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`___D_E__S_;K_____
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1021, p. 001
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`

`ADVERSE REACTIONS
`Drowsiness, dizziness, skin reactions, rash, dry mouth, in—
`somnia, amenorrhea, fatigue, muscular weakness, anorexia.
`lactation, blurred vision and neiuomuscular (extrapyrami—
`dal) reactions.
`Neuromuscular [Extrapyramldall Reactlons
`These symptoms are seen in a significant number of hospi-
`talised mental patients. They may be characterized by mo-
`tor restlessness, be of the dystonic type, or they may resem-
`ble parkinsonism.
`
`Depending on the severity of symptoms, dosage should be
`reduced or discontinued. If therapy is reinstituted, it should
`be at a lower dosage,.Should these symptoms occur in chil-
`dren or pregnant patients, the drug should be stopped and
`not reinstituted. in most cases barbiturates by suitable
`route of administration will sufice.
`(0r,
`injectable
`Benadryl®" may be useful.) In more severe cases, the ad-
`ministration of an anti-parkinsonism agent, except
`levodopa, usually produces rapid reversalof symptoms.
`Suitable supportive measures such as maintaining a clear
`airway and adequate hydration should be employed.
`
`
`
`If this phase becomes too troublesome, the symptoms can
`usually be controlled by a reduction of dosage or change of
`drug. Treatment with anti-parkinsonian agents, benzodias—
`epines or propranolol may be helpful.
`Dystnnias: Symptoms may include: spasm of the neck
`muscles, sometimes progressing to torticollis; extensor ri-
`gidity of back muscles, sometimes progressing to opisthoto-
`nos; carpopedal spasm, trismus, swallowing difl‘iculty, ocu-
`logyric crisis and protrusion of the tongue.
`These usually subside within a few hours, and almost al-
`tinued.
`ways-within 24- oz: 43 hours, after the drug has been discon-
`
`in mild cases, reassurance or a barbiturate is often sufi-
`cient. In. moderate cases, barbiturates will usually bring
`rapid relief. in more severe adult cases, the administration
`of an anti-parkinsonism agent, except levodopa, usually
`produces rapid reversal of symptoms. Also, intravenous caf-
`feine with sodium benzoate seems to be efl‘ective. in chil-
`dren, reassurance and barbiturates will usually control
`symptoms. (Or, injectable Benodiyl may be useful.) Note:
`See Beaodryl prescribing information for appropriate chil-
`dren‘s dosage. If appropriate treatment with anti-parkin-
`sonism agents or Bencdiyl fails to reverse the signs and
`symptoms, the diagnosis should be reevaluated.
`Pseudo-parklneoniam: Symptoms may include: mask—like
`facies; drooling; tremors: pill-rolling motion; cogwheel rigid-
`ity; and shuflling gait. Reassurance and sedation are impor—
`tant. In most cases these symptoms are readily controlled
`when an anti-parkinsonism agent is administered concomi—
`tantly. Anti-parkinsonism agents should be used only when
`required. Generally, therapy of a few weeks to 2 to 3 months
`will suflice. Alter this time patients should be evaluated to
`determine their need for continued treatment.
`(Note:
`levodopa has not been found efl'ective in pseudo—parkinson—
`ism) Occasionally it is necessary to louver the dosage of Stel-
`asine (triflucperazine HCl) or to discontinue the drug.
`
`therapy or may appear afici- drug therapy has been discon-
`‘
`. The syndrome can also develop, although much less
`frequently, alter relatively brief treatment periods at low
`doses. This syndrome appears in all age groups. Although
`its prevalence appears a: be highest among elderly patients.
`especially elderly women, it is impossible to rely upon prev—
`alence estimates to predict at the inception of neurcleptic
`treatment which patients are likely to develop the syn—
`drome, The symptoms are persistent and in some patients
`appear to be irreversible. The syndrome is characterised by
`rhythmical involuntary movements of the tongue, face,
`mouth or jaw (e.g., protrusion of tongue, puffing of checks,
`puckerlng of mouth, chewing movements). Sometimes these
`may be accompanied by involuntary movements of extrem-
`ities. In rare instances, these involuntary movements of the
`extremities are the only manifestations of tardive dyskine-
`sin, A variant of tardive dyskinesia, tardive dystonia, has
`also been described.
`
`There is no known efl‘ective treatment for tardive dyskine-
`sis; anti—parkinsonism agents do not alleviate the symp-
`mms of this syndrome. If clinically feasible, it is su
`that all antipsychotic agents be discontinued ifthese symp-
`toms appear. Should it be necessary to reinstitute treat—
`ment, or increase the dosage ofthe agent, or switch to a dif-
`ferent antipsychotic agent, the syndrome may be masked.
`It has been reported that fine vermicular movements of the
`tongue may be an early sign of the syndrome and if the med-
`ication is stopped at that time the syndrome may not de-
`velop.
`
`Adverse Reactions Reported with Stelazine itrifluoperazine
`HCI) or Other Phenothiezlne Derivatlvee: Adverse efl'ecta
`with diferent phenothiazines vary in type, frequency, and
`mechanism of oocm'rence, i.e., some are dose-related, while
`others involve individual patient sensitivity. Some adverse
`efi‘ects may he more likely to occur, or occur with greater
`intensity, in patients with special medical problems, e.g.,
`patients with mitral insulficiency or pheochromocytoma
`have experienced severe hypotension following recom-
`mended doses ofmWee _
`
`Gal: Usual starting dosage is 2 mg to 5 mg b.i.d. {Small or
`emaciated patients should always be started on the lowor
`dosage.)
`'
`
`Most patients will show optimum response on 15 mg or 20
`mg daily, although a few may require 40 mg a day or more.
`Optimum therapeutic dosage levels should he reached
`within 2 or 3 weeks.
`'
`
`When the Concentrate dosage lbrm is to be used, it should
`be added to 60 ml. (2 ii or.) or more of diluent just prior to
`administration to insure palatability and stability. Vehicles
`suggested ibr dilution are: tomato or fruit juice, milk, simple
`syrup, orange syrup, carbonated beverages, codee, tea or
`used.
`water. Semisolid foods (soup, puddings, etc.) may also be
`
`intramuscular (for prom condo! of severe symptom}:
`Usual dosage is 1 mg to 2mg (1!, to 1 mL) by deep intra-
`muscular injection q4 to 6b, p.r.n. More than 6 mg within 24
`hours is rarely necessary.
`Only in very exceptional cases should intramuscular dosage
`exceed 10 mg within 24 hours. Iniections should not be
`cumulative effect.
`given at intervals of less than at hours because of a possible
`
`Note: Stelsaine {trifluoperazirie HCl} Injection has been
`usually well tolerated and there is little, if any, pain and
`imitation at the site of injection.
`_
`This solution should be protected from light, This is a clear,
`colorless to pale yellow solution; a slight yellowish discolor-
`shnlilrl ho (limo-Ad
`ation will not alter potency. If markedly discolored, solution
`
`Neuroleptic Malignant Syndrome (NMS) has been reported
`in association with antipsychotic drugs. {See WARNINGS.)
`Not all of the following adverse reactions have been ob-
`served with every phenothiazine derivative, but they have
`inen reported with one or more and should be-borne in mind
`when drugs of this class are administered: extrapyramidal
`symptoms (opisthotonos, oculogyric crisis. hyperreflexia.
`dystonia, akathisia, dyskinesia, parkinscnism) some of
`which have lasted months and even years—particularly in
`elderly patients with previous brain damage; grand mal and
`petit mal convulsions, particularly in patients with EEG ab-
`normalities or history of such disorders; altered cerebrospi—
`as] fluid proteins; cerebral edema; intensification and pro-
`longation of the action of central nervous system depres-
`sants (opiates, analgesics, antihistamines, barbiturates,
`alcohol), atropine, beat, organophosphoms insecticides; au-
`tonomic reactions {dryness of mouth, nasal congestion,
`headache, nausea, constipation, obstipation, adynamic il-
`eus, ejaculatory disorders'impotence, priapism, atonic co-
`lon, urinary retention, mioais and mydriaaia); reactivation
`of psychotic processes, catatonic—like states; hypotension
`(sometimes fatal); cardiac arrest,- blood dyscrasias (pancyto
`penia, thmmbocytopenic purpura, leukopenia, agranulocy-
`tosis, eosinophilia, hemolytic anemia, aplastic anemia);
`liver damage (jaundice, biliary stasis); endocrine disturb-
`ances (hyperglycemia, hypoglycemia, glycosuria, lactation,
`galactorrhea, gynecornastia, menstrual irregularities, false-
`positive pregnancy tests): skin disorders {photosensitivity,
`itching, erythema, urticaria, eczema up to eid'oliative der‘
`matitis); other allergic reactions (asthma, laryngeal edema,
`angioneur'otic edema, anaphylactoid reactions); peripheral
`edema; reversed epinephrine effect; hyperpyrexia; mild fe-
`ver after large LM. doses; increased appetite; increased
`weight,- a systemic lupus erytheinatosus—like syndrome; pig-
`mentary retinopathy; with prolonged administration of sub-
`stantial doses, skin pigmentation, epithelial keratopathy,
`and lenticular and corneal deposits.
`EKG changes~particularly nonspecific, usually reversible
`Q and T wave diswrtions—have been observed in some pa-
`tients receiving phenothieaine tranquilizers. Although phe-
`nothiasines cause neither psychic nor physical dependence,
`sudden discontinuance in long-term psychiatric patients
`may cause temporary symptoms, e.g., nausea and vomiting,
`dizziness, tremulousness.
`Note: There have been Occasional reports of sudden death
`in patients receiving phenothiazines, In some cases, the
`cause appeared to be cardiac arrest or asphyxia due to fail—
`ure of the cough reflex.
`'
`DOSAGE AND'ADMJN‘ISTRATION—ADULTS
`Dosage should be adjusted to the needs of the individual.
`The lowest efl‘ective dosage should always be used.
`should be increased more gradually in debilitated or emaci-
`ated patients, When maximum response is achieved, dosage
`may be reduced gradually to a maintenance level. Because
`of the inherent long action of the drug, patients may be con—
`trolled on convenient b.i.d. administration; some patients
`may be maintained on once-a-day administration.
`When Stelazine (trifluoperazine HCl) is administered by in-
`tramuscular injection, equivalent oral dosage may be sub—
`stituted once symptoms have been controlled.
`Note: Although there is little likelihood of contact derma—
`titis due to the drug, persons with known sensitivity to phe-
`nothiasine drugs should avoid direct contact.
`Elderly Patients:
`In general, dosages in the lower range
`are suficient for most elderly patients. Since they appear to
`be more susceptible to hypotenaion and neuromuscuia: re-
`actions, such patients should he observed closely. Dosage
`should be tailored to the individual, response carefully mon-
`itored, and dosage adjusted accordingly, Dosage should be
`increased more gradually in elderly patients.
`Non-psychotic Anxiety
`Usual dosage is 1 or 2 mg twice daily, Do not administer at
`weeks.
`-
`doses of more than 6 mg per day or {or longer than 12
`Psychotic Disorders
`.
`
`cow-Iil-IKLINI: chCHAMBm
`
`DOSAGE AND
`CHILDREN
`
`ADMNISTRKI'ION—PSYCHOTIC
`
`severity of the symptoms. These dosages are for children.
`smn.
`'
`ages 6 to 12, who are hospitalized or under close supervi—
`
`or b.i.d. Dosage may be increased gradually until symptoms
`are controlled or until side effects become troublesome.
`While it is usually not necessary to exceed dosages of 15 mg
`daily, some older children with severe symptoms may re-
`quire higher dosages.
`imrarrmswiar: There has been little experience with the
`use of Stelazine {trifiuoperazine HCl) Injection in children.
`However, if it is necessary to achieve rapid control of severe
`symptoms, 1 mgl’lg mL) of the drug may be administered
`intramuscularly once or twice a day.
`OVERIXISAGE
`
`ofsomnclence or coma. Agitation and restlessness 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—It is important to determine other medica-
`tions taken by the patient since multiple dose therapy is
`common in overdosoge situations Theahnent is 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
`
`symptoms may be treated With anti-parkinsonism drugs.
`barbiturates, or Benadryl, See prescribing information for
`these products. Care should be taken to avoid increasing
`respiratory depression. If administration of a stimulant is
`desirable. amphetamine, dextroamphetaniine or cafl'eine
`with sodium benaoate is recommended. Stimulants that
`may cause convulsions (e.g., picmtoxin or pantylenetetrasml)1
`should be avoided.
`Ifhypotension occurs, the standard measures for managing
`circulatory shock should be initiated. [fit is desirable to ad
`minister a vasoconstrictor, Levophed and Neo-Synephrine
`otbiazine deriva-
`tives may reverse the usual elevating action ofthese agents
`and cause a further lowering ol’blood pressure.
`'
`Limited experience indicates that phenothiasines are not di-
`alyzable.
`HOW SUPPLIED
`
`Tablets. 1 mg, 2 mg, 5 mg and 10 mg in bottles of 100.-
`1 mg 100‘s: NBC 0108-49032!)
`2 mg 100's: N'DC 0108—4904-20
`5 mg loos: NDC owe-4906.20
`10 mg 100’s: NDC 0108—4190190
`Mufti-Doc- Vleic, 10 mL (2 mgme), in 1’s:
`NDC 0108-4902-01
`
`Concentrate (for institutional use), 10 mgimL, in 2 d or
`bottles and in cartons of 12 bottles.
`The Concentrate form is light-sensitive. For this reason, it
`should be protected from light and dispensed in amber
`bottles. Refrigcmrion is not required.
`10 mgi’mL 2 fl oz (carton of12}: NBC 0108-4901-1612
`Store all Stelazine (trifluoperazine HCl) formulations be
`
`tween 15' and 30°C (59" and EG‘F).
`
`cals.
`* norepinephzine bitartrate, Senofi Winthrop Pharmaceuti-
`
`ceuticals
`-
`T phenylephrine hydrochloride, Sanofi Winthrop Pharma-
`i phenytoin, Parke-Davis.
`fimetrizamide, Sanofi Winthrop Pharmaceuticals,
`diphenhydramine hydrochloride, Parke-Dams.
`Veterans AdminiatrationfMilltaryiPHS—Injection, 2 mgl
`ml... 1|] mL, 1's, 6505-01—220-14‘l9; Tablets. 1 mg, 100's,
`6505fl0-lfil-5658; 2 mg, 100’s, 6505-01-361-5235; 5 mg,
`100's, 6505-01—311-3734; 10 mg, 100's, 6505-01-246-1918.
`SZ:L7[|
`Shown in Product Identification Guide, page 33.9
`————_._.___,___
`
`TAGAMETO
`[tog “ah-met]
`brand of clmutidino tablets
`clmetidine hydrochloride liquid and
`cimetidine hydrochloride Injlctlon
`DESCRIPTION
`
`I}
`
`Tagamet (cimetidine) is a histamine Hg-reoeptor antagonist.
`Chemically it is N "-cyano- N methyl-N '-[2—[[(5-
`thyl-l
`H—imidazol-d—yl) methyl] tliiol-ethyll-g‘uanidine.
`
`Continued on next page
`
`lniormation on the SmitbKiine Beecharn Pharmaceuticals
`products appearing here is based on the labeling in effect on
`June 15. 1999. Further information on those and other
`
`
`
`

`

`Together—Cont.
`
`The empirical formula for (rimetidine is CmeNES and for
`cimetidine hydrochloride, CmI-IIENGSHCI; these represent
`molecular weights of 252.34 and 238.80, respectively.
`
`CH3
`
`_
`
`I
`{IllaSCH.‘,CH.‘N|-ICNHCHI
`N—C i N
`
`:
`;
`HNV N
`Clmetidlno
`
`Cimetidine contains an lmidasole ring. and is chemically re-
`lated to histamine.
`{The liquid and injection dosage forms contain cimetidine as
`the hydrochloride.)
`Cimetidine has a bitter taste and characteristic odor.
`Solubility Characteristics: Cimetidine is soluble in alcohol,
`slightly soluble in water, very slightly soluble in chloroform
`and insoluble in ether. Cimetidine hydrochloride is freely
`soluble in water. soluble in alcohol, very slightly soluble in
`chloroform and practically insoluble in other.
`Tablets for Oral Admlnlsttetlon: Each light green, film-
`coated tablet contains cimetidine as follows: 200 mg—
`round, imprinted with the product name TAGAM'ET, SKF
`and 200; 300 mgn—round, debossed with the product name
`TAGAMET, SB and 3001400 rug—oval Tlltab® tablets, de-
`bossed With the product name TAGAMET, SB and 400; 800
`mg—oval Tiltab® tablets, debossed with the product name
`TAGAMET, SB and 800. Inactive ingredients consist of cel-
`lulose, DSLC Yellow No. 10, FD&C Blue No. 2, FD&C Red
`No. 40, FD&U Yellow No. 6, hydrmpmpyl methylcellulose.
`iron oxides, magnesium stearate, povidone. propylene gly-
`col. sodium lauryl sulfate, sodium starch glycolabe, starch,
`titanium dioxide and hence amounts of other inactive ingrcL
`clients.
`Liquid for Oral Administration: Each 5 ml. (1 teaspoonfull
`of clear, light orange, mint-peach flavored liquid contains ci-
`metidine hydrochloride equivalent to cimetidine. 300 mg;
`alcohol, 2.8%. Inactive ingredients consist of FD&C Yellow
`No. 6, flavors, methylparaben, polyoxyethylene polyoxypro-
`pylene glycol, propylene glycol, propylparaben, saccharin
`sodium, sodium chloride, sodium phosphate, sorbitol and
`water.
`Injection:
`Single-Dose Vials for Intramuscular or Intravenous Admin-
`istration: Each 2 mL contains, in sterile aqueous solution
`(pH range 3.8 to 6}, cirnetidine hydrochloride equivalent to
`cimetidins, 300 mg; phenol, 10 mg.
`Mold-Dose Vlele for Intramuscular or Intravenous Admlnls-
`tra‘rlon:
`8 mL (300 mg'2 1111.): Each 2 mL contains, in ster—
`ile aqueous solution {pH range 3.3 to 6), cimetidine hydro-
`chloride equivalent to cimetidine, 300 mg", phenol, 10 mg.
`Single-Dose Premixed Plastlc Containers for Intravenous
`Admlnietration: Each 50 mL of sterile aqueous solution
`(pH range 5 to 7) contains cimetldine hydrochloride equiva-
`lent to 300 mg cimetidino and 0.45 grams sodium chloride.
`No preservative has been added.
`The plastic container is fabricated from spern‘ally formu-
`lated polyvinyl chloride. The amount of water that can pen
`meate from inside the container into the cveiwrap is insof-
`ficient to afl-‘ect the solution significantly. Solutions in con-
`tact with the plastic container can leach out certain of its
`chemical components in very small amounts within the ex-
`piration period, e.g., di 2-ethylhecryl phthalate (DEHP). up
`to 5 parts per million. However, the safety of the plastic has
`been confirmed in tests in animals according to the USP bi-
`ological tests for plastic containers as well as by tissue cul-
`ture toxicity studies.
`ADD—Vantageo“ Vials for Intravenous Administration:
`Each 2 mL contains, in sterile aqueous solution (pH range
`3.8 to 6), cimetidine hydrochloride equivalent to cimetidine,
`III mg; phenol, 10 mg.
`All of the above injection formulations are pyrogen fine, and
`mdium hydroxide N.F. is used as an ingredient to adjust the
`pa
`(IMCAL PHARMACOLOGY
`Eng—met. {cimetidine) competitively inhibits the action of
`ire-amine at the histamine H2 receptors of the parietal cells
`He thus is a histamine Ila—receptor antagonist.
`fay-amt is not an enticholinergic agent. Studies have
`burn that Thgamet inhibits both daytime and'ncctumal
`in; gastric acid secretion. Ihgamct also inhibits gastric
`Er; yeast-ion stimulated by food, histamine, pentsgastrin.
`utilize and insulin.
`lei-notary Aetlvlty
`2 Add Secretion: Nocturnal: Togomt 800 mg orally at
`bedtime reduces mean hourly H” activity by greater
`man 35% over an 3-hour period in duodenal ulcer pa-
`tients, with no effect on daytime acid secretion. Thgo-
`vnzr 1600 mg orally h.s. produces 100% inhibition of
`mo hourly H+ activity over an 8—hour period in duo-
`denal ulcer patients, but also reduces H’ activity by
`5'! for an additional 5 hours into the folIOWing mom—
`mg. Togas-net 4-00 mg b.i.d. and 300 mg q.i.d. decrease
`mal acid secretion in a dose-related manner, i.e.,
`m In 83% over a 6: to 3-hour period and 54% over a
`Lien: period. respectively:
`H Stimulated: During the first hour after a stan—
`H experimental meal, oral lbgumet 300 mg inhib-
`lld gastric acid secretion in duodenal ulcer patients
`:5 x least 50%. During the subsequent 2 hours tho-
`
`
`i
`'
`
`I
`
`
`
`met inhibited gastric acid secretion by at least 25%.
`The efi'ect ofa 300 mg breakfitst does offlbgomet 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 Them
`met given with lunch.
`In another study, Ihgomet 300 mg given with the meal
`increased gastric pH as compared with placebo.
`
`1 hour
`2 hours
`3 hours
`‘1 hours
`
`Mean Gastric pH
`Tagamet
`Placebo
`3.5
`2.6
`3.1
`1.6
`3.3
`1.9
`6.]
`2.2
`
`24-Hour Moon H * Activity: Thgamet 800 mg h.s., 400
`mg b i.r|. and 300 mg q.i.d. all provide a similar, moderate
`{less than 60%) level of 24-hour acid suppression. However,
`the 800 mg h.s. regimen exerts its entire efi‘ect on nocturnal
`acid. and does not afl'ect daytime gastric physiology.
`("hectic-Mb Stimulated: Oral Tagamet (cimetidincl sig-
`nificantly Inhibited gastric acid secretion stimulated by 139.
`tflmle I an isomer of histamine}. pentagaatrin, cafi'eine and
`insulin as follows:
`
`Stimulant
`Betazole
`
`Pentagastrin
`
`Stimulant
`0'. Inhibition
`Tammi
`Dose
`35% at 21: ,
`300mg
`1.5mgfkg
`hours
`(poi
`(so)
`60% at 1
`100mgfhr
`Smcgfkgf
`hour
`{iv}
`hr (iv)
`100% at 1
`300mg
`5mg’kgl'
`hour
`[pol
`hr (iv)
`82% at. 1
`100mgfhr
`0.03 units.l
`Insulin
`
`
`(iv)light (iv) hour
`
`Cafi‘eine
`
`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. either continuous 1V. infusion of Ibgomet 37.5
`mgjhour (900 mgl‘dayl or intermittent injection of
`Tagomet 300 mg q6h (1200 mgfdayl maintained gastric
`pH above 4.0 for more than 50% of the time under
`steady-state conditions.
`2] Pepein: Oral Ibgomet 300 mg reduced total pepsin
`output as a result of the decrease in volume of gastric
`Juice.
`3} Intrinsic Factor.
`Intrinsic factor secretion was studied
`with betazole as a stimulant. Oral Thgomet 300 mg in-
`hibited the rise in intrinsic factor concentration pro-
`duced by betazole, but some intrinsic factor was so
`creled at all times.
`s‘ADD-VantagelD is a trademark of Abbott Laboratories.
`Ddrer
`'
`Lower Esophageal Sphincter Pressure and Gastric Emp-
`wine
`Togomet has no effect on lower esophageal sphincter
`{LES} pressure or the rate of gastric emptying.
`Pharmeookinetics
`Thgomet is rapidly absorbed after oral administration
`and peak levels occur in 45 to 90 minutes. The half—life of
`Tagomet is approximately 2 hours. Both oral and paren-
`teral (LV. or 1M.) administration provide comparable pev
`riods of therapeutically etfectlve 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 of300 mg.
`Steadynstate blood concentrations of oimetidine with con-
`tinuous infusion of Ihgamet 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 normal re
`nal function, an infusion rate of 37.5 mgfhour produced
`average steady-state plasma cimetidine concentrations of
`about 0.9 mcgme. Blood levels with other infiision rates
`will vary in direct proportion to the iniusion rate.
`The principal mute of-eiocretion of lhgumet 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, 40% of the drug is recovered from the urine af-
`ter 24 hours as the parent compound. Following I.V. or
`LM. administration, approximately 75% of the drug is re-
`covered from the urine after 2-1 hours as the parent com-
`pound.
`CLINICAL TRIALS
`Duodenal Ulcer
`Tagamet fcimetidine} has been shown to be efiective in
`the treatment of active duodenal ulcer and, at reduced
`dosage, in maintenance therapy following healing of ac-
`tive ulcers.
`Active Duodenal Ulcer: Thgomet accelerates the rate of
`duodenal ulcer healing. Healing rates reported in US.
`and foreign controlled trials with Thgomel are summa—
`rized below, beginning with the regimen providing the
`lowest nocturnal dose.
`
`‘1 5-"
`Duodenal Ulcer Heeling Ratio
`with Various Mamet Dosage Rogimens'
`
`300 mg
`400 mg
`000 mg
`1800 Inc
`Regimen
`q.i.d.
`Ii.i.d.
`h.s.
`h.s.
`
`week 4
`63%
`73%
`30%
`86%
`week 6
`80%
`80%
`89%
`—
`
`—— 92% 04%week 8 —
`
`
`
`‘* Averages from mntrolled clinical trials.
`
`a 115., double-blind. placebo-controlled, dose-ranging
`study demonstrated that all once-daily at bedtime {h.s.}
`Ihgomet regimens were superior to placebo in ulcer heal-
`ing and that lhgomt 800 mg h.s. healed 75% ofpatients
`at 4 weeks. The beefing rate with 800 mg h.s. was signif-
`icantly superior to 400 mg h.s. (66%} and not significantly
`different from 1600 mg h.s. (31%].
`In the US dose-ranging trial, over 80% of patients re-
`ceiving Ibgamet 300 mg h.s. experienced nocturnal pain
`relief after 1 day. Relief from daytime pain was reported
`in approximately 70% of patients after 2 days. As with
`ulcer healing, the 800 mg h.s. dose was superior to 400
`mg h.s. and not difi‘enent fi‘orn 1500 mg h.s.
`In foreign, double‘blind studies with Mamet 800 mg
`h.s., 79% to 35% ofpatients were healed at 4 weeks.
`While shortrterm treatment with Tegamet (cimetidinel
`can result in complete healing of the. duodenal ulcer,
`acute therapy will not prevent ulcer recurrence after
`Tbgamet has been dimnfinued. Some follow-up studies
`have reported that the rate of recurrence once therapy
`was discontinued was slightly higher for patients healed
`on Slog-isms: than for patients healed on other forms of
`therapy; however. the Emmet-treated patients generally
`had more severe disease.
`Maintenance Therapy In Duodenal Ulcer: Treatment
`with a reduced dose of Thgomt has been proven efi’ective
`as maintenance therapy following healing of active duo-
`denal ulcers.
`In numerous placebomntrolled studies conducted world-
`wide, the percent of patients with observed ulcers at the
`end of 1 year‘s therapy with Mamet 400 mg h.s. was sig-
`nificantly lower (10% to 45%] than in patients receiving
`placebo (44% to 70%}. Thus, from 55% to 90% of patients
`were maintained free of observed ulcers at the end of 1
`year with Ibgomet 4-00 mg h.s.
`-
`_
`Factors such as smoking. duration and severity of dis-
`ease, gender, and genetic traits may contribute to varia—
`tions in actual percentages.
`Trials of other anti-ulcer therapy, whether placebo-con-
`trolled, positive-controlled or open. have demonstrated a
`range of results similar to that seen with Thgamet.
`Active Benlgn Gastric Ulcer
`lhgomet has been shown to be effective in the short-term
`treatment of active benign gastric ulcer.
`In a multicenter, double-blind U.S. study, patients with
`endoscopically confirmed benign gastric ulcer were
`treated with Togomet 300 mg four times a day or with
`placebo for 6 weeks. Patients were limited to those with
`ulcers ranging from 0.5 to 2.5 cm in size. Endoscopically
`continued healing at 0 weeks was seen in significantly"
`more Mamet-treated patients than in patients receiving
`placebo, as shown below:
`Tagame‘t
`1453 (22%}
`43055 {66%} *
`
`Placebo
`7363 (11%)
`30367 [45%)
`
`week 2
`total at week 5
`
`*p<0.05
`
`In a similar multioenter US. study of the 800 mg h.s. oral
`regimen, the endoscopically confirmed healing rates
`were:
`
`Tagamet
`W83 (76%} *
`
`Placebo
`4-930 (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 Ragtime: than with pla-
`cebo.
`Gostroeaophageel Reflux Disease
`In two multicenter, double—blind, placebo-controlled stud-
`ice in patients with gastroesophageal reflux disease
`(GERD} and endoscopically provcn erosions andl'or ulcers,
`Tbgomet was significantly more efi‘ective than placebo in
`healing lesions. The endoscopically confirmed healing
`rates were:
`
`p—Value
`{800 mg
`Tagemet Tagamet
`b.i.d. vs.
`(300 mg (400 mg
`
` Trial bid.) q.i.d.l Placebo placebo}
`
`
`l.
`Week 6
`45%
`52%
`26%
`0.02
`Week 12
`30%
`63%
`42%
`0.02
`Week 6
`50%
`20%
`40.01
`Week 12
`37%
`35%
`(0.01
`
`2
`
`In these trials ibgomet was superior to placebo by most
`measures in improving symptoms of day— and nighbtime
`
`
`
`

`

`
`heartburn, with many of the difi'erences statistically sig-
`mg h.s. regimen, particularly in subjects aged 54 years and
`and, very rarely, cases of pancytopenia or aplastic anemia
`nificant. The q.i.d. regimen was generally somewhat bet—
`older. Data beyond 10 days are not available. (Note: All pa-
`have also been reported. As with some other Hg—receptor an-
`ter than the b.i.d. regimen where these were compared.
`tients receiving theophylliue should be monitored appropri-
`tagonists, there have been extremely rare reports of im—
`Prevention of Upper Gastrointestinal Bleeding in Criti-
`ately. regardless of concomitant drug therapy}
`mune hemolytic anemia.
`sally III Patients
`Hepatobiliary: Dose-related increases in serum transami‘
`Dosage of the drugs mentioned above and other similarly
`A double~blind, placebo-controlled randomized study of
`metabolized drugs, particularly those of low therapeutic ra-
`nase have been reported. In most cases they did not prog-
`continuous infilsioin cimetidine was performed in 131 crit-
`tio or in patients with renal andlor hepatic impairment,
`ress with continued therapy and returned to normal at the
`ically ill patients {mean APACHE ll score = 15.99} to com-
`may require adjustment when starting or stopping concom-
`end of therapy. There have been rare reports of cholestatic
`pare the incidence of upper gastrointestinal bleeding,
`itantly administered I