravenous Adminis-
`trolled, positive-controlled or open, have demonstrated a
`tration:
`& mL (300 mg/2 mL): Each 2 mL contains,in ster-
`range of results similar to that seen with Tagamet.
`ile aqueous solution (pH range 3.8 to 6), cimetidine hydro-
`Active Benign Gastric Ulcer
`chloride equivalentto cimetidine, 300 mg; phenol, 10 mg.
`Tagamet has been shownto be effective in the short-term
`Single-Dose Premixed Plastic Containers for Intravenous
`treatment of active benign gastric ulcer.
`Administration: Each 50 mL of sterile aqueous solution
`In a multicenter, double-blind U.S. study, patients with
`(pH range 5 to 7) contains cimetidine hydrochloride equiva-
`endoscopically confirmed benign gastric ulcer were
`lent to 300 mg cimetidine and 0.45 grams sodium chloride.
`treated with Tagamet 300 mg four times a day or with
`No preservative has been added.
`placebo for 6 weeks. Patients were limited to those with
`The plastic container is fabricated from specially formu-
`ulcers ranging from 0.5 to 2.5 cm in size. Endoscopically
`lated polyvinyl chloride. The amountof water that can per-
`confirmed healing at 6 weeks was seen in significantly*
`meate from inside the container into the overwrapis insuf-
`more Tagamet-treated patients than in patients receiving
`ficient to affect the solution significantly. Solutions in con-
`placebo, as shown below:
`tact with the plastic container can leach out certain of its
`chemical components in very small amounts within the ex-
`Tagamet
`14/63 (22%)
`piration period, e.g., di 2-ethylhexyl phthalate (DEHP), up
`43/65 (66%) *
`to 5 parts per million, However, the safety of the plastic has
`been confirmedin tests in animals according to the USP bi-
`ological tests for plastic containers as well as by tissue cul-
`ture toxicity studies.
`ADD-Vantage®* Vials for Intravenous Administration:
`Esch 2 mL contains, in sterile aqueous solution (pH range
`48 to 6), cimetidine hydrochloride equivalentto cimetidine,
`300 mg; phenol, 10 mg.
`At of the aboveinjection formulations are pyrogenfree, and
`sedium hydroxide N_F.is used as an ingredient to adjust the
`oe
`CLINICAL PHARMACOLOGY
`Tagemet (cimetidine) competitively inhibits the action of
`‘sstamiine at the histamine H, receptors of the parietal cells
`aed thus is a histamine H,-receptor antagonist.
`Tseemet is not an anticholinergic agent. Studies have
`seen that Togamet inhibits both daytime and nocturnal
`wesel gastric acid secretion. Tagamet also inhibits gastric
`®e© secretion stimulated by food, histamine, pentagastrin,
`eee and insulin.
`SeGsecretory Activity
`| Acid Secretion: Nocturnal: Tagamet 800 mgorally at
`Sedtime reduces mean hourly H*activity by greater
`‘een 85% over an 8-hour period in duodenal ulcer pa-
`Gents, with no effect on daytime acid secretion. Taga-
`wer 1600 mgorally h.s. produces 100% inhibition of
`meen hourly H*activity over an 8-hour period in duo-
`‘ezal ulcer patients, but also reduces H* activity by
`© for an additional 5 hoursinto the following morn-
`me. Tagamet 400 mg b.i.d. and 300 mg q.i.d. decrease
`seeternal acid secretion in a dose-related manner,i.e.,
`27% t 83% over a 6- to 8-hour period and 54% over a
`SSeur period, respectively.
`Seed Stimulated: During the first hour after a stan-
`ere experimental meal, oral Tagamet 300 mg inhib-
`“et esstric acid secretion in duodenal ulcer patients
`
`
`When food and betazole were used to stimulate secre-
`tion, inhibition of hydrogen ion concentration usually
`ranged from 45% to 75% and the inhibition of volume
`ranged from 30% to 65%.
`Parenteral administration also significantly inhibits
`gastric acid secretion. In a crossover study involving
`patients with active or healed duodenal or gastric ul-
`cers, cither continuous I.V. infusion of Tagamet 37.5
`mg/hour (900 mg/day) or intermittent injection of
`Tagamet 300 mg q6h (1200 mg/day) maintained gastric
`pH above 4.0 for more than 50% of the time under
`steady-state conditions.
`2) Pepsin: Oral Tagamet 300 mg reduced total pepsin
`output as a result of the decrease in volumeofgastric
`Juice.
`3) Intrinsic Factor:
`Intrinsic factor secretion was studied
`with betazole as a stimulant. Oral Tagamet 300 mg in-
`hibited the rise in intrinsic factor concentration pro-
`duced by betazole, but some intrinsic factor was se-
`creted at all times.
`*“ADD-Vantage® is a trademark of Abbott Laboratories.
`Other
`:
`Lower Esophageal Sphincter Pressure and Gastric Emp-
`tying
`Tagamet has no effect on lower esophageal sphincter
`(LES) pressure or the rate of gastric emptying.
`Pharmacokinetics
`Tagamet is rapidly absorbed after oral administration
`and peak levels occur in 45 to 90 minutes. The half-life of
`Tagametis approximately 2 hours. Both oral and paren-
`teral (LV. or I.M.) administration provide comparable pe-
`riods of therapeutically effective blood levels; blood con-
`centrations remain above that required to provide 80%
`inhibition of basal gastric acid secretion for 4 to 5 hours
`following a dose of 300 mg.
`Steady-state blood concentrations of cimetidine with con-
`tinuous infusion of Tagamet are determined by the infu-
`sion rate and clearance of the drug in the individual pa-
`tient. In a study of peptic ulcer patients with normalre-
`nal function, an infusion rate of 37.5 mg/hour produced
`average steady-state plasma cimetidine concentrations of
`about 0.9 mcg/mL. Blood levels with other infusion rates
`will vary in direct proportion to the infusion rate.
`The principal route ofexcretion of Tagamet is the urine.
`Following parenteral administration, most of the drug is
`excreted as the parent compound; following oral adminis-
`tration, the drug is more extensively metabolized, the
`sulfoxide being the major metabolite. Following a single
`oral dose, 48%of the drug is recovered from the urineaf-
`ter 24 hours as the parent compound. Following I.V. or
`LM. administration, approximately 75% of the drugis re-
`covered-from the urine after 24 hours as the parent com-
`pound.
`CLINICAL TRIALS
`Duodenal Ulcer
`Tagamet (cimetidine) has been shown to be effective in
`the treatment of active duodenal ulcer and, at reduced
`dosage, in maintenance therapy following healing of ac-
`tive ulcers.
`Active Duodenal Ulcer: Tugamet accelerates the rate of
`duodenal ulcer healing. Healing rates reported in U.S.
`and foreign controlled trials with Tagamet are summa-
`rized below, beginning with the regimen providing the
`lowest nocturnal dose.
`
`week 2
`total at week 6
`
`*p<0.05
`
`Placebo
`‘7/63 (11%)
`30/67 (45%)
`
`In a similar multicenter U.S. study of the 800 mg h.s. oral
`regimen, the endoscopically confirmed healing rates
`were:
`
`Tagamet
`63/83 (76%) *
`
`Placebo
`44/80 (55%)
`
`total at week 6
`
`*p = 0.005
`
`Similarly, in worldwide double-blind clinical studies, en-
`doscopically evaluated benign gastric ulcer healing rates
`were consistently higher with Tagamet than with pla-
`cebo,
`Gastroesophageal Reflux Disease
`In two multicenter, double-blind, placebo-controlled stud-
`ies in patients with gastroesophageal reflux disease
`(GERD)and endoscopically proven erosions and/orulcers,
`Tagamet was significantly more effective than placebo in
`healing lesions. The endoscopically confirmed healing
`rates were:
`
`p-Value
`(800 mg
`Tagamet Tagamet
`bid. vs.
`(800 mg (400 mg
`
` Trial bid.) q.id.) Placebo placebo)
`
`
`1
`Week 6
`45%
`52%
`26%
`0.02
`Week 12
`60%
`66%
`42%
`0.02
`Week 6
`50%
`20%
`<0.01
`Week 12
`67%
`36%
`<0.01
`
`2
`
`In these trials Tagamet was superior to placebo by most
`measures in improving symptomsof day- and night-time
`
`

`

` mg h.s. regimen, particularly in subjects aged 54 years and
`
`
`heartburn, with many of the differences statistically sig-
`nificant. The q.id. regimen was generally somewhat bet-
`ter than the b.id. regimen where these were compared.
`Prevention of Upper Gastrointestinal Bleeding in Criti-
`cally Ill Patients
`A double-blind, placebo-controlled randomized study of
`continuous infusion cimetidine was performed in 131crit-
`ically ill patients (mean APACHE II score = 15.99) to com-
`pare the incidence of upper gastrointestinal bleeding,
`manifested as hematemesisor bright red blood which did
`not clear after adjustment of the nasogastric tube and a 5
`to 10 minute lavage, persistent Gastroccult® positi