Exclusively from

The only reimbursement program to

ensure access to Epoetin alfa therapy
The most comprehensive financial
assistance programs for patients receiving
Epoetin alfa therapy
Unsurpassed service and assistance
to physicians and patients
Continuing commitment to ongoing
research and clinical trials
PROCRIT"
EPOETIN ALFA
Available only to qualifying nondialysis patients.
ClOnro Biotech Inc. 1993 PCT1002 15870 2/93
THE
PACT
PROCRIT
Advantages In
CompreheRslve
Treatment*
Announcing a-

IN
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New dextrose IV bags-extending -"-
even more dosage form flexibility to the Diflucan lineup
Convenient for sodium-restricted patients, such asthose
with hypertension and congestive heart failure
-Contains dextrose (56 mg/ml.) as diluent
Convenient for the hospital and staff
-Premixed, ready to use, iso-osmotic .
-No reconstitution ordilution necessary
-Lightweight, no risk ofbreakage, and nospecial
storage requirements
In over 4,000 patient, who received Ditlucan for at least
7days, the most common adverse events were nausea
(3.7%), headache (1.9%), skin rash (l.SIX, vomiting
0.7%), abdominal pain (1.7%), and diarrhea (l SX.
Please see brief summary of prescribing information on
adjacent page
1993, Pfizer Inc
n;Fl ONCE-A-DAY

(!lq!?/l{//}g)
More dosing flexibility than any other "
systemic antifungal
With once-daily dosing forawiderange of patients
LOADING DAILY
INDICATION DOSE THERAPY
OROPHARYNGEAL
CANDIDIASIS 200mg 100mg
ESOPHAGEAL
CANDIDIASIS 200mg 100 mg '
SYSTEMIC
CANDIDIASIS 400mg 200mg
CRYPTOCOCCAL
MENINGITIS (acute) 400mg 200mg'
CRYPTOCOCCAL MENINGITIS
(maintenance
200mg to prevent relapse)
"Doses of upto 400mgldaymaybeused, based onmedical judgmenl of thepatient's responseto
therapy.
BrlolSllmmary
INDICATIONS ANllllSAGE
DIFLUCAN (nuconazole) isindlcaledlor Ihetreatment 01:
1. Oropharyngeal and esophageal candidiasis. DIFLUCAN is also eMecti vefor Ihe treatment of serious
systemic candidal infections. including urinary tract infection, peritonitis. andpneumonia.
2. Cryplococcal menmoms.
Specimensfor fungal cultureandother relevant laboratory studies(serology, histopathology) shouldbe
obtainedprior10 Iherapytoisolateandidenlil ycausativeorganisms. Therapymaybemstilutedbeforethe
results of Ihe cultures and other laboratory studiesare known; however, oncethese results become
available, anti -infectivetherapyshouldbeadjustedaccordingly.
CDNTRAINDICATIONS
DIFLUCAN (nuconazole)isconlraindicaledinpatientswhohaveshownhypersensilivitytonuconazoieorto
any 01 Itsexcipients. Thereisnoinformation regarding cross hypersensitivitybetweenfluconazole and
other azoleantifungalagents. CaulionshouldbeusedinprescribingDIFLUCAN topatientswithhypersen-
silivitytoother azoies .
WARNINGS
Inrarecases, anaphylaxishasbeenreported.
Patientswhodevelop abnormal liverfunctiontestsdUli ngDIFLUCAN Iherapy shouldbe rnorutorec forIhe
development 01moreseverehepatic injury. Althoughserioushepatic reactionshavebeenrare and Ihecausal
associationwithDIFLUCAN uncertain, if clinicalsignsandsymptomsconsistent withliver disease develop thai
may be attribulable10noconazoe, DIFLUCAN shouldbediscontinued. (See AdverseReactions.)
Immunocompromi sedpalients who develop rashes duringtreatment with DIFLUCAN shoul d be mon-
iloredclosel yandthedrugdiscontinuedIf lesionsprogress. (See AdverseReaclions.)
PRECAUTIONS
DrugInteractions(See Clinical Pharmacology)
DIFLUCAN (nuconazole) Increased Ihepmthrombintimeafter warfarinadministratien. Carelui momtonnq
01prothrombin timeinpatients receivingDIFLUCAN andcoumarin-typeanticoagulantsISrecommended
DIFLUCAN increasedmeplasmaconcentrations01phenytoin. Carefulmonitoringof phenytoinconcen-
trationsinpatientsreceivingDIFLUCAN andphenytoinis recommended.
DIFLUCAN has been inlreQuently associatedwith an increase in cyciosponneconcent rations in renal
transplant patientsWithor withoutimpairedrenal tunction. Carelul monuorinq01cyclosponneconcentra-
tions inpatients recei vingDIFLUCAN andcyclosporineisrecommended.
DIFLUCANincreasedtheplasma concentrationsandreducedthemetabolismol torautamioe. glyburide
andglipizide. WhenDIFLUCAN is usedconcomitantlywiththese or other sultonylureaoral hypoglycemic
agents, bloodglucose concenrranons should be carelully momtored. and the doseof thesultonylurea
shouldbeadjustedasnecessary
Rlfampin enhances the metabolismof concurrently admirnstered DIFLUCAN. Depending on ctirucal
circumstances, considerationshouldbegiventoincreasingIhedoseof DIFLUCANwhenit isadministered
with ritampin.
Physicians should beaware Ihatdrug-drug interaclionstudiesWi thother medications have not been
conducted, butsuchinteractionsmayoccur.
Carclnovenesls, MutagenesisandImpairment01Fertility
Fluconazoleshowednoevidenceof carcinogenicpotential inmiceandratstreatedorallyfor 24monthsat
dosesof 2.5, 5 or tomg/kg/day[approximately 2-7xtherecommendedhumandose). Malerats treated
with5and 10mg/kg/dayhadanincreasedincidence01hepatocellular adenomas.
Fluconazole, withor withoutmetaoouc acnvauon. wasnegativeintestsfor mutagenicityin4strains01
S. Iyphimurium, andin the mouse lymphoma L5178Ysystem. Cytogenelic studiesin vivo(murinebone
marrowcells, follOWing oral administration of fluconazole) and mvnm (human lymphocytes exposedto
fluconazoleat tOOO.,.g/mll showednoevidenceof chromosomal mutations.
Fluconazole didnot affect thefertility 01maleor femalerats treatedorally withdailydosesof 5, toor
20 mg/kgor with parenteral doses of 5, 25 or 75mg/kg, although theonset of parturilion was slightly
delayedat 20 mg/kgp.o. In anintravenousperinatal study in rats at 5, 20and 40 mg/kg, dystociaand
prolongationof parluritionwere observed in a fewdams at 20mg/kg (aaproxi mately 5-15xtherecom-
mendedhumandose) and40mg/kg,outnot al 5mg/kg. ThedisturbancesinparturiliOn werereflectedby
aslight increase in thenumber of stillbornpups anddecreaseof neonatal survival at thesedose levels.
The effects on parturitionin rats are consistent withthe species specific estrogen-loweringproperty
producedbyhighdosesof fluconazole. Suchahormonechangehasnot been observed inwomen treated
withnuconalole. (See Clinical Pharmacology.)
Pregnancy
Teratogenic Effects. Pregnancy Category C: Fluconazole was aomirustereoorally10 pregnanl rabbits
duringorganogenesis in two studies, al 5, to and20 mg/kg and at 5, 25, and 75mg/kg respecllvely.
Maternal weighl gainwas impairedat all doselevels, andabortionsoccurred at 75 mg/kg(approxi malely
20-60x the recommended humandose); no adverse letal effects were detected, In several studies in
whichpregnant rats weretreatedorally with fluconazol edurmg organogenesis. maternal weight gainwas
impairedandplacental weightswereincreasedat 25mg/kg. Therewerenotetal effectsal5 or10mg/kg;
increasesinfetal anatomical variants(supernumeraryribs. renal pelvisdilation) anddelaysinossification
wereobserved at 25 and 50 mg/ kg andhigher doses. AI doses ranging Irom80 mg/kg (approximatety
20-60x therecommended humandose) to 320 mg/kgembryolethalityin ratswas increased and letal
abnormalitiesincluded wavyribs, cleft palate andabnormal crania-facial ossification. Theseeffectsare
consistent withtheinhibitionof estrogensynthesis inratsandmaybearesultotknowneffects01lowered
estrogenonpregnancy, organogenesisandparturition.
There are noadequate and well controlled studies10 pregnant women. DIFLUCAN should beusedin
pregnancyonlyif thepotential benef it justifiesthepossiblerisk10thetetus.
Nursing Mothers
Fluconazoleis secreted in human milk at concentranons similar to plasma. tnererore. me useof
DIFLUCAN innursingmothersis notrecommended.
Pediatric Use
Efficacy 01 D 1 F L ~ C A N has not beenestablished In children. A small number 01patients tromage3 10
13 years havebeentreatedsalelywithDIFLUCAN usingdosesof 3-6mg/kgdaily
ADVERSE REACTIONS
Sixteenpercent of over 4000 patients treated with DIFLUCAN (fluconalole) in clinical trlals ot 7days or
moreexperienced adverseevents. Treatmentwasdiscontinuedin1.5%of patientsduetoadverseclinical
eventsandin 1.3%01patientsduetolaboratorytest abnormalities.
In combined clinical tnalsand foreign market109 experiencepnor 10 US. markelmg, patients with
seriousunderlyingdisease (predomi nanlly AIDS or mali gnancy) rarely have developed senous hepatic
reactions or exfoliative skin disorders during treatment with DIFLUCAN (See Warnings). Twoof these
hepatic reactionsandoneexfoliativeskindisorder (Stevens-Johnsonsyndrome) were associated with a
fatal outcome. Because mostof these patientswererecei.ving multipleconcomitantmedications, mclud-
ingmany known tobe hepatotoxicor associatedwithexfoliativeskindisorders. thecausal association of
thesereacttons wilhD1FLUCAN therapy isuncertain.
Clinical adverseeventswerereported morefreQuenllyinHIV infectedpatients(21%)thanInnon-HIVinfected
patients(13%); however, lhepall ernsinHIVintectedandnon-HIVinfecledpatientsweresimilar.Theproporti ons
ofpallentsdlscontinuingIherapyduetoclinical adverseeventswereSimilar inIhetwo groups(1. 5%).
The followingtreatment-related clinical adverse eventsoccurred at anincidence of 1%or greater in
4048patientsreceivingDIFLUCAN lor 7or moredaysincnmcattnars. nausea3.7%, headache1.9%, skin
rash1.8%, vnrnitinq1.7%, abdominal pain1.7%, anddiarrhea 1.5%.
In twocomparative tnals evaluating theefficacyof DIFLUCAN lor thesuppression of relapse01cryp-
tococcat meningitis, astatisticallysignilicant increasewasobservedinmedianAST(SGOT) levels Iroma
baseline valueof 30 IU/L to 41IU/Lin onetrial and34 IU/L 1066 IU/LIn Iheother. The overall rateof
serumtransaminaseelevationsof more than8 timestheupper limit of norma: wasapproXimately 1%In
fluconazole-treatedpatientsinclinical trials. Theseelevationsoccurredinpatientswithsevereunderlying
disease, predominantly AIDSor malignancies, most 01whomwerereceivingmultipleconcomnant medi -
cations, including manyknown to be hepatotoxic. The incidenceof abnormall y elevated serumtrans-
aminases was greater In patients taking DIFLUCAN concomitantly With one or more 01the lollowing
medications: rifampin, phenytoin, isoniazid, vaiorolc acid. or oral SUlfonylureahypoglycemic agents.
Inrarecases, anaphylaxishasbeen reported.
Thefollowingadverseexperiencesoccurredunder cone.nons(e.g. open trials, marketingerpenence)
whereacausal associ ation isuncertain:
Cenlral NervousSyslem: seirures.
Hematopoielic andLymphalic: leukopenia, Ihrombocytopenia.
1992, Pfizer Inc Hoerig 70-4526-00-5 IssuedMay 1992
Due to susceptiblestrains of indicated pathogens. See
indicatedorganisms in complete prescribing information.
' Tissuepenet ration is regarded asessential \0therapeutic
efficacy, but penetrationlevels have not been correlated
with specific therapeutic results.
' In vitroactivity does not necessarily imply acorrelation
with in vivo results.
NOTE: Concurrentadministration of ciprofloxacin with
theophyllinemay lead to elevated plasma concent rations
of theophyllineand prolongationof its eliminationhalf-life.
This may result inincreased risk of theophylline-related
adversereactions. If concomitant usecannot beavoided,
plasmalevels of theophyllineshould bemonitored and
dosage adjustments madeasappropriate.
Concurrent administrationof ciprofloxacin with antacids
containingmagnesium,aluminum,or calcium; with
sucralfateor divalentand trivalentcationssuchas iron may
substantially interferewiththeabsorption of ciprofloxacin,
resultingin serumand urinelevelsconsiderably lower than
desired. Toalesser extent this effect is demonstrated with
zinc-containingmultivitamins.
Ahistoryof hypersensitivityto ciprotloxacinis acontra-
indication to its use. Ahistoryof hypersensitivityto other
quinolones mayalsocontraindicate theuse of ciprofloxacin.
THESAFETY AND EFFECTIVENESS OFCIPROFLOXACIN
INCHILDREN, ADOLESCENTS (LESSTHAN18YEARS
OF AGE), PREGNANT WOMEN, AND LACTATINGWOMEN
HAVE NOTBEENESTABLISHED.
For manu patients uith Ioirer
respiratoru intections. includingthose
trith chronic bronchitis...
Power On Tract
=
Please seetniet SUII/mill\' of comoteteptescnbuu:
Inforll/atlOn Oil adJilcent page
The confidence ofwell-tolerated,
reliable efficacy based on 5 years
of US clinical use
TABLETS

(ciprofloXBCin HCU
The most poIent fluoroquinolone.*
Clinical coverage includes
Haemophilus influenzae and other
common lower respiratory
pathogens
Excellent penetration into
bronchial mucosa:
MILESA
Pharmaceutical Division
TABLHS

(ciprofioxacin HCU
ZENECA
Pharmaceuticals
A BusinessUnit of ZENECA Inc.
Wilmington,Delaware19897 USA
INDICATIONS AND USAGE
Cipro isindicated for thetreatment of infections caused bysusceptible
strains of thedesignated microorganisms intheconditions listed below.
LowerRespiratory Infections caused by Escherichia coli, Klebsiella
pneumoniae, Enterobacter cloacae, Proteus mirabi/is, Pseudomonas
aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or
Streptococcus pneumoniae.
Skin and Skin Structure Infections caused by Escherichia coli,
Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabi/is,
Proteus VUlgaris, Providencia stuartii, Morganella morganii, Citrobact-
er treunaii. Pseudomonas aeruginosa, Staphylococcus aureus,
Staphylococcus epidermidis, or Streptococcus pyogenes.
Bone andJoint Infections caused by Enterobacter cloacae, Serratia
marr:escens, or Pseudomonas aeruginosa.
UrinaryTract Infections caused by Escherichia coli, Klebsiella pneu-
moniae, Enterobacter cloacae, serratia marr:escens, Proteus mirabi/is,
Providencia rettgeri, Morganella morganii, Citrobacter diversus,
Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus epi-
dermidis, or Enterococcus taecalis.
Inlectious Diarrhea caused by Escherichia coli (enterotoxigenic
strains), Campylobacter jejuni, Shigella f/exneri' or Shigella sonnei'
when antibacterial therapy ISindicated.
Although treatment of infections dueto this organism in this organ
system demonstrated a clinically significant outcome, efficacy was
studied infewer than10patients.
If anaerobic organisms aresuspected of contributing to theinfection,
appropriate therapy should beadministered.
Appropriate culture andsusceptibility tests should beperformed before
treatment in orderto isolate and identify organisms causing infection
andto determine their susceptibility to ciprofloxacin. Therapy with
Cipro maybeinitiated before results of these tests areknown; once
results become available appropriate therapy should becontinued. As
withother drugs, some strains of Pseudomonas aeruginosa maydevel-
opresistance fairlyrapidly during treatment withciprofloxacin. Culture
andsusceptibility testing performed periodically during therapy will
provide information notonlyonthetherapeutic effect of theantimicro-
bialagent butalsoonthepossible emergence of bacterial resistance.
CONTRAINDICATIONS
Cipro (ciprofloxacin hydrochloride) iscontraindicated inpersons with
a historyof hypersensitivity to ciprofloxacin or anymember of the
quinolone class of antimicrobial agents.
WARNINGS
THE SAFETYAND EFFECTIVENESS OF C1PROA.OXACIN INCHILDREN,
ADOLESCENTS (LESS THAN 18YEARS OF AGE), PREGNANT WOMEN,
AND LACTATING WOMEN HAVE NOT BEEN ESt'ABUSHED. (SEE PRE-
CAUTIONS-PEDIATRIC USE, PREGNANCY AND NURSING MOTHERS
SUBSECTIONS.) Theoraladministration of ciproftoxacin caused lame-
ness in immature dogs. Histopathological examination of theweight-
bearing joints of these dogs revealed permanent lesions of thecartilage.
RelatelJ quinolone-class lJrugs alsoproduce erosions of cartilage of
weight-bearing jointsand other signs ofarthropathy inimmature ammals
of various Species. (SeeANIMAL PHARMACOLOGY.)
Convulsions have been reported in patients receiving ciprofloxacin.
Convulsions, increased intracranial pressure, and toxicjlsychosis have
been reported in patients receMng drugs inthisclass. QUlnolones may
alsocause central nervous system (CNS) stimulation Which maylead
to tremors, restlessness, Iightheadedness, confusion andhallucina-
tions. If these reactions occur in patients receiving ciprofloxacin, the
drugshould bediscontinued and appropriate measures instituted. As
with all quinolones, ciprofloxacin shouldbe used with caution in
patients withknown or suspected CNS disorders, such assevere cere-
bral arteriosclerosis, epilepsy, andotherfactors that predispose to
seizures. (SeeADVERSE REACTIONS.)
SERIOUS ANDFATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF
CIPROA.OXACIN AND THEOPHYLLINE. These reactions have included
cardiacarrest, seizure, statusepilepticus and respiratory failure.
Although similar serious adverse events have been reported inpatients
receiving theophylline alone, the thatthese reactions maybe
potentiated by clprofloxacin cannot beeliminated. If concomitant use
cannot beavoided, serum levels of theophylline should bemonitored
anddosage adjustments made asappropriate.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions,
some following thefirst dose, have been reported In patients receiving
quinolone therapy. Some reactions were accompanied bycardiovascu-
lar collapse, loss of consciousness, tingling, pharyngeal or facial
edema, dySpnea, urticaria, and itching. Only afewpatients had ahisto-
ry of hypersensitivity reactions. Serious anaphylactic reactions require
immediate emergency treatment with epinephrine. Oxygen, intra-
venous steroids, andairway management, including intubation, should
beadministered asindicated.
Severe hypersensitivity reactions characterized byrash, fever, eosinophil-
ia, jaundiCe, andhepatic necrosis withfatal outcome have alsobeen
rarely reported inpatients receiving ciproftoxacin alon9 withother drugs.
The possibility that these reactions were related to clprof\oxacin cannot
beexcluded. Ciprofloxacin should bediscontinued atthefirstappearance
ofaskin rash or anyother sign of hypersensitivity.
Pseudomembranous colilis has been reported with nearly all
antibacterial allents, Incl=dinciprofloxacin, and may rangeIn
severityfrommild to 11fe- nillll. T1Ierelore, it is important to
consider this diagnosis Inpatients wfiopresent withdianheasubse-
quenftotheadmmislratlon of antibacterial agents.
Treatment withantibacterial agents alters thenormal floraof thecolon
andmaypermitovergrowth of clostridia. Studies indicate thatatoxin
For further information, contort the Miles Information
Service: 1-800-642-4776. InVA,call coIect: 703-391-7888.
Miles Inc.
Pharmaceutical Division

Federal (USA) Lawprohibits dispensing withouta prescrip-
PZ100747BS 1/93 Bay 0 9867 5202-2-A-U.S.-4 2545
C09772R MIL-6513R February 1993,MilesInc., Phannaceutical Division
Renal
lossandan increased incidence of abortion. Noteratogenicity was
observed at either dose. Afterintravenous administration, at doses up
to 20mglkg, nomatemal toxicity was produced, andnoembryotoxicl-
ty orteratogenicity wasobserved. There are, however, noadequate and
well-eontrolled studies in pregnant women. Ciprofloxacin should be
used during pregnancy onlyif thepotential benefit justifies thepotential
risktothefetus. (SeeWAR'NINGS.)
Nursing Mothers: Ciprofloxacin isexcreted inhuman milk. Because of
the potential for serious adverse reactions in infants nursing from
mothers takinQ ciprolloxacin, adecision shoUld bemade either todis-
continue nursing or to discontinue thedrug, taking intoaccount the
importance of thedrugtothemother.
Pediatric use: Safety andeffectiveness in children and adolescents
lessthan18 years of agehave not been established. Ciprofloxacin
causes arthropathy injuvenile animals. (SeeWARNINGS.)
ADVERSE REACTIONS
During clinical investigation, 2,799 patients received 2,868 courses ofthe
drug.Adverse events that were considered likely to bedrugrelated
occurred in7.3% of patients treated, possibly related in 9.2% (total of
16.5% thought to bepossibly or probably related to drug therapy), and
remotely related in3.0%. Ciprofloxacin was discontinued because of an
adverse event in3.5% of patientstreated, primarily involving thegastroin-
testinal system (1.5%), skin(0.6%), and central nervous system (0.4%).
The mostfrequently reported events, related or not,were nausea
(5.2%), diarrhea (2'.3%), vomiting (2.0%), abdominal pain/discomfort
(1.7%), headache (1.2%), restlessness (1.1%), and rash (1.1%).
Additional events thatoccurred inlessthan 1%of ciproftoxacin treated
patients are listed below.
CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syn-
cope, hypertension, angina pectoris, myocardial infarction, car-
diopulmonary arrest, cerebral thrombosis
CENTRAL NERVOUS SYSTEM: dizziness, Iightheadedness, insom-
nia, nightmares, hallucinations, manic reaction, irritability, tremor,
ataxia, convulsive seizures, letharQY, drowsiness, weakness,
malaise, anorexia, phobia, depersonalization, depression, paresthe-
sia(Seeabove.) (SeePRECAUTIONS.)
GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dyspha-
gia, intestinal perforation, gastrointestinal bleeding (See above.)
Cholestatic jaundice hasbeen reported.
MUSCULOSKELETAL: joint or back pain, joint stiffness, achiness,
neck or chest pain, flareupof gout
RENALAJROGENITAL: interstitial nephritis, nephritis, renal tailure,
polyuria, urinary retention, urethral bleeding, vaginitis, acidosis
RESPIRATORY: epistaxis, laryngeal or pulmonary edema,
hiccough, hemoptysiS, bronchospasm, pulmonary embolism
SKIN/HYPERSENSITIVITY: pruritus, urticaria, photosensitivity,
flushing, fever, chills, angioedema, edema of theface, neck, lips,
coniunctivae or hands, cutaneous candidiasis, hyperpigmentation,
erythema nodosum (Seeabove.)
Allergic reactions ranging fromurticaria to anaphylactic reactions
have been reported. (SeeWARNINGS.)
SPECIAL SENSES: blurred vision, disturbed vision (change incolor
overbrightness of lights), decreased visual acuity,
diplopia, eye pain, tinnitus, hearing loss, bad taste
Mostof theadverse events reported were described asonlymildor
moderate inseverity, abated soon after thedrugwas discontinued, and
required notreatment.
In several instances nausea, vomiting, tremor, irritability or palpitation
were by investigators to berelated to elevated serum levels of
theopl1ylirne pOssIbly asaresult of druginteraction withciprofloxacin.
Other adverse events reported inthepostmarketing phase include ana-
phylactic reactions, erytl1ema multiformelStevens-Johnson syndrome,
exfoliative dermatitis, toxicepidermal necrolysis, vasculitis, jaundice,
hepatic necrosis, toxicpsychosis, postural hypotension, possible exac-
erbation of myasthenia gravis, anosmia, confusion, dysphasia, nystag-
mus,pseudomembranous colitis, pancreatitis, dyspepsia, flatulence,
andconstipation. Also were hemolytic anemia; agranulocyto-
sis;elevation of serum tnglycerides, serum cholesterol, blOod glucose,
serum potassium; prolongation of prothrombin time; albuminuria; can-
diduria, vaginal candidiasiS; renal calculi; andchange inserum pheny-
toin.(seePRECAUTIONS.)
Adverse Laboratory C2Ianges: Changes inlaboratory parameters listed
asadverse events without regard todrugrelationship:
Hepatic - Elevations of: ALT (SGPTl (1.9%),
AST (SGOn (1.7%), alkaline Ilhosphatase (0.8%),
LDH (O.4%), serum bilirubin (0.3%).
Hematologic - Eosinophilia (0.6%), leukopenia (0.4%), decreased
blood platelets (0.1%), elevated bloodplatelets
(0.1%), pancytopenia (0.1%).
- Elevations of: Serum creatinine {1.1%), BUN (0.9%).
CRYSTALLURIA, CYLINDRURIA AND HEMATURIA
HAVE BEEN REPORTED.
Other changes occurring in lessthan 0.1%of patients treated were:
Elevation of serum gammaglutamyl transferase, elevation of serum
amylase, reduction in blood glUcose, elevated uricacid, decrease in
hemoglobin, anemia, bleeding diathesis, increase in blood monocytes,
leukocytosis.
produced by Clostridium difficile is one primary cause of "antibiotic-
associated colitis".
After thediagnosis of pseudomembranous colitis has been established,
therapeutic measures should beinitiated. Mildcases of pseudomembra-
nous colitis usually respond todrug alone. Inmoderate
tosevere cases, consideration should beglVlln tomanagement withflu-
ids and electrolytes, protein supplementation andtreatment withan
antibacterial drugclinically ellectiVe against C. difficilecolitis.
PRECAUTIONS
General: Crystals of ciprofloxacin have been observed rarely in the
urine of human SUbjects butmore frequently intheurine of
animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.)
Crystalluria related to ciprofloxacin has been reported onlyrarely in
humans because human urine is usually acidic. Alkalinity of theurine
should beavoided in patients receiving ciproftoxacin. Patients should
bewellhydrated to prevent theformation of highly concentrated urine.
Alteration of thedosage regimen isnecessary for patients withimpair-
mentof renal function.
Moderate to severe phototoxicitv manifested by anexaggerated sun-
bumreaction hasbeen observed inpatients whoareexposed todirect
sunlight whilereceiving some members of the quinolone class of
drugs. Excessive sunlight shOUld beavoided. Therapy should bedis-
continued if phototoxicity occurs.
Aswithanypotent drug,periodic assessment of organ system func-
tions, including renal, hepatic, and hematopoietic function, isadvisable
during prolonged therapy.
Infonnation lor Patients: Patients should beadvised thatciprofloxacin
maybetaken withor without meals. The preferred timeof dosing is
twohours altera meal. Patients should also be advised todrinkfluids
liberally andnot take antacids containing magnesium, aluminum, or
calcium, products containing iron, or multivitamins containing zinc.
However, usual dietary intake of calcium hasnot been shown to alter
theabsorption of ciprofloxacin.
Patients should beadvised thatciprofloxacin may beassociated with
hypersensitivity reactions, even following asingle dose, and todiscon-
tinue thedrugatthefirst sign ofaskin rash orother allergic reaction.
Patients should beadvised toavoid excessive sunlight orartificial ultra-
violet lightwhile receiving ciprofloxacin and to discontinue therapy if
phototoxicity occurs.
Ciprofloxacin maycause dizziness andIightheadedness; therefore
patients should knowhowthey react tothisdrugbefore theyoperate
anautomobile or machinery or engage in activities requiring mental
alertness or coordination.
Patients should beadvised that ciprofloxacin may increase theeffects of
theophylline and caffeine. There isa possibility of caffeine accumulation
when products containing caffeine are consumed while taking quinolones.
Drug Interactions: Aswithsome other quinolones, concurrent admin-
istration of ciprofloxacin with theophylline maylead toelevated serum
concentrations of theophylline and prolongation of its elimination hall-
life. Thismayresult in increased nskof theophylline-related adverse
reactions. (See WARNINGS.) If concomitant usecannot beavoided,
serum levels of should bemonitored anddosage adjust-
ments made asappropriate.
Some quinolones, including ciprofloxacin, have also been shown to
interfere withthe metabolism of caffeine. This maylead to reduced
clearance of caffeine andaprolongation of itsserumhall-life.
Concurrent administration of ciprofloxacin withantacids containing
magnesium, aluminum, or calcium; with sucrallate or divalent and
trivalent cations suchas ironmaysubstantially interfere with the
absorption of ciprolloxacin, resulting inserum and urine levels consid-
erably lower than desired. To alesser extent thiseffect isdemonstrated
withzinc-containing multivitamins.
Some quinolones, including ciprofloxacin, have been associated with
transientelevations in serum creatinine in patients receiving cy-
closporine concomitantly.
Quinolones have been reported toenhance theeffects of theoral anti-
coagulant warfarin or its derivatives. When these products areadmin-
istered concomitantly, prothrombin timeor other suitable coagulation
testsshould beclosely monitored.
Probenecid interferes withrenaJ tubular secretion of ciprofloxacin and
produces an increase in thelevel of ciprofloxacin in theserum. This
should beconsidered if patients are receiving bothdrugs concomitantly.
Aswithother broad spectrum antimicrobial agents, prolonged useof
ciproftoxacin mayresultin overgrowth of nonsusceptible organisms.
Repeated evaluation of thepatienfs condition and microbial suscepti-
bility testingis essential. If superinfection occurs duringtherapy,
appropriate measures should betaken.
carcinogenesis, Mutagenesis, Impalnnem of fertility: Eight in vitro
mutagenici!Y tests have been conducted withciprofloxacin and thetest
results arelisted below:
SalmonellalMicrosome Test
E co/iDNA Repair Assay (Negative).
Mouse Lymphoma cell Forward Mutation Assay (Positive)
Chinese HamsterV
19
cellHGPRTTest (Negative)
Syrian Hamster EmDryo cellTransformation Assay (Negative)
saccharomyces cerevisiae Point Mutation Assay (Negative)
saccharomyces cerevisiae Mitotic Crossover and Gene Conversion
Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus 2of the8 tests were positive butresults of thefollowing 3 invivo
testsystems gave negative results:
RatHepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long termcarcinogenicity studies inmice and rats havebeen completed.
Afterdaily oraldosing for upto 2 years, there is noevidence thatcl-
proftoxacm had anycarcinogenic ortumorigenic effects inthesespecies.
Preanafll:Y: Teratogenic ElIects. Pr8ananc:y category C:Reproduction
stud'ies have been performed in rats and mice at doses upto 6 times
theusual dailyhuman dose and have revealed noevidence of impaired
fertility or harm to the fetus due to ciprofloxacin. In rabbits as with
most antimicrobial agents, (30and 100mglkgorally)
produced gastrointestinal disturbances resulting in maternal weight
1/93
CIPRO
(ciprofloxacin hydrochloride)
TABLETS
BRIEF SUMMARY
CONSULT PACKAGE INSERT FOR FULL PRESCRIBING
INFORMATION
PZ100747BS
In 5 years' time,
the incidence of MAC
has quadrupled.'
I t
'Now it's time to fight
back against MAC,
the epidemic within
the AI DS epidemic.
Introducing
15Dmg (rifabutincapsules) ~ _ # ~ ~ ,
The first and only prophylaxis
for disseminated MAC disease
An aggressive approach to
an aggressive challenge
Mycobutin protects patients from
.Mycobacterium avium complex (MAC)2
Proven in two double-blind, randomized, controlled
multicenter trials in 1146 patients with AIDS and CD4 < 200
Reduces the incidence of MAC by up to 65%
Reduces the signs and symptoms of disseminated MAC
: 1993 Adria tooorotonos
Mycobutin
fitseasily into
patients' lives
Convenient once-daily, 300-mg dose
helps ensure compliance*
Easy-to-swallow capsule can be taken with
or without meals
Lower zidovudine (ZDV) AUC; however, its
levelsremained ina range considered to be
thercpeutlc'
Systemic availability of didanosine (ddI) was
not oltered-
Fluconazole pharmacokinetics were not
compromised'
Mycobutin prophylaxis mustnot be administered
to patients with active tuberculosis
Rifabutin, structurally related to rifampin, may reduce the
activity of drugs affected by itsliver enzyme inducing properties,
References: 1. Havlik JA Jr,Horsburgh CRJr,
Metchock B, Williams Pp, Fann SA,Thompson SE III.
Disseminated fv1ycobacferium ovium complex
infection: clinical identification and epidemiologic
trends. J IntectDis. 1992;165:577580, 2. Data on file,
Adria Laboratories,
Please see brief summary of prescribing information
on last page of this advertisement.
January 1993 L119213
. ~ n e U i tl. rio;
1,I!lCOliUIiRM---',;--
150mg (rifabutincapsules) ~ ' ~ ' "
The first and only prophylaxis
for disseminated MAC disease
ADVERSE REACTIONS
MYCOBUTINwas generally well tolerated in the controlledclinical trials. Discontinuation
of therapyduetoanadverseevent was requiredin 16% ofpatientsreceivingMYCOBUTIN
comparedto 8%of patients receiving placebo in these trials. Primaryreasonsfor discon-
tinuationof MYCOBUTINwere rash (4% of treated patients),gastrointestinalintolerance
(3%), and neutropenia (2%).
The followingtable enumerates adverse experiences that occurredat a frequencyof 1%
or greater,among the patients treated with MYCOBUTIN in studies 023 and027.
.JlJIII!UIII. ,I-;
IrI!lCOliUIiRM'-Yr
15Dmg (rifabutincapsules)
PERCENTAGE OFPATIENTSWITH LABORATORY ABNORMALITIES
LABORATORY ABNORMALITIES
MYCOBUTIN PLACEBO
(n = 566)% (n = 580)%
Chemistry
Increased Alkaline Phosphatase
1
<1 3
Increased SGOT2 7 12
Increased SGPT2 9 11
Hematology
Anemia
3
6 7
Eosinophilia 1 1
t.eukopenla" 17 16
Neutropenia
5
25 20
Tnrombocytopenlaf 5 4
CLINICAL ADVERSEEVENTS REPORTED IN <1% OFPATIENTSWHORECEIVED
MYCOBUTIN
Considering data from the 023 and 027 pivotal trials, and from other clinical studies,
MYCOBUTINappearsto be a likelycause of the following adverseeventswhich occurred
in less that 1% of treated patients: flu-like syndrome, hepatitis, hemolysis, arthralgia,
myositis, chest pressure or pain with dyspnea, and skin discoloration.
The following adverse events have occurred in more than one patient receiving
MYCOBUTIN,but anetiologicrolehas not beenestablished:seizure, parathesia,aphasia,
confusion, and non-specific T wave changes on electrocardiogram.
When MYCOBUTIN was administered at doses from 1050 mg/day to 2400 mglday
generalizedarthralgiaand uveitiswere reported.These adverseexperiencesabatedwhen
MYCOBUTINwas discontinued.
The followingtable enumeratesthe changes in laboratoryvaluesthat wereconsidered as
laboratoryabnormalities in studies 023 and 027.
December 23, 1992
CLINICAL ADVERSE EXPERIENCES
REPORTED IN2<1% OFPATIENTSTREATED WITH MYCOBUTIN
ADVERSE EVENT
MYCOBUTIN PLACEBO
(n =566)% (n =580)%
BODY ASAWHOLE
Abdominal Pain 4 3
Asthenia 1 1
Chest Pain 1 1
Fever 2 1
Headache 3 5
Pain 1 2
DIGESTIVE SYSTEM
Anorexia 2 2
Diarrhea 3 3
Dyspepsia 3 1
Eructation 3 1
Flatulence 2 1
Nausea 6 5
Nausea andVomiting 3 2
Vomiting 1 1
MUSCULOSKELETAL SYSTEM
Myalgia 2 1
NERVOUS SYSTEM
Insomnia 1 1
SKIN AND APPENDAGES
Rash 11 8
SPECIAL SENSES
Taste Perversion 3 1
UROGENITAL SYSTEM
Discolored Urine 30 6
057001292
INCWDESGRADE3 OR4 mXICmESAS SPECIFIED.
1all values> 450 U/L 4all WBC values <1,500/mm
3
2allvalues>150 UlL 5all ANC values <750/mm
3
3all hemoglobin values <8.0 gldL 6all platelet count values <50,OOO/mm
3
The incidence of neutropenia in patients treated with MYCOBUTIN was significantly
greaterthan in patientstreated with placebo (p = 0.03). Althoughthrombocytopeniawas
not significantly more common among MYCOBUTIN treated patients in these trials,
MYCOBUTINhas been clearly linked to thrombocytopenia in rarecases. One patient in
study 023 developed thrombotic thrombocytopenic purpura, which was attributed to
MYCOBUTIN.
CAUTION: Federal lawprohibits dispensing without prescription.
Manufactured by:
FARMITALIA CARLO ERBA
ASCOU PICENO, ITALY
For: .....,.,
ADRIA LABORATORIES
COLUMBUS, OHIO 43216
MYCOBUTINTM (rifabutincapsules) 150mg
BRIEF SUMMARY
CONTRAINDICATIONS
Rifabutin iscontraindicated in patientswho havehad clinically significant hypersensitivity
to this drug, or to any other rifamycins.
WARNINGS
MYCOBUTIN prophylaxis must not be administered to patients with active tuberculosis.
Tuberculosis in HIV-positive patients is common and may present with atypical or
extrapulmonaryfindings. Patientsare likelyto haveanonreactivepurifiedproteinderivative
(PPD) despite active disease. In addition to chest X-rayand sputum culture, the following
studies may be useful in the diagnosis of tuberculosis in the HIV-positive patient: blood
culture, urine culture, or biopsy of a suspicious lymph node.
Patients who develop complaints consistent with active tuberculosis while on
MYCOBUTIN prophylaxis should be evaluated immediately, so that those with active
disease may be given an effectivecombination regimenof anti-tuberculosis medications.
Administration of single-agent MYCOBUTIN to patients with active tuberculosis is likely
to lead to the development of tuberculosis that is resistant both to MYCOBUTIN and to
rifampin.
There is no evidence that MYCOBUTIN is effective prophylaxis against Mycobaterium
tubelCuiosis. Patientsrequiringprophylaxisagainst bothM. tubelCuJosis andMycobacterium
aviumcomplex may be given isoniazid and MYCOBUTIN concurrently.
PRECAUTIONS
Because MYCOBUTIN may be associated with neutropenia, and more rarely throm-
bocytopenia, physicians should consider obtaining hematologic studies periodically in
patients receiving MYCOBUTIN prophylaxis.
Informationfor patients
Patientsshould be advised of the signs and symptomsof both MACand tuberculosis,and
should be instructedto consult their physicians if they develop newcomplaints consistent
with either of these diseases. In addition, since MYCOBUTIN may rarely be associated
with myositis and uveitis, patients should be advised to notify their physicians if they
develop signs or symptoms suggesting either of these disorders.
Urine, feces, saliva, sputum, perspiration, tears, and skin may be colored brown-orange
with rifabutinand someof its metabolites.Soft contact lensesmay bepermanentlystained.
Patientsto be treated with MYCOBUTI N should be made aware of these possibilities.
DrugInteractions
In 10 healthy adult volunteers and 8 HIV-positive patients, steady-stateplasma levelsof
zidovudine(ZDV),an antiretroviralagent which is metabolizedmainlythrough glucuronida-
tion, weredecreasedafter repeatedMYCOBUTINdosing; the mean decreasein C
max
and
AUC was 48% and 32%, respectively. In vitro studies have demonstrated that
MYCOBUTINdoes not affect the inhibition of HIV by ZDV.
Steady-state kinetics in 12 HIV-positive patients show that both the rate and extent of
systemic availability of didanosine (ddl), was not altered after repeated dosing of
MYCOBUTIN.
MYCOBUTIN has liver enzyme-inducing properties. The relateddrug rifampin is known
to reduce the activity of a number of other drugs, including dapsone, narcotics (including
methadone),anticoagulants,corticosteroids,cyclosporine,cardiac glycosidepreparations,
quinidine, oral contraceptives, oral hypoglycemic agents (sulfonylureas),and analgesics.
Rifampin has also been reported to decrease the effects of concurrently administered
ketoconazole, barbiturates,diazepam, verapamil, beta-adrenergicblockers,clofibrate, pro-
gestins, disopyramide, mexiletine, theophylline, chloramphenicol, and anticonvulsants.
Because of the structural similarity of rifabutin and rifampin, MYCOBUTIN may be
expected to have some effect on these drugs as well. However, unlike rifampin,
MYCOBUTINappears not to affect the acetylation of isoniazid. When rifabutin wascom-
pared with rifampin in a study with 8 healthy normal volunteers, rifabutin appeared to be
a lesspotentenzyme inducer than rifampin. The significanceof this finding for clinicaldrug
interactions is not known. Dosaae of drugs listed above may be necessary if
they aregivenconcurrentlfi WithMYC auTIN. Patientsusmgoral contraceptivesshould
consider changing to non ormonal methOdsof birth control.
carcinogenesis, Mutagenesis, Impairmentof Fertilty:
Long term carcinogenicity studies were conducted with rifabutin in mice and in rats.
Rifabutin was not carcinogenic in mice at doses upto 180 mg/kglday, or approximately36
times the recommended human daily dose. Rifabutin was not carcinogenic in the rat at
doses up to 60 mg/kg/day, about 12 times the recommended human dose.
Rifabutin was not mutagenic in the bacterial mutation assay (Ames Test) using both
rifabutin-susceptible and resistant strains. Rifabutin was not mutagenic in Schizosac-
charomycespombe PI and was not genotoxic in V-79Chinese hamster cells, human lym-
phocytes in vitro, or mouse bone marrow cells in vivo.
Fertility was impaired in male rats given 160 mg/kg (32 times the recommended human
daily dose).
Pregnancy:
Pregnancy Category B: Reproduction studies have been carried out in rats and rabbits
given rifabutinusingdose levelsup to200 mglkg (40times the recommended humandaily
dose). Noteratogenicitywas observed in either species. In rats,given200 mglkglday,there
was adecreasein fetal viability. In rats,at 40 mglkglday (8times the recommendedhuman
daily dose), rifabutin caused an increase in fetal skeletal variants. In rabbits, at 80
mglkglday (16times the recommended human daily dose), rifabutin caused maternotox-
icity and increase in fetal skeletal anomalies. There are no adequate and well-controlled
studies in pregnant women. Because animal reproduction studies are not alwayspredic-
tive of human response, rifabutin should be used in pregnant women only if the potential
benefit justifies the potential risk to the fetus.
Nursing Mothers:
It is not known whether rifabutin is excreted in human milk. Because many drugs are
excretedin human milk and because of the potential for serious adversereactionsin nur-
sing infants,a decision should be made whether to discontinue nursingor discontinuethe
drug, taking into account the importance of the drug to the mother.
PediatricUse:
Safety and effectiveness of rifabutin for prophylaxis of MAC in children have not been
established. Limited safety data are available from treatment use in 22 HIV-positive
children with MAC who received MYCOBUTIN in combination with at least two other
antimycobacterialsfor periods from 1to 183weeks. Mean doses(mglkg) for thesechildren
were: 18.5(range 15.0to 25.0) for infants one year of age; 8.6(range 4.4 to 18.8)forchildren
2 to 10yearsof age; and 4.0 (range 2.8 to 5.4) for adolescents 14to 16 years of age.There
is no evidencethat doses greater than 5 mglkg daily are useful. Adverseexperienceswere
similar tothose observed in the adult population, and included leukopenia, neutropenia
and rash. Doses of MYCOBUTIN may be administered mixed with foods such as
applesauce.
A N N o u N c I N G
A NEW
NONSU LFONAMI DE
THERAPY FOR
THE TREATMENT OF
AN EFFECTIVE
ORAL OPTION FOR MILD
TO MODERATE
PNEUMOCYSTIS CARINII PNEUMONIA
IN INDIVIDUALS
WHO ARE INTOLERANT TO
TMP-SMX.
GMS stain
MEPRONTM
ATOVAQUONE
250 MG TABLETS
PROVEN EFFECTIVE
AND WELL TOLERATED IN
RANDOMIZED, MULTICENTER
STUDIES OF
PCP
Chest radiographs of person with PCP before (left ) and after (right ) t reatment with MEPRON.
Clinical experience with MEPRON has been limited to patients with
mild to moderate PCP (defined in the study protocol as an alveolar-
arterial. oxygen diffusion gradient [(A-a)D0
2
] 1 ~ 4 5 mm Hg and Pa0
2
;::60 mm Hg on room air). Treatment of more severe episodes of
PCP has not been systematically studied with this agent. MEPRON
has not been evaluated as an agent for PCP prophylaxis.
STUDY 1
COMPARATIVE TRIAL OF MEPRON AND
TRIMETHOPRIM-SULFAMETHOXAZOLE.
- Therapeutic success rates of MEPRON and TMP-
SMX were 62% and 64%, respectively, based on an
intent-to-treat analysis. '
- Fewer patients treated with MEPRON failed therapy
due to toxicity (7% vs 20%); more failed due to lack
of therapeutic response (17% vs 6%).1
- Although survival was high, more deaths occurred in
the group treated with MEPRON (8%) than in the
TMP-SMX group (3%) (P=0.03). 1 This difference in
mortality appeared to be partially due to a dispropor-
tionate number of fatal bacterial infections in the
group treated with MEPRON.
- Rash (23%), nausea (21%), and diarrhea (19%) were
the most common adverse events reported with
MEPRON.
1
TREATMENT-LIMITI NG ADVERSE EVENTS
OBSERVED I N > 3 % OF PAT IENTS'
TH ERAPEUTIC SUCCESS' OF
MEPRON VS TMP-SMX'
100
80
62% 64%
~
(n=160) (n=162)
60
I
'"
....
Z
UJ
40
>=
~
20
0
1'=0.75 MEPRON TMP-SMX
10
8
~
6
'"
....
z
UJ
4
~
2
o
UVER
OYSFUNCTION
RASH VOMITING NAUSEA
_ M EPRON (n- 203)
_ TMP-S MX ( n =205)
FEVER NEUTROPENIA
Improvementin clinical and respiratory measures
persistingat least 4 weeks after end of treatment.
STUDY 2
t Some patients had more than one adverse event.
COMPARATIVE TRIAL OF MEPRON AND
INTRAVENOUS PENTAMIDINE.
- Approximately 80% of patients either had a history
of, or were currently experiencing, intolerance to
TMP-SMX.1
- MEPRON and pentamidine had comparable thera-
peutic success rates: 57% vs 40%, respectively
(P=0.09, NS).l
- Eight weeks after discontinuation of therapy, survival
rates for the groups treated with MEPRON and pen-
tamidine were the same (86%). 1
- The only treatment-limiting adverse event that
occurred in more than one patient in the group treat-
ed with MEPRON was rash (4%). Forty-one percent of
patients receiving pentamidine experienced treat-
ment-limiting adverse events. '
FEWER TREATMENT-LIMITING TOXICITIES IN PATIENTS INTOLERANT TO TMP-5MX.
Please see full prescribing informat ion on the las t pages of th is ad.
TH ERAPY.
TM
E
NOW... A NEW
250 MG TABLETS
ORAL NONSULFONAMIDE
- A well -tolerated option for patients with mild to
moderate PCP who are intolerant to TMP-SMX.
MEPRO
ATOVAQ U 0 N
- The most commonly reported adverse events are
rash, nausea, fever, and diarrhea.
DOSAGE REGIMEN.
- Oral dosing with MEPRON permits outpatient
treatment.
- Recommended regimen: 750 rng (three 250 rng
tablets) tid for 21 days with food.
ADMINISTRATION WITH FOOD IS IMPOR"JANT.
- Meals with a fat content of ~ 2 3 g improve absorption
significantly, increasing bioavailabil ity approximately
threefold. '
- Patients with gastrointestinal disorders that may limit
absorption of orally administered drugs may not
achieve optimal results. Parenteral therapy with other
agents should be considered for patients having diffi-
culty taking food.
Reference: 1. Data on file. Burroughs Wellcome Co.
FEWER TREATMENT-LIMITING TOXICITIES IN PATIENTS INTOLERANT TO TMP-5MX.
Please see full prescribing information on the last pages of t his ad.
~ Burroughs Wellcome Co.
~ Research Triangle Park, NC 27709
Copr, 1992 Burroughs Well come Co. All rights reserved. Printed in U.S.A. MPY04562 December 1992
o
DESCRIPTION: MEPRON (atovaquone) is anantiprotozoal agent. Thechemical name of atovaquone is.trans-
2-[4-(4-ehlorophenyl)cyclohexylj-3-hydroxy-1,4-naphthalenedione. Atovaquone IS a yellow crystalhne sohd that
ispractically insoluble in water. It hasa molecular weight of 366.84 andthemolecular formula C22HtgCI03 The
compound hasthefollowing structural fonnula:
Once DailywithFood Twice Daily with Food
750mg 1500mg 3000mg 750mg 1500mg
(1'1=15) (1'1=15) (1'1=14) (1'1=12) (1'1=13)
Steady-State AUC
(hr'llglmL) 181 84 253126 322135 231 59 314109
Steady-State Average
Concentrations (llglmL) 7.53.5 10.65.3 13.45.6 9.62.5 13.1 4.5
dY
el
W
o _", .... 1
I I
OH
Primary Treatment salvage Treatment
MEPRON Pentamidine MEPRON Pentamidine
Outcome of Therapy (1'1=56) (n=53) PValue (1'1=14) (1'1=11) PValue
Therapy Success 32 (57%) 21 (40%) 0.09 13 (93%) 7 (64%) 0.14
Therapy Failure
- Lackof Response 16 (29%) 9 (17%) 0.18 0 0 ---
- Adverse Experience 2 (3.6%) 19 (36%) <0.01 0 3 (27%) 0.07
- Unevaluabie 6 (11%) 4 (8%) 0.75 1 (7%) 1 (9%) 1.00
Required Alternate
PCP Therapy
4 (36%) 0.03
During Study 19 (34%) 29 (55%) 0.04 0
Table2
Outcome of Treatment for PCP-Positive PatientsEnrolledin theTMP-5MX Comparative Study
Dataon ChronicUse:MEPRON hasnotbeensystematically evaluated asachronic suppressive agent topre-
ventthedevelopment of PCPinpatients at highriskfor Pneumocystis cariniidisease. Ina pilotdosing study of
MEPRON inAIDS patients, 5of 31patients hadPCP breakthroughs: onepatient at 750mgonce daily(after 20
days), three patients at 750mgtwice daily(after14,70,and97days), and patient at 1500mg daily
(after74days). Thedoseused in theacute treatment studies (750mgthreelimesdally) wasnotstudied and,
therefore, therearenodataontherateof breakthrough at thisdose.
CONTRAINDICATIONS: MEPRON tablets arecontraindicated for patients whodevelop or havea history of
potentially life-threatening allergic reactions to anyof thecomponents ofthefonnulation.
WARNINGS: Clinical experience with MEPRON hasbeen limited to patients with mild tomoderate PCP [(A-a)D02
mmHg]. Treatment of more severe episodes of PCP hasnotbeen systematically studied with thisagent. Also,
theefficacy of MEPRON in patients whoarefailing therapy withTMP-SMX hasnot been systematically studied.
MEPRON hasnotbeen evaluated asanagent forPCP prophylaxis.
PRECAUTIONS:
General: Absorption of orally administered MEPRON is limited butcanbesignificantly increased when the drug is
taken with food. MEPRON plasma concentrations have been shown tocorrelate withthelikelihood of successful
treatment andsurvival. Therefore, parenteral therapy with other agents should beconsidered forpatients whohave
difficulty taking MEPRON withfood(seeCLINICAL PHARMACOLOGY). Gastrointestinal disorders maylimit
absorption of orally administered drugs. Patients withthese disorders alsomaynotachieve plasma concentrations
ofatovaquone associated with response totherapy incontrolled trials.
Based upon thespectrum of in activity, atovaquone isnot therapy !or
monary conditions suchas. vl.ral or fungal pneumonia or diseases. Chn'?l!l
in patients maybedueto Infections With otherpathogens, as wellas PCP. All patlen!s with.acute
PCP should becarefully evaluated for otherpossible causes of pulmonary disease andtreated withadditional
agents asappropriate.
Informationfor Patient$:The importance of takingthe prescribed doseof MEPRON should be
Patients should beinstructed totaketheirdailydoses of MEPRON withmeals as thepresence of foodwillsig-
nificantly improve theabsorption of thedrug.
DrugInteractions: Atovaquone ishighly to protein Therefore, should beused
when administering MEPRON concurrently With other highly plasma protein bound drug.s narrow
tic indices ascompetition for binding sitesmayoccur. Theextent of plasma protein binding of atovaquone In
Study participants randomized to MEPRON treatment were to receive 750mgMEPRON (three 250mgtablets)
three times dailyfor 21daysandthose randomized to TMP-SMX were to receive 320mgTMPplus1600 mg
SMX three times dailyfor21days.
Therapy success wasdefined as improvement in clinical andrespiratory measures persisting at leastfour
weeks aftercessation of therapy. Therapy failures included lackof response, lneatment discontinuation dueto
anadverse experience, andunevaluable.
There wasa significant difference (P= 0.03)in mortality ratesbetween thetreatment groups. Among the 322
patients withconfinned PCP, 13of 160(8%)patients treated withMEPRON andfourof 162(2.5%) patients
receiving TMP-SMX diedduring the21-day treatment course or 8-week follow-up period. In theintent-to-treat
analysis for all 408randomized patients, therewere 16(8%)deaths in theMEPRON armandseven (3.4"10)
deaths in theTMP-SMX ann (P= 0.051). Of the 13patients treated with MEPRON whodied, 4 diedof PCP
and5 diedwitha combination of bacterial infections andPCP; bacterial infections didnotappear tobea factor
inanyof the4deaths among TMP-SMXtreated patients.
A correlation between plasma atovaquone concentrations anddeath wasdemonstrated; in general, patients
withlower plasma concentrations weremorelikelyto die. Forthose patients for whom day4 atovaquone plas-
maconcentration dataareavailable, 5 (63%) of the8patients withconcentrations <5!J.g1mL diedduring partici-
pation inthestudy. However, only1(2.0%) of the49patients withday4plasma concentrations jlglmLdied.
Sixty-two percent of patients on MEPRON and64%of patients on TMP-SMX were classified as protocol-
defined therapy successes (Table 2).
'As defined bytheprotocol anddescribed instudy description above.
Thefailure ratedueto lackof response wassignificantly larger for MEPRON patients while thefailure rate due
toadverse experiences wassignificantly larger forTMP-SMX patients.
There were nosignificant differences intheeffect of eithertreatment onadditional indicators of response (i.e.,
arterial blood gasmeasurements, vitalsigns, serum LDH levels, clinical symptoms, andchest radiographs).
Pentamidine Comparative Study: Thisunblinded, randomized trial initiated in 1991 wasdesigned tocompare
thesafety andefficacy of MEPRON to thatof pentamidine for thetreatment of histologically confinned mild or
moderate PCP inAIDS patients. Approximately 80%of thepatients hada history of intolerance totrimethoprim
or suRa-antimicrobials (theprimary therapy group) or were experiencing intolerance toTMP-SMX withtreatment
of anepisode of PCP at thetimeof enrollment inthestudy (thesalvage treatment group).
Patients randomized to MEPRON were to receive 750mgatovaquone (three 250mgtablets) three times daily
for 21daysandthose randomized to pentamidine isethionate wereto receive a 3 to4mg/kg single intravenous
infusion dailyfor21days.
Atotal of 174patients were enrolled intothetrialat 22study centers. Thirty-nine patients without histologic con-
finnation of PCP were excluded fromtheefficacy analyses. Of the 135patients withhistologically confirmed
PCP, 70were randomized to receive MEPRON and65 to pentamidine. Onehundred andten(110) of these
were intheprimary therapy group and25were inthesalvage therapy group. Onepatient intheprimary therapy
group randomized toreceive pentamidine didnotreceive study medication.
There wasnodifference in mortality rates between the treatment groups. Among the 135patients with con-
finned PCP, 10of 70(14%) patients randomized toMEPRON andnineof 65(14%) patients randomized topen-
tamidine diedduring the21-day treatment course or 8-week follow-up period. Intheintent-to-treat analysis for
all randomized patients, therewere11(12.5%) deaths in theMEPRON armand12(14%) deaths inthepen-
tamidine arm. Forthose patients for whom day4 atovaquone plasma concentration areavailable, 3 of 5(60%)
patients withconcentrations <5 IlglmL died during participation in thestudy. However, only2 of 21 (9%)
patients withday4plasma concentrations IlglmLdied.
Thetherapeutic outcomes for the 134patients whoreceived studymedication in this trial arepresented in
Table 3.
Table3
Outcome of Treatment for PCP-Positive PatientsEnrolledin thePentamidine Comparative Study
Number of Patients (%ofTotal)
MEPRON TMP-SMX
Outcome ofTherapy' (1'1=160) (1'1=162) PValue
Therapy Success 99 (62%) 103 (64%) 0.75
Therapy Failure
- Lack of Response 28 (17%) 10 (6%) <0.01
- Adverse Experience 11 (7%) 33 (20%) <0.01
- Unevaluable 22 (14%) 16 (10%) 0.28
Required Alternate PCP
(34%) 0.95 Therapy During Study 55 (34%) 55

Wallcoma
'MeanSD
In thecontrolled efficacy trialsfor thetreatment of PCPwhere AIDS patients received 750mgMEPRON three
timesdaily,themean steady-state atovaquone concentration was13.96.8IlglmL (1'1=191).
Ina human study where volunteers received MEPRON at a dose of 750mgfourtimes dailyfortwoweeks, the
cerebrospinal fluid levels inthree volunteers were 0.04IlglmL,0.14IlglmLand0.26IlglmL.Thecorresponding
CSF/plasma ratios were lessthan1%.
Thepharmacokinetics of atovaquone havebeen evaluated in 10immunocompromised children (age: 5 months
to 13years; weight: 3.5to 85.5kg).Themean half-life was2.7 1.6days. Adosage regimen of 10mg/kg once
dailyachieved a steady-state average concentration of 7.5 4.6IlglmL (range 2.5 to 15.2IlglmL). For3 of
these children whoalsoreceived a dosage regimen of 40mglkg oncedaily, a steady-state average concentra-
tionof 14.02.2IlglmL(range 10.9to 15.6IlglmL)wasachieved.
Thepharmacokinetics of MEPRON hasnotbeen studied inpatients withhepatic or renal impainnent.
INDICATIONS ANDUSAGE: MEPRON is indicatedfor the acute oral treatment of mild to moderate
Pneumocystis carinii pneumonia inpatients whoareintolerant totrimethoprim-sulfamethoxazole (TMP-SMX).
Thisindication is based ontheresults of a randomized, double-blind trialcomparing MEPRON toTMP-SMX in
AIDS patients with mildto moderate PCP (defined inthestudy protocol asanalveolar-arterial oxygen diffusion
gradient [(A-a)D02J1 545mmHg andPa02 mmHg onroom air)andarandomized trialcomparing MEPRON
to intravenous pentamidine isethionate inpatients withmildto moderate PCP intolerant totrimethoprim or sulfa-
antimicrobials. These studies aresummarized below:
TMPSMX Comparative StUdy: Thisdouble-blind, randomized trialinitiated in 1990wasdesigned tocompare
the safety andefficacy MEPRONto thatof TMP-SMX for thetreatment of AIDS patients withhistologically
confirmed PCP. Onlypatients With mildtomoderate PCPwere eligible forenrollment.
totalof 408patients were enrolled intothetrialat 37studycenters. Eighty-six patients without histologic con-
firmation of PCP were excluded fromtheefficacy analyses. Of the 322patients withhistologically confirmed
PCP, 160were randomized toreceive MEPRON and162toTMP-SMX.
MEPRON tablets arefor oral administration. Each film-coated tablet contains 250mgof atovaquone andthe
inactive ingredients hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrys-
talline cellulose, polyethylene glycol, povidone, sodium starch glycolate, titanium dioxide, andyellow iron oxide.
CLINICAL PHARMACOLOGY:
Mechanism of Action: Atovaquone is a hydroxy-1,4-naphthoquinone, ananalog of ubiquinone, with antipneu-
mocystis activity. Themechanism of action against P. cariniihas not beenfully elucidated. In Plasmodium
species, thesiteof action appears tobethecytochrome bel complex (Complex III).Several metabolic enzymes
are linked to themitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by ato-
vaquone will result inindirect inhibition of these enzymes. Theultimate metabolic effects of suchblockade may
include inhibition of nucleic acidandATPsynthesis.
Microbiology:
Pneumocystis carinii: Several laboratories, using different in vitromethodologies, haveshown theICso(50%
Inhibitory Concentration) of atovaquone against rat P. cariniitobeintherange of 0.1 to3.0IlglmL.
Pharmacokinetics: Atovaquone is a highly lipophilic compound witha lowaqueous solubility. Phannacokinetic
andbioavailability studies indicate thatthebioavailability of thedrugislow,variable, anddecreases significantly
withsingle doses above 750mg.Following single-dose administration of MEPRON tofasted normal volunteers,
theatovaquone plasma concentration-time profile displayed a distinct double-peak, withthefirstpeak occurring
between 1and8 hours afterdosing andthesecond peakoccurring 24to 96hourspost-dose. Thisdouble-peak
profile is suggestive of enterohepatic cycling, whereby drugin thesystemic circulation is excreted into thebile
andissubsequently reabsorbed.
Thebioavailability of MEPRON is increased approximately 3-fold when administered withmeals. Inparticular,
fat hasbeenshown to enhance absorption significantly. Inonestudy, 18volunteers received a single dose of
500mgMEPRON afteranovernight fastandfollowing a breakfast (23g fat: 642kCal). Themean (SD) AUC
values were93.845.7 and288 77hr'llglmL,underfasting andfedconditions, respectively. In another vol-
unteer studywhere MEPRON wasadministered under fasting conditions, with28 g butter (23g fat)and56g
butter(46g fat) ontoast, mean AUC values increased 2.7-and4.0-fold, respectively, compared to thefasting
state. Significant differences in thebioavailability of MEPRON havebeen observed between normal volunteers
or HIV-seropositive asymptomatic volunteers andAIDS patients. Steady-state atovaquone plasma concentra-
tionsintheAIDS patients areabout one-third toone-half thelevels achieved intheasymptomatic HIV-infected
volunteers. Thereasons forthisdifference arenotclear.
Atovaquonehas a long half-life in normal volunteers (2.9 0.8 days; 1'1=27) and in AIDSpatients
(2.2 0.6days; 1'1=14), dueto presumed enterohepatic cycling andeventual fecalelimination. Ina study where
14C-labelled atovaquone wasadministered tohealthy volunteers, greater than94%of thedose wasrecovered in
thefecesover21days. There waslittleor noexcretion of atovaquone intheurine (less than 0.6%). There isno
evidence that thedrugis metabolized in man. Atovaquone is extensively bound to plasma proteins (>99.9%).
In vitrobinding interaction studies with phenytoin (15IlglmL) didnot showmutual displacement from binding
proteins.
During a multiple-dose studyof MEPRON administered withfoodincohorts of 4 HIV-seropositive asymptomatic
volunteers, dose-proportionality wasdemonstrated for dosage regimens of 100to 750mgonce daily. However,
at doses above 750mgoncedailywithfood, therelative oralbioavailability decreased. Themaximum dose test-
ed, 3000 mg once daily, produced a mean SD steady-state average plasma concentration of
40.0 19.0IlglmL compared to 26.9 10.0IlglmL in volunteers receiving 750mgonce daily. In a multiple-
doseescalation study(Table 1) conducted in volunteers withAIDS, where a single cohort of 15individuals
received 15- to 17-day consecutive courses of MEPRON administered withfoodat regimens of 750, 1500,
3000mg once daily, 750mgtwice daily, and1500 mg twice daily, the lackof doseproportionality was also
demonstrated; however, therewasamodest increase inconcentrations withincreasing totaldailydose. Altering
doseintervals without changing totaldailydose didnot affectconcentrations. In thisstudy, theCmaxlCmin con-
centration ratio values were low;approximately 1.5,andindependent of thedosage regimen.
Table1
Atovaquone AUCValuesandPlasmaConcentrations in Volunteers with AIDS'
MEPRONTM Tablets
(atovaquone)
Table7
Treatment-Emergent LaboratoryTest Abnormalitiesin the
PentamidineComparative PCPTreatmentStudy
Rash wasnotsevere inanypatient. Nootherreason for discontinuation of MEPRON wascitedmore thanonce.
Themostfrequently cijedreasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and
vomijing (9%).
Table6
Treatment-Emergent AdverseExperiences in the PentamidineComparative PCPTreatment Study
(PrimaryTherapyGroup)
'P=<O.05
tP=<0.001
Laboratory testabnormalijies reported in~ 5 % of patients inthepentamidine comparative studyarepresented in
Table 7. Laboratory abnormality was reportedas the reason for discontinuation of treatment in two of
73 patients who received MEPRON. One patient (1%) had elevatedcreatinine and BUNlevelsandone
patient (1%) hadelevated amylase levels. Laboratory abnormalities werethe soleor contributing factor in
14patients whoprematurely discontinued pentamidine therapy. In the71 patients whoreceived pentamidine,
laboratory parameters mostfrequently reported as reasons for discontinuation werehypoglycemia (11%), ele-
vated creatinine levels (6%), andleukopenia (4%).
403621 November 1992
ULN= upper limitof normal range
LLN= lowerlimijof normal range
OVERDOSAGE: There havebeennoreports of overdosage fromtheoraladministration of MEPRON.
DOSAGE ANDADMINISTRATION:
Adults: Therecommended oraldoseis750mg(three250mgtablets) administered wijhfoodthreetimesa day
for21days(total dailydose2250mg).Failure to administer MEPRON withfoodmayresult inloweratovaquone
plasma concentrations andmay limij response to therapy (seeCLINICAL PHARMACOLOGY andPRECAU-
TIONS).
HOW SUPPLIED: MEPRON tablets, 250mg, are yellow, round, film-eoated tablets engraved with"P7F" and
"WELLCOME." Bottles of 200(NDC0081-0126-62).
Store at 15to250C (59
0
to77"F).
Dispense inwell-elosed container as defined inU.S.P., if product package issubdivided.
1(A-a)DO:1=[(713 x F;02) - (PaC02/0.8)]- PaD:! (mmHg)
U.S.Patent No.5053432
U.S.Patent No.4981874 (UsePatent)
MidbyTheWellcome Foundation Ltd.
London, England NW1 2BPfor
BurroughsWeUcome Co.
Research Triangle Park, NC27709
Printed InU.S.A.
Patients Developing a
Laboratory TestAbnormality
(%ofTotal)
Laboratory TestAbnormalijy MEPRON Pentamidine
Anemia (Hob<8.0om/dL) 4% 9%
Neutropenia (ANC <750cellslmm
3
) 5% 9%
HVPOnatremia (<0.96 x LLN) 10% 10%
Hyperkalemia (>1.18 xULN) 0% 5%
Alkaline Phosphatase (>2.5x ULN) 5% 2%
Hyperglycemia (>1.8 x ULN) 9% 13%
Elevated AST(>5xULN) 0% 5%
Elevated Amylase (>1.5x ULN) 8% 4%
Elevated Creatinine (>1.5x ULN) 0% 7%
Number of Patients wijhTreatment-Emergent
Adverse Experience (%of Total)
Treatment-Emergent MEPRON Pentamidine
Adverse Experience (n=73) (n=71)
Fever 29 (40%) 18 (25%)
Nausea 16 (22%) 26 (37%)
Rash 16 (22%) 9 (13%)
Diarrhea 15 (21%) 22 (31%)
Insomnia 14 (19%) 10 (14%)
Headache 13 (18%) 20 (28%)
Vomijing 10 (14%) 12 (17%)
Cough 10 (14%)' 1 (1%)
Abdominal Pain 7 (10%) 8 (11%)
Pain 7 (10%) 7 (10%)
Sweat 7 (10%) 2 (3%)
Monilia,Oral 7 (10%) 2 (3%)
Asthenia 6 (8%) 10 (14%)
Dizziness 6 (8%) 10 (14%)
Anxiety 5 (7%) 7 (10%)
Anorexia 5 (7%) 7 (10%)
Sinusijus 5 (7%) 4 (6%)
Dyspepsia 4 (5%) 7 (10%)
Rhinijis 4 (5%) 5 (7%)
Taste Perversion 2 (3%) 9 (13%)'
Hypoglycemia 1 (1%) 11 (15%)'
Hypotension 1 (1%) 7 (10%)'
No.Patients Discontinuing
Therapy duetoan
(41%)t Adverse Experience 5 (7%) 29
No.Patients Reporting
at leastone
Adverse Experience 46 (63%) 51 (72%)
TableS
Treatment-Emergent LaboratoryTest Abnormalitiesin the
TMP-SMX ComparativePCPTreatmentStudy
'P=<0.05
Although an equal percentage of patients receiving MEPRON andTMP-SMX reported at least one adverse
experience, morepatients receiving TMP-SMX required discontinuation of therapy dueto an adverse event.
Ninepercent of patients receiving MEPRON wereprematurely discontinued fromtherapy dueto an adverse
eventversus 24%of patients receiving TMP-SMX. Fourpercent of patients receiving MEPRON hadtherapy dis-
continued dueto development of rash. Themajorijyof cases of rashamong patients receiving MEPRON were
mildanddidnot require thediscontinuation of dosing. Theonlyotherclinical adverse experience that ledtopre-
mature discontinuation of MEPRON dosing by morethanonepatient wasthedevelopment of vomiting 1%).
Twenty-four percent of patients receiving TMP-SMX wereprematurely discontinued fromtherapydueto an
adverse experience versus 9%of patients receiving MEPRON. Themostcommon adverse experience requiring
discontinuation of dosing intheTMP-SMX groupwasrash(8%).
Laboratory test abnormalities reported for ~ 5 % of thestudypopulation duringthetreatment period aresumma-
rizedinTable5. Twopercent of patients treated withMEPRON and7%of patients treated wijhTMP-SMX had
therapyprematurely discontinued due to elevations in ALT/AST. In general, patients treated with MEPRON
developed fewerabnormalities inmeasures of hepatocellular function (ALT, AST,alkaline phosphatase) oramy-
lasevalues thanpatients treated withTMP-SMX.
human plasma isnot affected bythepresence of therapeutic concentrations of phenytoin (15IlglmL), noristhe
binding of phenytoin affected bythepresence of atovaquone.
DruglLaboratoryTest Interactions:It is not known if MEPRON interferes withclinical laboratory test or assay
results.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies in ratsand mice have not
beencompleted. Atovaquone wasnegative withor wijhout metabolic activation in theAmes Salmonella muta-
genicity assay, the Mouse Lymphoma mutagenesis assay, andthe Cultured Human Lymphocyte cytogenetic
assay. Noevidence of genotoxicity wasobserved intheinvivo Mouse Micronucleus assay.
Pregnancy:Pregnancy Category C. Atovaquone wasnot teratogenic anddidnot cause reproductive toxicitx in
ratsat plasma concentrations upto5timestheestimated human exposure. Atovaquone caused matemal tOXICI-
ty in rabbits at plasma concentrations that wereapproximately equal to theestimated human exposure. Mean
fetal bodylengths andweights weredecreased and therewerehighernumbers of earlyresorption andpost-
implantation lossperdam.It is notclearwhether theseeffects werecaused by atovaquone or weresecondary
to maternal toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30%of theconcurrent maternal
plasma concentrations. In a separate studyin rats givena single14C-radiolabelled dose, concentrations of
radiocarbon in rat fetuses were18%(middle gestation) and60%(lategestation) of concurrent maternal plasma
concentrations. There arenoadequate andwell-controlled studies in pregnant women. Atovaquone should be
usedduring pregnancy onlyif thepotential benefit justifies thepotential risktothefetus.
Nursing Mothers: It is not known whether MEPRON is excreted intohuman milk. Because manydrugs are
excreted intohuman milk,caution should beexercised when MEPRON is administered to a nursing woman. In
a rat study, atovaquone concentrations inthemilkwere30%of theconcurrent atovaquone concentrations inthe
maternal plasma.
PediatricUse:There arenoefficacy studies inchildren. Clinical experience withMEPRON inthepediatric pop-
ulation is limited to a pharmacokinetic andsafetystudy. Nochildren under4 months of ageparticipated inthe
phase I trial.
Geriatric Use: MEPRON has not beensystematically evaluated in patientsgreaterthan65 years of age.
Caution should beexercised when treating elderlypatients reflecting thegreater frequency of decreased hepat-
ic, renal andcardiac function inthispopulation.
ADVERSE REACTIONS:
Because manypatients whoparticipated inclinical trialswithMEPRON hadcomplications of advanced HIVdis-
ease, it wasoftendifficult to distinguish adverse eventscaused by MEPRON fromthosecaused by underlying
medical conditions. Therewerenolife-threatening or fataladverse experiences caused byMEPRON.
Table4 summarizes all the clinical adverse experiences reported by ~ 5 % of the studypopulation during the
TMP-SMX comparative studyof MEPRON (n=408), regardless of attribution.
Table4
Treatment-Emergent AdverseExperiencesin theTMP-SMX Comparative PCPTreatmentStudy
Patients Developing a
Laboratory TestAbnormality
(%ofTotal)
Laboratory TestAbnormalijy MEPRON TMP-SMX
Anemia (Hgb<8.0gmldL) 6% 7%
Neutropenia (ANC <750c/mm
3
) 3% 9%
Elevated ALT (>5x ULN)
6% 16%
Elevated AST(>5x ULN) 4% 14%
Elevated Alkaline Phosphatase (>2.5x ULN) 8% 6%
Elevated Amylase (>1.5x ULN) 7% 12%
Hyponatremia 0.96 x LLN) 7% 26%
Number of Patients wijhTreatment-Emergent
Adverse Experience (%of Total)
Treatment-Emergent MEPRON TMP-SMX
Adverse Experience (n=203) (n=205)
Rash (including maculopapular) 47 (23%) 69 (34%)'
Nausea 43 (21%) 90 (44%)'
Diarrhea 39 (19%)' 15 (7%)
Headache 33 (16%) 44 (22%)
Vomiting 29 (14%) 72 (35%)'
Fever 28 (14%) 52 (25%)'
Insomnia 20 (10%) 18 (9%)
Asthenia 17 (8%) 16 (8%)
Pruritus 11 (5%) 18 (9%)
Monilia, Oral 11 (5%) 21 (10%)
Abdominal Pain 9 (4%) 15 (7%)
Constipation 7 (3%) 35 (17%)'
Dizziness 7 (3%) 17 (8%)'
No.Patients Discontinuing
Therapy duetoan
Adverse Experience 19 (9%) 50 (24%)'
No.Patients Reporting at
leastoneAdverse Experience 127 (63%) 134 (65%)
ULN= upperlimitof normal range
LLN= lowerlimitof normal range
Table6 summarizes theclinical adverse experiences reported by ~ 5 % of the primary therapy studypopulation
(n=144) durinqthe comparative trial of M E P ~ O N and intravenous pentamidine, regardless of attribution. A
slightly lower percentage of patients whoreceived MEPRON reported occurrence of adverse eventsthan did
those who received pentamidine (63%vs 72%). However, only7%of patients discontinued treatment with
MEPRON due to adverse events while41% of patients whoreceived pentamidine discontinued treatment for
this reason (P<0.001). Of thefivepatients whodiscontinued therapy withMEPRON, threereported rash (4%).
Now..
100 mg capsules
sporanox
CitraconazoleJ
. world leader in antimycotic research
J
'I\ NSSEN ~ .PHARMACEUTICA'
~ ~ RESEARCH FOUNDATION'
Titusville. NJ 08560-0200
Please see brief summary of prescribing information. including BOX WARNING, on adjacent page.
c> Janssen Pharmacautlca Inc. 1993 May 1993 Printed inU.S.A.
spqranOX
(Itraconazole)
Before prescribing, please consult complete prescribing information ofwhich the following isabrief summary.
WARNING: Coadministration of terfenadine with itraconazole iscontraindicated. Rare cases of serious cardiovascular
adverse events, including death, ventricular tachycardia and torsades depointes have been observed inpatients taking
itraconazole with terfenadine, due toincreased terfenadine concentrations induced byitraconazole. See
CONTRAINDICATIONS, WARNINGS and PRECAUTIONS sections
For information about individual journals,
write to Sandra Willis, Subscription
Fulfillment, The University of Chicago Press,
Journals Division, P.O. Box 37005,
Chicago, Il 60637.
*New from Chicago in 1993
History of Science
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Osiris
Perspectives on Science: Historical,
Philosophical, Social*
Technology and Culture
Journals
from
The University of
Chicago Press
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for a century, the University of Chicago
Press brings you the highest standards
of scholarship.
Biological and Medical
Sciences
The American Journal of Human
Genetics
The American Naturalist
International Journal of Plant Sciences
(formerly Botanical Gazette)
Clinical Infectious Diseases
(formerly Reviews of Infectious
Diseases)
The Journal of Infectious Diseases
Molecular Biology and Evolution
Perspectives in Biology and Medicine
Physiological Zoology
The Quarterly Review of Biology
Work1wide
Total number ofpatients 602 5751
BodySystem/Adverse Event Incidence (%)
'/Incidence> t%l
Psychiatric Disorders
1.2 0.2 Ltidodecreased
Somnolence 1.2 0.3
Cardiovascular Disorders
Hypertension 3.2 0.3
Metabolic and Nutritional

2.0 0.2
UrinarYSystem Disorders
0.1 Altiumlnuna 1.2
b::gBiliary System
Hepatic function abnormal 2.7 03
Rl!P.roduetive Disorders, Male
02 Impotence 1.2

Total number ofpatients 602 5751
BodySystem/Adverse Event Incidence ('!o)
Incidence 1%1
Gastrointestinal Disorders
Nausea 10.6 2.4

5.1 0.8
3.3 0.6
Abdominal Pain 1.5 1.4
Anorexia 1.2 03

dema 35 0.4
Fatigue 2.8 0.5
Fever 2.5 0.3
Malaise 1.2 0.1
Skin and Appendages
Rash 86' 1.1
Pruritus 2.5 0.7
Central andPeripheral
Nervous SY.Stem
Headache 3.8 1.5
Dizziness 1.7 0.7
Rash tends tooccur IOOIe frequently In Immunocompromised
patients receMng ImmullOSlIpp'essive medCatioos
Adverse. events reported bylesstllan 1% of patients InU.S. clinical trials included: flatulence, depression, insomnia, tinnitus,
adrenallnsulficlency, gynecomastia and male breast pain.
OVERDOSAGE: Itraconazole isnot removed bydialysis. Intileevent ofaccidental overdosage, supportive measures, including
gastnc lavage with sodium bicarbonate, should beemployed.
Nosignificant was observed when itraconazole was administered orally tomice andrats atdosage levels of320 ITlgI1(g orto
dogs at200 mg/kg.
Store atcontrolled room temperature, 15'30C (59'-86F). Protect from light and moisture. JANSSENiii-==:
U.S. Patent No. 4,267,179 Edition: september 1992 Titusville, NJ 08560-0200
CONTRAINDICATIONS: CoadministratIOn ofterfenadlne Wltll SPORANOX (rtraconazole) IS contraindICated. (See BOX WARNING
and WARNINGS and PRECAUTIONS sections.)
SPORANOX iscontraindicated inpatients who have shown hypersensitivity totiledrug oritsexcipients. There isnoinfonnat.ion
regarding cross between and otller azole antifungai agents. Caution should beused inprescnblng
SPOAANOX topatients wM toother azoles.
WARNINGS: InU.S. clinical trials prior tomarketing, there have been three cases of reversible idiosyncratic hepatitis reported
among more tIlan 2500 patients taking SPORANOX One patient outside the U.S. developed fulminant hepatitis and
died during SPORANOX administration. Since tillS patient was on medications, the causal association wMSPORANOX IS
uncertain. Ifclinical signs and symptoms consistent wMliver disease develop that may beattributable tortraconazole, SPORANOX
should bediscontinued.
Prior toU.S. marketing, tIlere have been tIlree cases ofIlle-tIlreatening cardiac dysrhythmias and one deatll reported inpatients
receiving terfenadine and itraconazofe. (See BOX WARNING and CONTRAINDICATIONS and PRECAUTIONS sections.)
PRECAUTIONS: General: Hepatic enzyme test values should bemonitored inpatients with preeXisting hepatic function
abnormalities.
Information for patients: Patients should beinstructed totake SPORANOX (itraconazole) wM food
Patients should beinstructed toreport any signs and symptoms that may suggest liver dysfunction sothat the appropriate
laboratory testing can bedone. Such signs and symptoms may include unusual fatigue, anorexia, nausea andlor vomiting, jaundioe,
dark urine orpale stool.
Drug interactions: Coadministration ofterfenadine wthSPORANOX has ied toeievated plasma concentrations of terfenadine,
resulting in rare instances of life-threatening cardiac dysrhythmias and one death. (See BOX WARNING and
CONTRAINOICATIONS and WARNINGS sections.)
Coadministration ofSPORANOX and cyclosporine ordigoxin has led toincreased plasma concentrations oftilelatter two drugs.
When digoxin isgiven concurrently with SPORANOX, the physician isadvised tomonitor digoxin concentrations and reduce tile
dosage asneeded. Mhough nostudies have been conducted, literature case reports suggest tIlat tiledose ofcyclosporine should
bereduced by50% when SPORANOX doses greater than 1DO mg daily are given. Cyclosporine concentrations should be
frequently and tiledose adjusted appropriately.
When SPORANOX was coadministered wMphenytoin, rifampin, or antagonists, reduced plasma concentrations ofitraconazole
were reported. The physician isadvised to the plasma concentrations ofrtraconazole when any oftIlese drugs istaken
concurrently, and toincrease the dose of SPORANOX II necessary. Anhough nostudies have been conducted, concomitant
administration ofSPORANOX and phenytoin may the metabolism ofphenytoin; therefore, plasma concentrations ofphenytoin
should also bemonitored when itisgiven concurrently wMSPORANOX.
If has been reported that SPORANOX enhances the anticoagulant effect ofcoumarin-like drugs. Therefore, prothrombin time
should becarefully monitored inpatients receiving SPORANOX and coumarin-like drugs simuttaneously.
Plasma concentrations ofazole antifungal agents are reduced when given concurrently with isoniazid. Itraconazole plasma
concentrations should bemonitored when SPORANOX and isoniazid are coadministered.
Severe hypoglycemia has been reported inpatients receiving azole antifungal agents and oral hypoglycemic agents.
Blood glucose concentrations should becarefully monitored when SPORANOX and oral hypoglycemic agents are coadministered.
Carcinogenesis, Mutagenesis and Impairment of Fertility: Itraconazole showed noevidence ofcarcinogenicity potential inmice
treated orally lor23montlls atdosage levels upto80 [approximately lOx tilemaximum recommended human dose
(MRHOn. Male rats treated with 25 (3.1 x MRHD) had aslightly increased incidence ofsoft tissue sarcoma These
sarcomas may have been aconsequence ofhypercholesterolemia, which isaresponse ofrats, but not dogs orhumans, toc!lronic
rtraconazole administration. Female rats treated witll 50 (6.25x MRHD) had anincreased incidence 01 squamous cell
carcinoma ofthe lung (2150) ascompared totileuntreated group. Although the occurrence ofsquamous cell carcinoma inthe lung
isextremely uncommon inuntreated rats, the increase inthis study was not statistically signllicanl.
Itraconazole produced nomutagenic effects when assayed inappropriate bacterial, non-mammalian and mammalian test systems.
Itraconazole did not affect the lertility ofmale orfemale rats treated orally witll dosage levels ofup to40 (5x MRHD)
even though parental was present atthis dosage level. More severe signs ofparental toxicity, including death, were present
inthe next higher dosage level, 160 (2OX MRHD}.
Pregnancy: Teratogenic Effects. Pregnancy Category C:Itraconazole was found tocause adose-related increase inmatemal
embryotoxicity and teratogenicity inrats atdosage levels ofapproximately 40-160 (5-2OX MRHO) and inmice at
dosage levels ofapproximately 80 (lOx MRHO). Inrats, the consisted ofmajor skeletal defects; inmice it
consisted ofencephaloceles andlor macroglossia.
There are nostudies inpregnant women. SPORANOX should beused inpregnancy only lithebenefit outweighs the potential risk.
Nursing Mothers: Itraconazole isexcreted inhuman milk; tIlerefore, SPORANOX should not beadministered toanursing woman.
Pediatric Use: The efficacy and safety ofSPORANOX have not been established inchildren. No pharmacokinetic data are available
inchildren. Asmall number ofpatients from age 3to16years have been treated with 100 of itraconazole for systemic
lungal infections and noserious adverse effects have been reported.
Toxicological studies have shown tIlat when administered torats, can produce bone toxicity. While nosuch toxicity
has been reported inadult patients, the long term effect of itraconazole inchildren isunknown. (See ANIMAL TOXICOLOGY
section.)
Histoplasmosis inHIV-infected Patients: Data from asmall number ofHIVinfected patients suggested tIlat the response rate of
histoplasmosis inHIV-infected patients issimilar tonon-HIV-infected patients. The clinical course ofhistoplasmosis inHIV-infected
patients ismore severe and usually requires maintenance therapy toprevent relapse. The optimal dosage regimen fortreatment
and maintenance therapy are unknown. Studies toinvestigate tileefficacy and safety ofSPORANOX, including optimal dosage and
duration inHIV-Infeeted patients, are ongoing.
Because hypochlorhydria has been reported inHIV-infected individuals, the absorption ofitraconazole intIlese patients may be
decreased.
The resutts from astudy inwhich eight HIV-infected individuals were lTeated wM zidovudine , 80.4 wMorwithout
SPORANOX, 100 mg b.i.d., showed that the pharmacokinetics ofzidovudine were not affected during concornrtant administration of
SPORANOX.
ADVERSE REACTIONS: InU.S. clinical trials prior tomarketing, there have been three cases ofreversible idiosyncratic hepatitis
reported among more tIlan 2500 patients. One patient ourtside the U.S. developed fulminant hepatitis and died during SPORANOX
(itraconazole) administration. Because this patient was onmultiple medications, the causal association with SPORANOX is
uncertain. (See WARNINGS.)
U.S. adverse experience data are derived from 602 patients with systemic fungal disease, who were immunocompromised or
receiving muttiple concomitant medications. Ofthese patients, treatment was discontinued in10.5% ofpatients due toadverse
events. The experience data are derived from 5751 patients treated for atleast seven days inclinical triats primarily of
non-systemic fungal infections. Ofthese patients, treatment was discontinued in3% ofpatients due toadverse events. The table
below lists adverse events reported byat least 1% ofpalients treated with SPORANOX inU.S. clinical trials. The worldwide
experience data are included forcomparison.
Clafcdii
(cefotaxime sodium)*
Although there isnoclinical evidence supporting the necessity ofchanging the dosage ofcefotaxime sodium
inpatients with even profound renal dysfunction, it issuggested that, until further data are obtained, the dose of
cefotaxime sodium be halved inpatients with estimated creatinine clearances ofless than 20mUmin/1. 73m'.
When only serum creatinine isavailable, the follOWing formula (based onsex, weight, and age ofthe patient)
may be used toconvert thisvalue intocreatinine clearance. The serum creatinine should represent asteady state
ofrenal function
Males: Weight (kg) x(140 - age)
72xserum creatinine
Females: 0.85 xabove value
71789T
Revised 6/92
Q74620-1192
C10
HoechstrB
Frequency andRoute
1gram 1M (single dose)
1gram every 12hours 1M orIV
1-2grams every 8hours 1M orIV
Type of Infection
Gonorrhea
Uncomplicated infections
Moderate tosevere infections
Infections commonly needing
antibiotics inhigher dosage
(e.g., septicemia) 6-8 2grams every 6-8hours IV
Life-threatening infections upto12 2grams every 4hours IV
To prevent postoperative infection incontaminated orpotentially contaminated surgery, the recommended dose
isasingle 1gram 1M orIVadministered 30to90minutes priortostart ofsurgery.
Cesarean Section Patients
The first dose of1gram isadministered intravenously assoon asthe umbilical cord isclamped. The second and
third doses should begiven as1gram intravenously orintramuscularly at6and 12hours after the first dose.
Neonates, Infants, andChildren
The following dosage schedule isrecommended:
Neonates (birth to1month):
0-1 week ofage 50mg/kg IVq12h
1-4weeks ofage 50mg/kg IVq8h
It isnotnecessary todifferentiate between premature and normal-gestational-age infants.
Infants and Children (1month to12years): For body weights less than 50kg, the recommended daily dose is50
to180 mg/kg ofbody weight 1M orIVdivided intofour tosixequal doses. The higher dosages should be used
formore severe orserious infections, including meningitis. For body weights 50kgormore, the usual adult
dosage should be used; the maximum daily dosage should notexceed 12grams.
ImpairedRenal Function - see PRECAUTIONS section.
NOTE: As with antibiotic therapy ingeneral, administration ofClaforan should becontinued foraminimum of48
to72hours after the patient defervesces orafter evidence ofbacterial eradication has been obtained; aminimum
of10days oftreatment isrecornmendec forinfections caused byGroup A streptococci inorder to
guard against the risk ofrheumatic orglomerulon.ephfltls; frequent and clinical appraisal is
necessary during therapy ofchronic urmary tract imection and may be required forseveral months after therapy
has been completed; persistent infections may require treatment ofseveral weeks and doses smaller than those
indicated above should notbeused.
*USPatent 4,152,432 Claforan REG TM ROUSSEL-UCLAF
Viaflex and PL 146 REG TM Baxter International Inc.
Hoechst-Roussel Pharmaceuticals Inc.
Somerville, New Jersey 08876-1258
The name and logo HOECHST are registered trademarks of Hoechst AG.
As with other antibiotics, prolonged use ofClaforan may result inovergrowth ofnonsusceptible organisms.
Repeated evaluation ofthe patient's condition isessential. If superinfection occurs during therapy, appropriate
measures should betaken.
As with other beta-Iactam antibiotics, granulocytopenia and, more rarely, agranulocytosis may develop during
treatment with Claforan, particularly if given over long periods. For courses oftreatment lasting longer than 10
days, blood counts should therefore bemonitored.
Parenteral antibiotics may belocally irritating totissues. Inrare instances, perivascular extravasation ofantibi-
otics including Claforan may result intissue damage requiring surgical intervention. Inmost cases, perivascular
extravasation ofClaforan infusion requires nospecific measures beyond changing the infusion site. To minimize
the potential fortissue inflammation, infusion sites should bemonitored regularly and changed as appropriate.
DrugInteractions: Increased nephrotoxicity has been reported follOWing concomitant administration of
cephalosporins and aminoglycoside antibiotics.
Carcinogenesis, Mutagenesis: Long-term studies inanimals have notbeen performed toevaluate carcino-
genic potential. Mutagenic tests included amicronucleus and an Ames test Both tests were negative formuta-
geniceffects.
Pregnancy (Category B): Reproduction studies have been performed inmice and rats atdoses upto30times
the usual human dose and have revealed noevidence ofimpaired fertility orharm tothe fetus because ofceto-
taxi me sodium. However, there are nowell-controlled studies inpregnant women. Because animal reproductive
studies are not always predictive ofhuman response, thisdrug should be used during pregnancy only if clearly
needed.
Nonteratogenic Effects: Use ofthe drug inwomen ofchildbearing potential requires that the anticipated bene-
fit be weighed against the possible risks.
Inperinatal and postnatal studies with rats, the pups inthe group given 1200 mg/kg ofClaforan were signifi-
cantly lighter inweight atbirth and remained smaller than pups inthe control group during the 21 days ofnurs-
ing.
Nursing Mothers: Claforan isexcreted inhuman milkinlowconcentrations. Caution should be exercised
when Claforan isadministered toanursing woman.
PediatricUse:The potential fortoxic effects inchildren from chemicals that may leach from the plastic insin-
gledose Viaflex Plus containers (premixed Claforan Injection) has notbeen determined.
ADVERSE REACTIONS
Claforan isgenerally well tolerated. The most common adverse reactions have been local reactions following 1M
orIVinjection Other adverse reactions have been encountered infrequently.
Themostfrequentadversereactions (greaterthan1%) are:
Local (4.3%)-lnjection site inflammation with IVadministration. Pain, induration, and tenderness after 1M
injection
Hypersensitivity (2.4%)- Rash, pruritus, fever, eosinophilia and less frequent urticaria and anaphylaxis.
Gastrointestinal (1.4%)- Colitis, diarrhea, nausea, and vomiting.
Symptoms ofpseudomembranous colitis can appear during orafter antibiotic treatment
Nausea and vomiting have been reported rarely.
Lessfrequentadverse reactions(lessthan1%) are:
Hematologic System- Neutropenia, transient leukopenia, eosinophilia, thrombocytopenia and agranulocy-
tosis have been reported. Some individuals have developed positive direct Coombs Tests during treatment with
Claforan and other cephalosporin antibiotics. Rare cases ofhemolytic anemia have been reported.
Genitourinary System- Moniliasis, vaginitis
Central Nervous System - Headache.
Liver- Transient elevations inSGOT, SGPT, serum LDH, and serum alkaline phosphatase levels have been
reported.
Kidney-As with some other cephalosporins, interstitial nephritis and transient elevations ofBUN have been
occasionally observed with Claforan.
DOSAGE AND ADMINISTRATION
Adults
Dosage and route ofadministration should bedetermined bysusceptibility ofthe causative organisms, severity
ofthe infection, and the condition ofthe patient (see table fordosage guidelines). Claforan may beadministered
1M orIVafter reconstitution. Premixed Claforan Injection isintended forIVadministration after thawing. The
maximum daily dosage should notexceed 12grams.
GUIDELINES FOR DDSAGE OFCLAFORAN
Daily
Dose
(grams)
1
2
3-6
Brief Summary
INDICATIONS AND USAGE
Treatment
Claforan isindicated forthe treatment ofpatients with serious infections caused bysusceptible strains ofthe des-
ignated microorganisms inthe diseases listed below.
(1)Lowerrespiratorytract infections, including pneumonia, caused byStreptococcus pneumoniae (for-
merly Diplococcus pneumoniae), Streptococcus pyogenes
t
(Group Astreptococci) and other streptococci (ex-
cluding enterococci, e.q., Streptococcus faecalis) , Staphylococcus aureus (penicillinase and non-penicillinase
producing), Escherichia coli, Klebsiella species, Haemophilus inffuenzae (including ampicillin-resistant strains),
Haemophilus parainffuenzae, Proteus mirabilis, Serratia mecescens) Enterobacterspecies, indole-positive
Proteus, and Pseudomonas species (including P. aeruginosa)
(2)Genitourinary infections. Urinary tract infections caused byEnterococcus species, Staphylococcus epi-
dermidis, Staphylococcus aureus
t
(penicillinase and non-penicillinase producing), Citrobacterspecies,
Enterobacter species, Escherichia coli, Klebsiella species, Proteus mirabilis, Proteus vulgaris, t Proteus
inconstans Group B,Morganella morganii,1 Providencia rellgeri,t Serratia marcescens, and Pseudomonas
species (including P. aeruginosa). Also, uncomplicated gonorrhea ofsingle ormultiple sites caused by
Neisseria gonorrhoeae, including penicillinase producing strains.
(3)Gynecologic infections, including pelvic inflammatory disease, endometritis and pelvic cellulitis caused
byStaphrlococcus epidermidis, Streptococcus species, Enterococcus species, Enterobacterspecies, t Klebsiella
species, Escherichia coli, Proteus mirabilis, Bacteroides species (including Bacteroides fragilis
t),
Clostridium
species, anaerobic cocci (including Peptostreptococcus species and Peptococcus species), and Fusobacterium
species (including F. nucleatum
t).
(4)Bacteremia/Septicemia caused byEscherichia coli, Klebsiella species, Serratia marcescens,
Staphylococcus aureus, and Streptococcus species (including S. pneumoniae).
(5)Skinandskin structureinfectionscaused byStaphylococcus aureus(penicillinase and non-penicilli-
nase producing), Staphylococcus epidermidis, Streptococcus pyogenes (Group Astreptococci) and other strep-
tococci, Enterococcus species, Acinetobacterspecies,t Escherichia coli, Citrobacterspecies (including C.
freundii
t),
Enterobacterspecies, Klebsiella species, Proteus mirabilis, Proteus vulgaris,t Morganella morganii,
hovidencis rettgeri, t Pseudomonas species, Serratia marcescens, Bacteroides species, and anaerobic cocci (in-
cluding Peptostreptococcus
t
species and Peptococcus species).
(6)Intra-abdominal infections, including peritonitis caused byStreptococcus species,' Escherichia coli,
Klebsiella species, Bacteroides species, anaerobic cocci (including Peptostreptococcus
t
species and
Peptococcus
t
species), Proteus mirabilis,t and Clostridiumspecies.'
(7)Boneand/orjoint infectionscaused byStaphylococcus aureus (penicillinase and non-penicillinase pro-
ducing strains), Streptococcus species (including S.pyogenes
t),
Pseudomonas species (including P
aeruginosa
t)
, and Proteus mirabilis.
t
(8)Centralnervoussysteminfections, e.q., meningitis and ventriculitis, caused byNeisseria meningitidis,
Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, t and Escherichia colit
tEfficacy forthisorganism, inthisorgan system, has been studied infewer than 10infections.
Although many strains ofenterococci (e.g., S. faecalis) and Pseudomonas species are resistant tocefotaxime
sodium invitro, Claforan has been used successfully intreating patients with infections caused bysusceptible
organisms.
Specimens forbacteriologic culture should beobtained prior totherapy inorder toisolate and identify
causative organisms and todetermine their susceptibilities toClaforan. Therapy may beinstituted before results
ofsusceptibility studies are known; however, once these results become available, the antibiotic treatment should
be adjusted accordingly
Incertain cases ofconfirmed orsuspected gram-positive orgram-negative sepsis orinpatients with other se-
rious infections inwhich the causative organism has notbeen identified, Claforan may beused concomitantly
with an aminoglycoside. The dosage recommended inthe labeling ofboth antibiotics may begiven and depends
onthe severity ofthe infection and the patient's condition. Renal function should be carefully monitored, espe-
cially if higher dosages ofthe aminoglycosides are tobeadministered orif therapy isprolonged, because ofthe
potential nephrotoxicity and ototoxicity ofaminoglycoside antibiotics. Some B-Iactam antibiotics also have a
certain degree of nephrotoxicity. Although, todate, thishas notbeen noted when Clatoran was given alone, it is
possible that nephrotoxicity may bepotentiated if Clatoran isused concomitantly with anaminoglycoside.
Prevention
The administration ofClaforan preoperatively reduces the incidence ofcertain infections inpatients undergoing
surgical procedures (e.q., abdominal orvaginal hysterectomy, gastrointestinal and genitourinary tract surgery)
that may beclassified ascontaminated orpotentially contaminated.
Inpatients undergoing cesarean section, intraoperative (after clamping the umbilical cord) and postoperative
use ofClaforan may also reduce the incidence ofcertain postoperative infections. (See DOSAGE ANDADMIN-
ISTRATION section)
Effective use forelective surgery depends onthe time ofadministration. To achieve effective tissue levels,
Claforan should begiven 112 to11/2 hours before surgery. (See DOSAGE AND ADMINISTRATION section)
For patients undergoing gastrointestinal surgery, preoperative bowel preparation bymechanical cleansing as
well aswith anon-absorbable antibiotic (e.o., neomycin) isrecommended.
Ifthere are signs ofinfection, specimens forculture should be obtained foridentification ofthe causative or-
ganism sothat appropriate therapy may beinstituted.
CONTRAINDICATIONS
Claforan iscontraindicated inpatients who have shown hypersensitivity tocefotaxime sodium orthe
cephalosporin group ofantibiotics.
WARNINGS
BEFORE THERAPY WITH CLAFORAN ISINSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE
WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFOTAXIME SODIUM,
CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS THIS PRODUCT SHOULD BE GIVEN WITH CAUTION
TO PATIENTS WITH TYPE I HYPERSENSITIVITY REACTIONS TO PENICILLIN. ANTIBIOTICS SHOULD BEAD-
MINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PAR-
TICULARLY TO DRUGS. IFAN ALLERGIC REACTION TO CLAFORAN OCCURS, DISCONTINUE TREATMENT
WITH THE DRUG. SERIOUS HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER
EMERGENCY MEASURES.
Pseudomembranous colitis hasbeenreported withthe useof cephalosporins (andother broad
spectrumantibiotics); therefore, it is importantto considerits diagnosisin patientswho develop
diarrheain associationwith antibiotic use.
Treatment with broad spectrum antibiotics alters normal flora ofthe colon and may permit overgrowth of
clostridia. Studies indicate atoxin produced byClostridium difficile isone primary cause ofantibiotic-associ-
ated colitis. Cholestyramine and colestipol resins have been shown tobind the toxin invitro.
Mildcases ofcolitis may respond todrug discontinuance alone.
Moderate tosevere cases should bemanaged with flUid, electrolyte, and protein supplementation asindicated.
When the colitis isnotrelieved bydrug discontinuance orwhen it issevere, oral vancomycin isthetreatment
ofchoice forantibiotic-associated pseudomembranous colitis produced byC. difficile. Other causes ofcolitis
should also beconsidered.
PRECAUTIONS
Claforan should beprescribed with caution inindividuals with ahistory ofgastrointestinal disease, particularly
colitis
Clatoran has notbeen shown tobenephrotoxic; however, because high and prolonged serum antibiotic con-
centrations can occur from usual doses inpatients with transient orpersistent reduction ofurinary output be-
cause ofrenal insufficiency, the total daily dosage should bereduced when Claforan isadministered tosuch pa-
tients. Continued dosage should bedetermined bydegree ofrenal impairment, severity ofinfection, and suscep-
tibilityofthe causative organism.
At least ;0%
of neutropenic
leukemia patients
with disseminated
candidiasis do not
have positive blood
cultures.'

Reference: 1. AM. PrO:Jlems "'1 the diagnosIs of mvasive
cenoic.as.s .n the In:fTlurocomprom:sea canem. In Richardson RG
ec. oooonontsttc Fungal Infections Focus on Fluconazole
!nerrat:onai Cong'ess and symcos.ern Series No. 153 London
Eng:and Ro/a! Societj of r"ec,cine Ser/ices LIIT'lted 19891724
PROCRIT"
EPOETIN ALFA

ORTHO BIOTECH
From the Initial Visit. ..
PROCRITline'" 1-800-553-3851.
Provides easy access to third-party bill ing information and
maximizes potential for reimbursement.
Through the Course of Therapy.. .
Cost Sharing Program 1-800-441-1366.
Protects patients and payers from catastrophic costs.
Financial Assistance Program (FAP'") 1-800-447-3437
Offers support and assistance to patients lacking financial
resources and insurance coverage.
To Reimbursement Assurance
Reimbursement Assurance Program 1-800-553-3851.
Ifreimbursement isdenied to apatient, Ortho Biotech will provide
the dispensing physician with afree supply of PROCRIT equal to
the amount the patient has already received. Additional PROCRIT
will be provided to patients qualifying for the Financial Assistance
Program (FAP'").
L eaders in comprehensive reimbursement supp ort services
All reimbursement programs are available only to qualifying nondialysis patients.
ROCEPHIN" (celtrinDne sodlumlRDche)
BelDre prescribing, please cDnsultcDmplete prDduct InformallDn, a summary Df which fDIIDWS:
INDICATIONS AND USAGE: Rocephin is indicated for the treatment of the following infections when
caused by susceptible organisms:
LOWER RESPIRATORY TRACT INFECTIONS caused by Streptococcus pneumoniee, Staphylo-
coccus aureus, Haemophilus influenzae. Haemophilus para influenzae, Klebsiella pneumomae,
Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or Serratia marcescens.
SKIN AND SKIN STRUCTURE INFECTIONS caused by Staphylococcus aureus, Staphylococcus
epidermidis, Streptococcus pyogenes, vtridene group streptococci, Escherichia coli . Enterobac-
ter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae. Proteus mirebitis, Morganella morgami*,
Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus , Bacteroides tie-
gilis'" or Peploslreptococcus species
URINARY TRACT INFECTIONS (complicated and uncomplicated) caused by Escherich/a coti,
Proteus muebius, Proteus vulgaris, Morgana/la morganii or Klebsiella pneumoniae.
UNCOMPLICATED GONORRHEA (cervical/urethral and rectal) caused by Neisseria gonor-
rnoeee , including both penicillinase- and nonpenicillinase-producing strains, and pharyngeal
gonorrhea caused by nonpenicillinase-producing strains of Neisseria gonorrhoeae
PELVIC INFLAMMATORY DISEASE caused by Neisseria gonorrhoeae,
BACTERIAL SEPTICEMIA caused by Staphylococcus aureus , Streptococcus pneumoniae,
Esche,;chia coli, Haemophilus influenzae or Klebsiella pneumoniae.
BONE AND JOINTINFECTIONS caused by Staphylococcus sureus, Streptococcus pneumoniae,
Eecnertcnte coli, Proteus mirabilis, Klebsiella pneumoniae or Enterobacter species .
INTRA-ABDOMINAL INFECTIONS caused by Escherichia coli, Klebsiella pneumoniae, Bac-
teroides tragilis, Clostridium species (Note: most strains of C. diftieile are resistant) or Pepto-
streptococcus species
MENINGITIS caused by Haemophilus influenzae, Neisseria meningilidis or Streptococcus pneu-
moniae. Rocephin has also been used successfully in a limited number of cases of meningitis and
shunt infection caused by Staphylococcus epidermidis and
Escherichia coli. "
"Efficacy for this organism in this organ system was studied in
fewer than ten infections
SURGICAL PROPHYLAXIS: The preoperative administration of a
single 1gm dose of Rocephin may reduce the incidence of post-
operative infections in patients undergoing surgical procedures
classified as contaminated or potentially contaminated (e .g. ,
vaginal or abdominal hysterectomy, or cholec ystectomy for
chronic calculous cholecystiti sin high-risk patients. such as those
over 70 year s of age, with acute cholecyst itis not requiring thera-
peutic antimicrobials, obstructive jaundice or common duct bi le
stones) and in surgical patients for whom infection at the operative
site would present serious risk (e.g., during coronary artery by-
pass surgery). Although Rocephin has been shown to have been
as effective as cetazotin in the prevention of infection following
coronary artery bypass surgery, no placebo-controlled trial s have
been conducted to evaluate any cephalosporin antibiotic in the
prevention of infection following coronary artery bypa ss surgery.
When administered prior to surgical procedures for which it is
indicated, a single 1 gm dose of Rocephin provides protection
from most infections dueto susceptible organisms throughout the
course of the procedure.
Before instituting treatment with Rocephin, appropriate speci-
mens should be obtained for isolation of the causative organism
and for determination of its susceptibility to the drug. Therapy may
be instituted prior to obtaining results of susceptibi lity testing.
Note: Most st rains of enterococci are resistant to ceftriaxone.
CONTRAINDICATIONS: Rocephin is contraindicated in patienls with known allergy to the cephalo-
sporin class of antibiotics.
WARNINGS: BEFORE THERAPY WITH ROCEPHIN IS INSTITUTED, CAREFUL INQUIRY SHOULD
BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY
REACTIONS TO CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS, THIS PRODUCT
SHOULD BEGIVEN CAUTIOUSLYTOPENICILLIN-SENSITIVEPATIENTS. ANTIBIOTICS SHOULD
BEADMINISTERED WITH CAUTION TOANYPATIENTWHO HAS DEMONSTRATED SOMEFORM
OF ALLERGY, PARTICULARLY TO DRUGS . SERIOUS ACUTE HYPERSENSITIVITY REACTIONS
MAY REQUIRE THE USE OF SUBCUTANEOUS EPINEPHRINE AND OTHER EMERGENCY
MEASURES ,
PseudDmembranDuscDIIUs, repDrted with nearly ell anllbacterlal agents, including celtrl'"Dne, may
range i n severlly lrom mitd 10life-threalening. Therelore, consider this dlagnDsls In paUents WhD present
with diarrhea sUbsequentlD adminislratlDn DI antlbaclerial agents,
Treatment with antibacterial agents alters nor mal flora of the colon and may permit overgrowth
01 clostridia. Studies indicate a toxin produced by Clostridium difticile is one primary cause of
"antibiotic-associated colitis. "
After establishing diagnosis of pseudomembranous colitis, initiate therapeutic measures, Mild
cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate
to severe cases, consider management with fluids and electrolytes, protein supplementation and
treatment with an oral antibacterial drug effective against C. ditficile.
PRECAUnONS: GENERAL: Although transient elevations of BUN and serum creatinine have been
observed, at the recommended dosages, the nephrotoxic potential of Rocephin is similar to that
of other cephalosportns
Ceftriaxone is excreted via both biliary and renal excretion (see CLINICAL PHARMACOLOGY in
complete product information). Therefore. patients with renal failure norma lly require no adjust-
ment in dosage when usual doses of Rocephin are administered, but concentrations of drug inthe
serum should be monitored periodically. If evidence of acc umulation exi sts , dosage should be
decreased accordingly.
Dosage adjustments should not be necessary in patient s with hepatic dysfunction; however, in
patients with both hepatic dy sfunction and significant rena l di sease , Rocephin dosage should not
exceed 2 gm daily without close monitoring of serum concentrations.
Alterat ions in prothrombin times have occurred rarely in patients treated with Rocephin. Patients
with impaired vitamin K synthesis or low vitamin K store s (e.g. chronic hepatic disease and mal-
nutrition) may require monitoring of prothrombin ti me during Rocephin treatment. Vitamin K
administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or
during therapy.
Prolonged useof Rocephin may result in overgrowth of nonsusceptible organi sms . Careful obser-
vation of the patient is essential. If superinfection occurs during therapy. appropriate measures
should be taken .
Rocephin shouid be prescribed with caution in individuals with a history of gastrointestinal dis -
ease , especially colitis
Rare cases reported of sonog raphic abnormalities seen in the gallbladder; patients may also have
symptoms of gallbladder disease. These abnormalities, variously described as sludge, pre-
cipitations, echoes with shadows, may be misinterpreted as concretions. Chemic al nature of son-
ographically-detected material not determined. Condition appears to be tran sient and reversible
upon discontinuation of Rocephin and conservative management . Therefore, discontinue
Rocephin if signs and symptoms suggestive of gallbladder disease and/or the sonographic find-
ings described above develop.
CARCINOGENESIS, MUTAGENESIS, tMPAIRMENT OF FERTILITY: Carcinogenesis: Considering
the maximum duration of treatment and the class of the compound, carcinogenicity studies with
ceftriaxone in animals have not been performed. The maximumduration of animal toxicity studies
was six months.
ROCEPHIN(celtri8l0ne sDdiumlRoche)
Mutagenesis: Genetic toxicology tests included the Ames test, a micronucleus test and a test for
chromosomal aber rations in human lymphoc ytes cultured in vitro with ceftriaxone. Ceftriaxone
showed no potential for mutagenic activity in these studies.
Impairment of Fertility: Ceftriaxone produced no impairment offertility when given intravenouslyto
rats at daily doses up to 586 mg/kg/day, approximately 20 times the recommended clinical dose
of2 gmlday,
PREGNANCY: Teratogenic Effects : Pregnancy Category 8. Reproductive studies have been per-
formed in mice and rats at doses up to 20 times the usual human dose and have no evidence of
embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was
demonstrated at a dose approximately Ihree times the human dose.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal
reproductive studies are not always predicti ve of human response, this drug should be used dur-
ing pregnancy only if clearly needed.
Nonteratogenic Effects: In rats. in Ihe Segment I (fertility and general reproduction) and Segment III
(perinatal and postnatal) studieswith intravenouslyadministered ceftriaxone. noadverse effects were
nol ed on various reproductive parameters during gestation and lactation, including postnatal
growth, functional behavior and reproductive ability of the offspring ,at doses of 586 mglkg/day or less.
NURSING MOTHERS..Low concentrat ions of cettrtaxone are excreted in human milk . Caution
should be exercised when Rocephin is administered to a nursing woman.
PEDIATRIC USE: Safety and effectiveness of Rocephin in neonates, infants and children have
been sstabushed for the dosages described in the DOSAGE AND ADMINISTRATION section, In
vitro studies have shown ceftriaxone, like some other caphajnsponns, can displace bilirubin from
serum albumin. Roceph in shou ld not be admi nistered to hyperbilirubinemic neonates, especially
prematures.
ADVERSE REACTIONS: Rocephin is generally well tolerated. In clinical trials , the following adverse
reactions, wr.ich were considered to be related to Rocephin therapy or of uncertain etiology, were
observed:
LOCAL REACTIONS - pain, induration or tenderness at the site of
injec tion (1%). Less frequently reported (less than 1%) was phle-
bitis after I.V. administration.
HYPERSENSITIVITY-rash (1.7%) , Less frequently reported (less
than 1%) were pruritus, fever or chills
HEMATOLOGIC-eosinophilia (6%), thrombocytosis (5,1%) and
leukopenia (2.1%). Less frequently reported (less than 1%) were
anemia, hemolytic anemia, neutropenia, lymphopenia, thrombo-
cytopenia and prolongation of the prothrombin time .
GASTROINTESTINAL - diarrhea (2,7%) , Less frequently reported
(les s than 1%) were nausea or vomit ing, and dysgeusia. Onset of
pseudomembranous colitis symptoms may occur during or after
antibiotic treatment (see WARNINGS) .
HEPATIC-elevati ons of SGOT (3,1%) or SGPT (3,3%), Less fre-
quently reported ( less than 1%) were elevation s of alkaline phos-
phatase and billrubin,
RENAL-elevat ions of the BUN (1,2%) , Less frequently reported
(less than 1%) were elevations of creatinine and the presence of
ca sts in the urine .
CENTRAL NERVOUS SYSTEM- headache or dizziness were
report ed occasionally (less than 1%).
GENITOURINARY- moni Iiasis or vaginitis were reported occa-
siona lly (less than 1%).
MISCELLANEOUS-diaphoresis and flushing were reported
occasionally (less than 1%)
Other rarely observed adverse reactions (less than 0.1%) include leukocytosis, lymphocytosis,
monocytosis, basophilia, a decrease in the prothrombin time, jaundice, gallbladder sludge, gly-
cosuria, hematur ia, anaph ylaxis, bronchospasm. serum sickness, abdominal pain, colitis . flatu-
lence. dyspepsia, palpitations and epistaxis.
OOSAGE ANDAOMINISTRATION: Rocephin may be administered intravenously or intramuscularly,
ADULTS: The usual daily dose is 1 to 2 grams given once a day (or in equally divided doses twice
a day) depending on the type and severity of infection. The total daily dose should not exceed
4 grams.
For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg
is recommended.
For preoperative use (surgical prophylaxis). a single dose of 1 gram administered intravenously
1/2 to 2 hours before surgery is recommended.
CHILDREN: For the t reatment of skin and skin structure infections. the recommended total daily
dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day) . The total daily
dose should not exceed 2 grams.
For the treatment of serious miscel laneous infections other than meningitis , the recommended total
daily dose is 50 to 75 mg/ kg, given in divided doses every 12 hours. The total daily dose should not
exceed 2 grams.
In the treatment of meningit is. a daily dose of 100 mg/kg (not to exceed 4 grams), given in divided
doses every 12 hours, should be administered with or without a loading dose of 75 mg/kg.
Generally, Rocephin therapy should be continued for at least two days after the signs and symp-
toms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated
infections, longer therapy may be required.
When treating infections caused by Streptococcu s pyoqenes, therapy should be continued for at
least ten days .
No dosage adjustment is necessary for patients with impairment of renal or hepatic function; how-
ever, blood levels should be monitored in patients with severe renal impairment (e.g ., dialysis
patients) and in patients with both renal and hepatic dysfunctions.
Revised : August 1992
Roche Laboratories
adivisionof Hoffmann-La RocheInc,
340Kingsland Sneer
Nutley. NewJersey 011101199
As with any cephalosporin, there exists the possibility of
hypersensitivity reactions, especially in individuals with a
history of sensitivity.
Clinlcal Cure: Bimination of the clinical signs and symptoms
of the disease, with no recurrence at the time the drug was
discontinued or during follow-up.
A significant lessening of the
clinical signs and symptoms of the disease.
Reference: 1. Data on file lAbs. #073-<J30l,
. Hoffmann-La Roche Inc., Nutley, NJ.
Rocephin,vUV1
ceftriaxone sodium/Roche
Usual adult daily dosage: 1 to 2 gm once a day
Please see adjacent page for summary of product
information, which !ncludes a list of adverse reactions.
Copyright 1992 by Hoffmann-La Roche Inc.
_ All rights reserved.

Still shining at 24 hours

in septicemia
In nosocomial or community-
acquired infections, a single 1- or
2-gm daily dose of ROCEPHIN'
(ceftriaxone sodium/Rochel in
adults provides 24-hour kill power
and produces favorable clinical
resRonses in 96% of Ratients
(77% cured." 19% irnproved)
with septicemia due to:
Stepbvtococcus aureus
Streptococcus pneumoniae
Escherichia coli
Heemoprnius influenzae
Klebsiella pneumoniae
Not only has once-a-day efficacy
of ROCEPHIN been confirmed, but
this dosing schedule has been found
to provide cost-effective quality
patient care. ROCEPHIN is generally
well tolerated, so while ifstough
on pathogens, it's easy on patients.
MEDICAL DIRECTOP:S PAGE
13ruce H. Medd. M. D.. AssociateVice President and Director.
Professional Services
Home IV Antibiotic Therapy: An Introduction
Lowering health care costs while maintaining high
quality care is a goal that all physicians strive for. An
important step toward this goal is the development of
home health care that is both therapeutically effective
and economically feasible. One particular aspect of
home health care that is gaining acceptance is home
intravenous antibiotic therapy.
Evolution of an Industry
Experts anticipate that over the next several years
home IV antibiotic therapy will be one of the fastest
growing segments of the home health care market.
Today, physicians have access to an industry that
provides necessary technology, personal services
and pharmaceutical supplies - an industry devoted
to home health care. With the growth of this indus-
try, most physicians will be able to successfully
manage many patients with a minimum of acute
hospital care.
The Home IV Therapy Decision
Almost any patient who requires IV antibiotic therapy,
and is hospitalized to receive that therapy, could be
considered for treatment at home. However, four crite-
ria are often applied before implementing home IV
therapy:
1
1. No suitable oral therapy is available.
2. The patient's condition is stable enough for dis-
charge, and the patient can monitor his/her own
therapy.
3. The patient agrees to outpatient therapy after a
full disclosure of responsibilities and potential
problems.
4. The patient has a suitable home environment,
including a phone for emergency communica-
tions and a refrigerator for antibiotic storage.
Any infection that responds to IV therapy can
potentially be treated at home, including osteomyelitis,
endocarditis, wound infections, urinary tract infec-
tions, septic arthritis and others.s
Many classes of antibiotics appear suitable for home
IV infusion; however, antibiotics used in outpatient
care should have low toxicity, a broad spectrum of
activity and a long half-life, allowing for less frequent
dosing. Antibiotics with long half-lives enhance the
convenience and cost effectiveness of home therapy
and facilitate patient compliance.
Advantages
Home IV antibiotic therapy removes the risk of
nosocomial infection. Receiving therapy at home in
warm and familiar surroundings also provides psy-
chological benefits. Another benefit is that patients in
the home care environment become more active in
their recovery. These intangibles appear to contribute
to more rapid and predictable recovery.
There are also considerable financial advantages to
home IV antibiotic therapy. For those patients who are
able to work while receiving therapy, the benefits are
obvious. Of course, savings are also accrued be-
cause patients are not hospitalized for long periods of
time. In one study, the calculated savings ranged from
$2,791 to $4,651 per patlent.>
In addition, reimbursement for home services has
greatly improved during the past five years. Many
insurers now pay for outpatient therapy that can
replace treatment given in the hospital. Congress is
considering legislation that would provide for such
reimbursement in a manner similar to that intended for
the catastrophic health insurance law.
The success of home IV antibiotic therapy depends
on a team effort employing sound case management
by the physician and quality service from the home
health care industry. Teamwork by these two groups
will help ease the medical profession into a new era of
health care.
References
1. Larson SE: Home IV antibiotic therapy: The
primary-care physician's role. Drug Therapy,
Nov 1987:67-74.
2. Rising JB: Home IV antibiotic therapy: Roles you
can play. U.S. Pharmacist, Oct 1987:H9-H14.
3. Graves G, Jackson Jp, Maxwell A, Woods T:
Home intravenous antibiotic therapy in Arkansas.
J Arkansas Med Soc 1987;84:55-57.
Roche Laboratories
_ adivision of Hoffmann-La Roche Inc.
340 KingslandStreet
Nutley. New Jersey 07110-1199
Speed: fas'er ba,'eriallcilling in vitro
than other anfimicrobials.*
Kills Pseudomonas aeruqinosa in vitro faster than ceftazidime.
piperacillin, imipenern, and tobramycin"
Power: E._len,penetra,ion
info lung tissue:
Mean tissue concentration above MIC
90s
of common
respiratory pathogens.
5.63 (mglkg)
60
CD
50
.><:
til
.s
4.0
c
Q
'
C
~ 30
(,)
c:;
0
o
a>
~
20
~
0>
c
~
......J
'0
Organism (MIC90)
S pneumoniae (2.0)
P aeruginosa (1.0)
K pneumoniae (q.25)
E cloacae (0.12)
Ecoli(0.06)
P mirabilis (0.03)
H influenzae (0.03)
Lung tissue (3 h)
'Ctorottoxacm administered orally: 500mg Cioro' Tablet bioequivalent to 400 mgCtpro I.V.
THE SAFETY AND EFFECTIVENESS OF CIPROFLOXAC1N IN
CHILDREN. ADOLESCENTS (LESS THAN 18 YEARS OF AGE).
PREGNANT WOMEN. AND LACTATtNG WOMEN HAVE NOT BEEN
ESTABLISHED
SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN
PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF
INTRAVENOUS CIPROFLOXACIN AND THEOPHYLLINE. These
reactions have included cardiac arrest. seizure. status epueoncus.
and respiratory failure. Aitnough similarserious adverse events
have been reported 'n patients receivmq tneopnyihne alone. the
possibility that these reactions may bepotentiated by
ccrouoxac.n cannot beeliminated. If concomitant use cannot be
avo.ceo serum levels of theophylline should bemonitored and
dosage adjustments maae asacoroorare
Cipro IV (ciprotloxacin: is contraindicated III persons witha
historyof hypersensitivity to cmrouoxacm or anymember of the
oumolone class of antimicrobial agents. '
In vitroactivity does not necessarily implya correianon
VJith in I'/Va results.
. Arepresentative clinical Isolate of Paeruginosa.
: Tissue penetration is regarded asessenna: to therapeutic
efficacy but penetration levels have not been correlated with
specific therapeutic results.
Please see folla,vmg page for brief summa".,;
of complete prescnblng iniotmstion
<Power.
elin;,al power demonstrated;na
..ent Mult;,enter Study
...Even in some patients who had not responded to other antibiotics.
Favorable clinical response in lower respiratory infections."
Resolution/improvementS (6.62 days)? (58/61 patients) 95.1
0
/0
o 20 40 60 80 100
Defervescence in less than 1% days.
1.24 days I Mean time to defervescence"
o Day 1 2 3 4 5 6 7
Inaseparate clinicalevaluation, experience with Cipro" 1.E
wasconsistent with the MulticenterStudy.
.. Due to susceptible strains of indicated pathogens See indicated
organisms and dosage and administration sections In complete
prescribing information.
, Clinical response at theend of I.V.therapy (400mgq12h),
"Favorable response" defined asresotunon (disappearance or
sufficient reduction of all signs and symptoms of infection to
allow discontinuance of antimicrobial therapy) and improvement
(reduction in severity/number of signs and symptoms. but requu-
ingcontinued antimicrobial therapy). Most "improved" patients
were then switched to C i p r o ' ~ oral therapy. At posttreatment
evaluation, 85.3%of patients had theirinfections resolved.
C Average duration of Cipro" t.V.therapy.
oForthose febrile patients whose temperatures returned to
normal and remained sofor atleast 48hOUfS.
The most potent fluoroquinolone.*
Cipro I.V.
(ciprofloxacin)
ForIntravenous Infusion
BRIEF SUMMARY
CONSULT PACKAGE INSERT FOR FUll
PRESCRIBING INFORMATION
800mg
NDC NUMBER
0026-8562-20
0026-8564-64
0026-8552-36
0026-8554-63
Q12h 400 mg
STRENGTH
200mg,1%
400 mg, 1%
100mLS% dextrose 200mg, 0.2%
200mLS% dextrose 400mg, 0.2%
STORAGE
Vials: Store between 41 - 7rF (5- 25"C).
Flexible Container: Store between 41 - 7rF (5- 2S"C).
Protect from light, avoid excessive heat, from freezing.
Ciprofloxacin is also avaitable asCipro (ciprofloxacin HCI) Tablets 250, SOO
and 750mg.
Caution:Federal(USA) Lawprohibits dispensing withouta prescription.
PZ100736 Issued: January, 1991 Bay q3939 5202-4-A-U.S.-1
06-4745 1991 Miles Inc. 1578
Flexible
Container
;::30 See usual dosage
5- 29 200- 400 mgq18- 24hr
Creatinine Clearance Dosage
(mLJmin)
MILES A Miles Inc.
Pharmaceutical Division
400 Morgan Lane
Pharmaceutical Division West Haven, CT 06516
September 1992, Miles Inc. Pharmaceutical Division F09112 MIL-6420
Intravenous Dally
Locationof Infection Typeor Severity Unit Dose Frequency Dose
Urinary tract Mild/Moderate 200 mg 912h 400 mg
Severe/Complicated 400 mg q12h 800 mg
When only the serum creatinine concentration is known, the following formula may
beused toestimate creatinine ctearance.
Men' Creatinine
clearance (mUmin)= 72xserum creatinine mg/dL)
Women: 0.85 xthevalue calculated formen.
The serum creatinine should represent asteady state ofrenal function.
For patients with changing renal function orforpatients with renal impairment
and hepatic insufficiency, measurement ofserum concentrations ofciprofloxacin will
provide addition,,: 1uidance foradjusting dosage.
INTRAVENOUS ADMINISTRATION
Cipro" I.V.should beadministered by intravenous infusion over a period of 60
minutes. Slow infusion of adilute solution into a large vein will minimize patient
discomfort and reduce theriskofvenous irritation.
Vials (Injection Concentrate): THISPREPARATION MUST BEDILUTED
BEFORE USE. Theintravenous doseshouldbe prepared by aseptically

mg/mL. (See COMPATIBILITY AND STABiLITY.) The resulting solution should be
infused overa period of 60 minutes by directinfusion or through a Y-type
intravenous infusion set which may already beinpiace.
If thls method or the"piggyback" method of administration is used, it is
advisable todiscontinue temporarily theadministration ofany other solutions during
theinfusion ofCipro"I.V.
FlexibleContainers: Cipro"I.V. isalso available asa0.2% premixed solution in
5%dextrose inflexible containers 01100 mLor 200mL. The solutions inflexible
containers may beinfused asdescribed above.
COMPATIBILITY ANDSTABILITY
Ciprofloxacin injection 1%(10mg/mL), when diluted with the following intravenous
solutions to concentrations of 0.5to 2.0mg/mL, is stable for upto14days at
refrigerated or room temBerature storage.
USP
If Cipro" I.V. istobegiven concomitantly with another drug, each drug should be
given separately in accordance with the recommended dosage and route of
administration foreach drug. HOWSUPPLIED

issupplied invials' while the premixed solution issupplied infleXible containers as
follows:
CONTAINER SIZE
Vial: 20mL
40mL
Hepatic-Elevations ot AST (SGOT), ALT(SGPT), alkaline phosphatase, LDH
and serum bilirubin.
andplatelet counts, decreased platelet
Renal-Elevations ofserum creatinine, BUN, uricacid.
. Other-Elevations of serum creatinine phosphokinase, serum theophylline (in
patients receiving theophylline concomitantly), blood glucose, and tnglycendes.
Other changes occurring infrequently were: decreased leukocyte count,
elevated atypical lymphocyte count, immature WBCs, elevated serum calcium,
elevation of serum gamma-glutamrltranSpeptidaSe (-YGT), decreased BUN,
decreased uricacid, decreased tota serum protein, decreased serum albumin,
decreased serum potassium, elevated serum potassium, elevated serum cholesterol.
Other changes occurring rarely during administration of ciprofloxacin were:
elevation of serum amylase, decrease of blood glucose, pancytopenia, leukocytosis,
phenytoin, decreased prothrombin
OVERDOSAGE
Intheevent ofacute overdosage, thepatient should becarefully observed and given
supportive treatment. Adequate hydration must bemaintained. Only asmall amount
of ciprofloxacin (<10%) is removed from thebody after hemodialysis or peritoneal
dialysis. DOSAGE ANDADMINISTRATION
The recommended adultdosage for urinary tract infections ot mildto moderate
severity is200mgevery 12hours. Forsevere orcomplicated urinary tract infections
the recommended dosage is400mgevery 12hours.
The recommended adult dosage for lower respiratory tract infections, skin and
skin structure infections and bone and jointinfections ofmildtomoderate severity is
400 mgevery 12hours.
The determination of dosage for anyparticular patient must take into
consideration theseverity andnature of theinfection, thesusceptibility of the
causative organism, theintegrity of thepatient's host-defense mechanisms and the
status ofrenal and hepatic function.
DOSAGE GUIDELINES
Cipro"I.V. shouldbeadministeredby Intravenous infusionovera
periodof 60 minutes.
The duration of treatment depends upon the severity of infection. Generally,
ciprofloxacin should becontinued forat least 2 days after thesigns and symptoms
of infection have disappeared. The usual duration is 7 to 14days. Bone and joint
oral administration are
available. Parenteral therapy may bechanged to oral Cipro
s
tablets when the
condition warrants, at thediscrelion of thephysician. Forcomplete dosage and
administration information, see Cipro"tablet package insert.
Impaired Renal Function: The following table provides dosage guidelines for
use in patients withrenal impairment; however, monitoring of serum drug levels
provides themost reliable baSIS fordosage adjustment.
RECOMMENDED STARTING AND MAINTENANCE DOSES
FOR PATIENTS WITHIMPAIRED RENAL FUNCTION
should beavoided.
Aswithanypotent drug, periodic assessment of organ system functions,
including renal, hepatic, and hematopoietic, isadvisable during prolonged therapy.
Informationfor Patient.: Patients should beadvised that ciprofloxacin may be
associated withhypersensitivity reactions, even follOWing a single dose, and to
discontinue thedrug atthefirst ofaskin rash orother allergic reaction.
Ciprofloxacin may cause dizziness and lightheadedness; therefore, patients
should know howthey react to thisdrug before they operate anautomobile or
machinery orengage inactivities requiring mental alertness orcoordination.
Patients should beadvised that clptotloxacin may increase theeffects of
theophylline andcaffeine. There isapossibility of caffeine accumulation when
products containing caffeine areconsumed while taking quinolones.
Drug Interactions: Aswith other qulnolones. concurrent administration of
ciprofloxacin withtheophylline may lead to elevated serum concentrations of
theophylline andprolongation of itselimination half-life. Thismay result in
increased risk of theophylline-related adverse reactions. (See WARNINGS.) If
concomitant usecannot beavoided, serum levels of theophylline should be
monitored and dosage adjustments made asappropriate.
Some quinolones, including ciprofloxacin, have also been shown to inter/ere
with themetabolism ofcaffeine. This may lead toreduced clearance ofcaffeine and
aprolongation ofitsserum half-life.
Some quinolones, including ciprofloxacin, have been associated with transient
elevations inserum creatinine inpatients receiving cyclosporine concomitantly.
Quinolones have been reported 10enhance theeffects ofthe oral anticoagulant
warfarin or itsderivatives. When these products are administered concomitantly,
prothrombin time orother suitable coagulation tests should beclosely montored.
Probenecid interferes with renal tubular secretion ofciprofloxacin and produces
anincrease inthelevel of ciprofloxacin inthe serum. This should beconsidered if
patients arereceiving both drugs concomitantly.
Aswith other broad-spectrum antimicrobial agents, prolonged useof

essential. If superinfection occurs during therapy, appropriate measures should be
taken.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight invitro
mutagenicity tests have been conducted with ciprofloxacin. Test results are listed
below:
salmonel/aiMicrosome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse LWPhoma Cell Forward Mutation Assay (Positive)
(Negative)
saccharomyces cerevisiae Point Mutation Assay (Negative)
saccharomyces cereVisiae Mitotic Crossover and Gene Conversion
Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, twoof the eight tests were positive, butresults of the following three invivo
test
Micronucleus Test (Mice)
Oominant Lethal Test (Mice)
Long-term carcinogenicity studies inmice and rats have been completed: After daily
oral dosing for upto 2 years, there is noevidence thatctprottoxacin has any
carclnoqenic ortumorigenic effects inthese species.
Pregnancy:Teratogenic Effects. Pregnancy CategoryC: Reproduction
studies have been performed inrats and mice atdoses upto6times the usual daily
human dose and have revealed noevidence ofImpaired fertility or harm tothe fetus
due to ciprofloxacin. Inrabbits, ciprofloxacin (30and 100mg!kg orally) produced
gastrointestinal disturbances resulting in maternal weight loss and anincreased
incidence of abortion. Noteratogenicity was observed at either dose. Alter
intravenous administration of doses upto 20 mg/kg, nomaternal toxicity was
produced, andno embryotoxicity or teratogenicity was observed. There are,
however, noadequate and well-controlled studies inpregnant women. Ciprofloxacin
should beused during pregnancy only if the potentiat benefit justifies thepotential
risktothefetus. (See WARNINGS.)
Nursing Mothers: Ciprofloxacin is excreted in human milk. Because of the
potential for serious adverse reactions in infants nursing from mothers taking
ciprofloxacin, a decision should be made either to discontinue nursing or to
discontinue thedrug, taking intoaccount the importance ofthe drug tothe mother
Pediatric Use:Safety and effectiveness inchildren and adolescents less than 18
Ciprofloxacin causes arthropathy injuvenile
ADVERSE REACTIONS
The most frequently reported events, without regard to drug relationship, among
patients treated with intravenous ciprofloxacin were nausea, diarrhea, central
nervous system disturbance, local ivsite reactions, abnormalities ofliver associated
enzymes (hepatic enzymes) and eosinophilia. Headache, restlessness and rash were
also noted in greater than 1% of patients treated with themost common doses of
ciprofloxacin.
Local iv site reactions have been reported with theintravenous administration
ofciprofloxacin. These reactions are more frequent If the infusion time is30minutes
or less. These may appear as local skinreactions which resolve rapidly upon
completion of the infusion. Subsequent intravenous administration is not
contraindicated unless thereactions recur orworsen.
Additional events, without regard to drug relationship or route of
administration, that occurred in1%orless ofciprofloxacin courses are listed below:
GASTROINTESTINAL: ileus; jaundice; gastrointestinal bleeding; C. anucue-
associated diarrhea; pseudomembranous colitis; pancreatitis; hepatic necrosis:
intestinalperforation; dyspepsia; epigastric or abdominal pain; vomiting;
constipation; oral ulceration; oral tandldiasis: mouth dryness; anorexia; dysphagia;
flatulence.
CENTRAL NERVOUS SYSTEM: convulsive seizures, paranoia, toxic psychosis,
depression, dysphasia, phobia, depersonalization, manic reaction,
unresponsiveness, ataxia, confusion, hallucinations, dizziness, lightheadedness,
paresthesia, anxiety, tremor, insomnia, nightmares, weakness, drowsiness,
anaphylactic reactions; erythema multiforme/
Stevens-Johnson syndrome; exfoliative dermatitis; toxicepidermal necrolysis;
vasculitis: angioedema: edema ofthe lips, face, neck, conjunctivae, hands or lower
extremities; purpura; fever; chills; flushing; pruritus; urticaria; cutaneous
candidiasis; vesicles; increased perspiration; hyperpigmentation; erythema
nodosum; photosensitivity.
Allergic reactions ranging from urticaria to anaphylactic reactions have been
reported. (See WARNINGS)
SPECIAL SENSES. decreased visual acuity, blurred vision, disturbed vision
(flashing lights, change Incolor perception, overbnghtness of lights, diplopia), eye
pain, jointstiffness; neck
and interstitial nephritis, hemorrhagic cystitis,
renat calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary
retention, gynecomastia, candiduria, vaginitis. Crystalluria, cylindruria, hematuria,
and albumlOuria have also been reported.
CAROIOVASCULAR: cardiovascular collapse, cardiopulmonary arrest,
myocardial infarction, arrhythmia, tachycardia, palpitation, cerebral thrombosis,
syncope, cardiac murmur, hypertension, hypotension, angina pectoris
RESPIRATORY: respiratory arrest, pulmonary embolism, dyspnea, pulmonary
edemlt
erythema, swelling.
Also' reported were agranulocytosis, prolongation of prothrombin time and
possible exacerbation ofmyasthenia gravis.
Many of these events were described asonly mildor moderate in severity,
abated soon after thedrug was discontinued and required notreatment.
Inseveral instances, nausea, vomiting, tremor, irritability or palpitation were
judged by investigators to berelated to elevated serum levels of theophylline
reported changes in
laboratory parameters with intravenous ciprofloxacin without regard todrug
relationship, were:
INDICATIDNS ANDUSAGE
Cipro" IV is indicated forthe treatment of infections caused bysusceptible strains
of thedesignated microorganisms in thecondaions listed below when theintra-
venous administration offers aroute ofadministration advantageous tothe patient:
Urinary Tract Infections-mild, moderate, severe and complicated
infectionscaused byEscherichia coli (including cases with secondary bacteremia),
Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia

mild to moderate lower
respiratory tracf infections, skinandskinstructure infections and bone andjoint
infections dueto the organisms listedIn each section below. In severe and
complicated lower respiratory tract infections, skin and skin structure infections and
bone and joint intections, safety and effectiveness of theiv formulation have not
been established.
Lower Respiratory Infections-mild to moderate infections caused by

Haemophilus parainfluenzae and Streptococcus pneumoniae
Skin and Skin StrucfureInfecllons-mild to moderateInlections caused
by Escherichia coli, Klebsiella pneumoniae subspecies pneumoniae, Enterobacter
ctoscse; Proteus mirabilis, Proteus vulgaris, Ptoviaencis stuartii, Morganella
morganil, Citrobacter freundii, Pseudomonas aeruginosa, Staphylococcus aureus,
Staphylococcus epidermidis, and Streptococcus pyogenes.
Bone and Joint Infections-mild to moderate infections caused by
Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa.
If anaerobic organisms aresuspected of contributing to the infection,
appropriate therapy should beadministered.
Appropriate culture andsusceptibility tests should beperformed before
treatment in orderto Isolate andidentify organisms causing infection andto
determine their susceptibility to cmronoxacln, Therapy withCipro" I.V. may be
initiated before results of these tests are known; once results become available,
appropriate therapy should becontinued.
Aswith other drugs, some strains of Pseudomonas aeruginosa may develop
resistance fairly rapidly during treatment with ciprofloxacin. Cultureand
susceptibility testing performed periodically during therapy will provide information
notonlyonthetherapeutic effect of the antimicrobial agent butalso onthepossible
emergence ofbacterial resistance.
CONTRAINDICATIONS
Cipro"I.V. (ciprofloxacin) is contraindicated in persons with a history of hyper-
senSitiVity to cipronoxacln or any member of the quinolone class of antimicrobial
agents.
WARNINGS
THESAFETY ANDEFFECTIVENESS OFCIPROFLOXACIN IN CHILDREN,
ADOLESCENTS (LESS THAN 18 YEARS OFAGE), PREGNANT WOMEN,
AND LACTATINGWOMEN HAVENOT BEEN ESTABLISHED. (SEE
PRECAUTIONS-PEDIATRIC USE, PREGNANCY AND NURSING
MOTHERS SUBSECTIONS.) Ciprofloxacin causes lameness in immature dogs.
Histopathological examination of theweight-bearing joints of these dogs revealed
permanent lesions of the cartilage. Related quinolone-class drugs alsoproduce
erosions of cartilage of weight-bearing jointsandother signs of arthropathy in
immature animals of various species. (See ANIMAL PHARMACOLOGY section in
full prescriblOg information.)
Convulsions have been reported in patients receiving ciprofloxacin.
Convulsions, increased intracranial pressure, andtoxicpsychosis have been
reported 10 patientsreceiving ciprotloxac!n andother drugs of this class.

these reactions occurin patients receiving ciprofloxacin, thedrugshould be
discontinued andappropriate measures instituted. As with all quinolones,
clprntloxacln should beused with caeuon Inpatients with known orsuspected CNS
disorders, such assevere cerebral arteriosclerosis, epilepsy, and other factors that
predispose toseizures. (See ADVERSE REACTIONS.)
SERIOUS ANDFATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS
CIPROFLOXACIN ANDTHEOPHYLLINE. These reactions have included cardiac
arrest, seizure, status epilepticus and respiratory failure. Although similar serious
adverse events have been reported In patients receiving theophylline alone, the
possibuity that these reactions may bepotentiated by ciprofloxacin cannot be
eliminated. If concomitant use cannot beavoided, serum levels of theophylline
should bemonitored and dosage adjustments made asappropnate.
Serious andoccasionally fatal hypersensitivity (anaphylactic) reactions, some
following thefirst dose, have been reported inpatients receiving quinolone therapy.
Some reactions wereaccompanied by cardiovascular collapse, loss of
consciousness. tingling, pharyngeal orfacial edema, dyspnea, urticaria, and itching.
Only fewpatients had ahistory of hypersensitivity reactors, Serious anaphylactic
reactions require immediate emergency treatment withepinephrine andother
rssuscrtatton measures, Including oxygen, intravenous fluids, intravenous
antihistamines, corticosteroids, pressor amines andairway management, as
clinically mdicated
. Severe hypersensitivity reactions characterized byrash, fever, eosinophilia,
Jaundice, and hepabc necrosis with fatal outcome have atso been reported extremely
rarely 10patients receiving ciprofloxacin along with other drugs The possibility that
these reactions were related to ciprotloxacin cannot beexcluded. Ciprofloxacin
should bediscontinued at the firstappearance of a skin rash or any other sign of
hypersensitivity.
Pseudomembranous colitis has been reported with nearly all
antibacterial agents, includingciprolloxacin, andmay rangein severity
from mild to life-threatening. Therefore,it is Importantto considerthis
diagnosis in patients who present with diarrhea subsequent to the
administration of antibacterial agents.
Treatment withantibacterial agents alters thenormal flora ofthecolon and may
permit overgrowth of clostridia Studies indicate that a toxin produced by
Clostridium difficile isone primary cause of"antibiotic-associated colitis."
Afterthe diagnosis of pseudomembranous colitis hasbeen established,
therapeutic measures should beinibated. Mildcases of pseudomembranous colitis
usually respond to drugdiscontinuation alone. In moderate to severe cases,
consideration should begiven tomanagement with fluids and electrolytes, protein
supplementation, andtreatment withanantibacterial drugeffective against C.
difficile
PRECAUTIONS
General: INTRAVENOUS CIPROFLOXACIN SHOULD BE AOMINISTERED BY
SLOW INFUSION OVER A PERIOD OF 60 MINUTES. Local iv site reactions have
been reported withtheintravenous administration of ciprofloxacin. These reactions
aremore frequent if infusion timeis30minutes or less or if small veins of thehand
areused. (See ADVERSE REACTIONS.)
Crystals of ciprofloxacin have been observed rarely in theurine of human
subjects but more frequently in theurine of laboratory animals, which is usually
alkaline. (See ANIMAL PHARMACOLOGY section in full prescribinq information.)
Crystalluria related to ciprofloxacin hasbeen reported onlyrarely in humans
because human unne is usually acidic. AlkaliOity of theurine should beavoided in
should bewell hydrated to prevent the
patients with impairment of
Moderate to severe phototoxicity manifested by anexaggerated sunburn
reaction has been observed in some patients who were exposed to direct sunlight
while receiving some members of thequinolone class of drugs. Excessive sunlight
NUTRITIONALASPECTS OF
AMBULATORYCARE
OXYGENRADICALS
AND DISEASE-No. I
The first organisms which evolved in the early anoxic
atmosphere utilized fermentative processes in order to gen-
erate energy; i.e., they broke down existing chemical
compounds and captured the energy released.t.s Later, solar
energy was employed through the photosynthetic process
yielding free oxygen. As atmospheric oxygen levels increased
slowly over eons, selective pressure on the existing biota
gave rise to organisms which could merely tolerate molecu-
lar oxygen; eventually new forms appeared which had the
ability to use oxygen through respiration for a higher energy
yield.' However, the shuffling of electrons which is intrinsic
to the process of respiration placed these organisms at a new
risk: damage from oxygen-derived free radicals.
Free radicals are defined as molecules which have an
unpaired or odd number of electrons in their outer orbital.
Since the chemical reactivity of a molecule is dependent
upon this outer orbital conformation (with its reactivity
directly proportional to the ease with which it can accept or
donate one or more electrons), the unpaired electron makes
the radical highly reactive as it seeks to acquire or give up a
single electron to achieve stability. Because of the extreme
level of reactive potential possessed by most free radicals, it
is theorized that they played a seminal role in the origin of
life from simple components of the primitive atmosphere.f
Aerobic organisms thus developed defenses against these
substances, but oxygen remains lethal for modern obligate
anaerobic bacteria lacking these neutralizing systems."
Molecular oxygen 10
2
1has two unpaired electrons in its
outer orbitals and is technically a free (bi) radical. It would
thus appear to easily accept a pair of electrons from another
compound, reducing oxygen and oxidizing the other com-
pound. However, because oxygen's two outer electrons are
orbiting with a parallel spin, the direct reduction of molecu-
lar oxygen with the addition of two electrons would result in
two electrons spinning in the same direction in the same
orbit: an impossibility according to quantum theory. There-
fore, reduction of oxygen in biologic systems requires
electrons to be added one at a time. It is this process that
generates free oxygen radicals.
When a single electron is added to 0
21
the superoxide
radical, O
2
is generated. Adding another electron and two
hydrogen ions yields hydrogen peroxide IH
202);
combining
H ~ 0 2 withO
2
results in the formation of the hydroxyl radi-
cal, OR'. The hydroxyl radical is the most active of all the
free radicals in biologic systems, reacting as soon as it is
formed with any nearby compound. It is a high priority of all
aerobic cells to avoid the generation of this radical.
Another reactive species of oxygen, singlet oxygen,
while not technically a free radical, behaves as one. Singlet
oxygen has the same number of electrons present as molecu-
lar oxygen, but the spin restriction referred to above is
removed as the two outer electrons now spin in opposite
directions.
The importance of free radical reactions in the ran-
cidification of fats and oils was first appreciated in the
194Os.
S
Their presence in biologic systems was debated for
years until an enzyme, superoxide dismutase (SOD), was
reported in 1969
6
providing evidence that cells had the
means to deal with the superoxide radical.
Although the fact that free radicals exist in biologic sys-
tems is now beyond debate, their importance in specific
disease states such as atherosclerosis, cancer, cataracts, isch-
emic injury, Parkinson's disease, rheumatoid arthritis and
the aging process itself as primary or secondary etiologic
agents is the subject of intense investigation, discussion and
debate.v'
Free radicals also have a positive role to play in the pha-
gocytic defense against microbial invaders. The respiratory
burst of neutrophils produces the superoxide and hydroxyl
radicals which kill the engulfed bacterium. It has also been
proposed that free radical damage may "tag" neoplastic cells
for removal by the immune systern.>
SOURCES OFFREE RADICALS
On a quantitative basis, the most important source of free
oxygen radicals from normal metabolic processes takes place
within the mitochondria (see Table II.
TABLE I. SOURCES OF FREE RADICALS WITHIN CELLS
ENDOGENOUS SOURCES
MITOCHONDRIAL ELECTRON TRANSPORT CHAIN
MICROSOMAL ELECTRON TRANSPORT CHAIN
OXIDANT ENZYMES
XANTHINE OXIDASE
INDOLAMINE DIOXYGENASE
TRYPTOPHAN DIOXYGENASE
GALACTOSE OXIDASE
CYCLOOXYGENASE
LIPOXYGENASE
MONOAMINE OXIDASE
PHAGOCYTIC CELLS
NEUTROPHILS
MONOCYTES AND MACROPHAGES
EOSINOPHILS
ENDOTHELIAL CELLS
AU'IO-OXIDATION REACTIONS IFOR EXAMPLE, FE++,
EPINEPHRINE)
EXOGENOUS SOURCES
REDOX-CYCLING SUBSTANCES (FOR EXAMPLE,
PARAQUAT, DIQUAT, ALLOXAN, DOXORUBICIN)
DRUG OXIDATION (FOR EXAMPLE, ACETAMINOPHEN,
CCI
4
)
CIGARETTE SMOKE
IONIZING RADIATION
SUNLIGHT
HEAT SHOCK
SUBSTANCES THAT OXIDIZE GLUTATHIONE
NITROGEN DIOXIDE & OZONE lAIR POLLUTANTS)
NITROUS OXIDE
Adapted from Halliwell B. Free radicals: aging and disease. In: Cross CEo moderator. Oxy-
gen radicals and human disease. Ann Intern Med. 1987;107:528, with permission of author
and publisher.
However, under normal conditions, the cytochrome sys-
tem, in transferring electrons and generating ATP within the
safety of the specialized mitochondrial membranes, is able
to keep the great majority of the radicals away from other
vital cytoplasmic structures.
Additional metabolic sources of free radicals include
the oxidant enzymes such as cyclooxygenase (involved in
the synthesis of prostaglandins from arachidonic acid) and
the auto-oxidation of the catecholamines. In addition to
their formation under these normal circumstances,
increased free radical production accompanies certain patho-
logic processes such as the activation of phagocytic cells and
the reperfusion of ischemic tissue.v?
Important exogenous sources of free radicals are ioniz-
ing radiation (a direct source of hydroxyl radicals), sunlight
(which generates singlet oxygen), cigarette smoke, alcohol,
air pollutants and certain anti-cancer drugs.
CELLULAR COMPONENTS AT RISK
While all major organic constituents of the cell are at risk for
oxidative damage from free radicals, two of the most impor-
tant are lipid membrane peroxidation and damage to DNA.
TABLE II-CELLULAR COMPONENTS DAMAGED
BY FREERADICALS
LIPIDS: PEROXIDATION OF POLYUNSATURATED FATTY
ACIDS IN ORGANELLES, PLASMA MEMBRANES
PROTEINS: OXIDATION OF SULFHYDRYL-CONTAINING
ENZYMES - > INACTIVATION OF ENZYMES
CARBOHYDRATES: POLYSACCHARIDE DEPOLYMERIZATION
NUCLEIC ACIDS: BASEHYDROXYLATION, "NICKING,"
CROSS-LINKAGE, SCISSION OF DNA STRANDS
(CAUSING MUTATION AND INHffiITION OF PRO-
TEIN, NUCLEOTIDE, AND FATTY ACID
SYNTHESIS)
Reprinted from Southom PA, Powis G. Free radicals in medicine 1. Chemical nature and
biologic reactions. Mayo Clin Proc. 1988;63:386, with permission of author and publisher.
The lipid bilayers that compose the cellular membranes
and those of the intracellular organelles are subject to a par-
ticularly damaging peroxidative insult. The initial
interaction with a free radical sets off a chain reaction in the
membrane which can lead to extensive cellular damage. The
lipid peroxides that form can inhibit many enzymes;'? cause
a loss in membrane fluidity and receptor site alignment!'
and lead to the lysis of organelles and eventually the cell
itself.f
DNA can be damaged at either the sugar (resulting in
strand breaks) or the purine or pyrimidine base (resulting in
an altered basej.'? Both of these kinds of DNA damage can be
repaired by nuclear enzymes.
NATURAL DEFENSES AGAINST
FREERADICALS
Although cytochrome oxidase is not a specific defense
against free radicals, in sequestering the great majority of
consumed oxygen it prevents most of the 02 from forming
the free radicals in vulnerable areas. 13 However, small
amounts of free radicals may reach the cytoplasm from the
mitochondria through a "univalent leak"? in addition to the
other endogenous and exogenous sources noted above. Thus,
cells have an array of both genetically programmed and
Hoffmann-La Roche
nutritionally derived substances which are needed in both
their aqueous and lipid compartments for protection from
free radicals, whatever their source.
Two distinct types of superoxide dismutase exist in cells
to intercept the superoxide radical before it can react with
other compounds. The mitochondria have a manganese-based
SOD, whereas the free cytoplasmic fonn of the enzyme uses
copper and zinc at the active sites. The amino acid sequences
of the two SODs are distinct, supporting a convergent evolu-
tionary pathway for these proteins and emphasizing the
importance of this defense for aerobic organisms. SOD con-
verts 0; to H
202
, a non-radical, but a powerful oxidizing
agent which the cell needs to dispose of.
Small amounts of H
202
can be handled by reduced glu-
tathione peroxidase, but once higher levels accumulate, the
enzyme catalase becomes more important. 13 Water and
are formed in this key step in cellular defense, otherwise the
hydrogen peroxide generated from the superoxide radical in
the presence of ferrous or cupric ions, would lead to the for-
mation of the hydroxyl radical.
Another aqueous-based scavenger of free radicals is
ascorbic acid (vitamin C], which may be especially impor-
tant in extracellular fluids where the above-mentioned
enzymes are essentially absent.
Evidence supports vitamin C's role in reacting directly
with aqueous lipid peroxides, the superoxide radical and sin-
glet oxygen. 14 A recent study suggests that ascorbate in
human plasma is the most important first line of defense
against peroxy radical-mediated damage to lipids. 15
In the lipid phase of the cell, the most important anti-
oxidant appears to be alpha-tocopherol, or vitamin E.16
Here, the lipid-soluble vitamin E is capable of break-
ing the self-propagating chain reaction of lipid peroxidation,
thus preventing damage to the plasma membrane. 10 It is
interesting to note that vitamin e helps restore the anti-
oxidant properties of vitamin E itself after the latter reacts
with a free radical. 14
Beta-carotene (pro-vitamin AI, is acknowledged as one
of the most effective quenchers of singlet oxygen. 17 In addi-
tion to this function, it appears that beta-carotene is also an
effective anti-oxidant with unusual properties: it is most
effective at lower oxygen tensions, a situation that exists at
the organelle level. 17
Future papers in this series will discuss the possible role
of free radicals in the pathogenesis of various diseases and
strategies which may offer protection from their effects.
REFERENCES: 1. Schopf JW The evolution of the earliest cells. Am Sci. September
1978;239:111-138. 2. Del Maestro REAn approach to free radicals in medicine and biology.
Acta Physiol Scand Suppl. 1980;492:153-168.3. Harman D. Free radicals: aging and disease.
In: Cross CE, moderator. Oxygen radicals and human disease. Ann Intern Med.
1987;107:526-545.4. Smith ELet al. Introduction to metabolism: principles of bioenerget-
ics. In: Principles ofBiochemistry: General Aspects, seventh ed., New York, McGraw-Hill
Book Co., 1983; chap. 12:241-267. 5. Dormandy TL. In praise of peroxidation. Lancet.
1988;2:1126-1128.6. McCord TM,Fridovich 1. Superoxide dismutase: an enzymic function
for erythrocuprein [hemocupreinl.J Biol Chern. 1969;244:6049-6055. 7. Cross CE, modera-
tor. Oxygen radicals and human disease. Ann Intern Med. 1987;107:526-545.8. Ernster L.
Biochemistry of reoxygenation injury. Ctit Care Med. 1988;16(10):947-953.9.McCord JM.
Oxygen-derivedfree radicals in postischemic tissue injury. N Engl!Med. 1985;312(3): 159-163.
10. Jenkinson se. Oxygen toxicity. Intensive Care Med. 1988;3:137-152. n. Machlin LJ,
Bendich A. Free radical tissue damage: protective role of antioxidant nutrients. FASEBf.
1987;1:441-445.12.Imaly TA, Linn S. DNAdamage and oxygen radical toxicity. Science.
1988;240:13021309.13. Southom PA, Powis G. Free radicals in medicine I. Chemical nature
and biologic reactions. Mayo Clin Ptoc, 1988;63:381-389.14. Bendich A et al. The antioxi-
dant role of vitamin C. Free Radic Biol Med. 1986;2:419-444.15. Frei B, England L, Ames BN.
Ascorbate is an outstanding antioxidant in human blood plasma. Ptoc Natl Acad Sci
USA. 1989;86:6377-638L16. Halliwell B. Oxygen radicals and metal ions: potential antioxi-
dant intervention strategies. In: Cross CE, moderator. Oxygen radicals and human disease.
Ann Intern Med. 1987;107:526-545.17. Burton GW; Ingold KU. Beta-carotene: an unusual
type of lipid antioxidant. Science. 1984;224:569-573.
HHN 5416
In the intensive
care unit,
Candida is the
fourth most
common
pathogen.'
VERWHELMING
ANTIFUNGAL SUCCESS
\l'utnll)hil Candida albirans.
* Results of a multicenter, open-label, randomized clinical trial using
Diflucan 100 mg/day for 7 days; c1otrimazole 50 mg/day for 14 days.
Results reflect complete resolution (clinical cure) or substantial (clinical)
improvement of baseline signs and symptoms of infection and therapy for
5 days with Diflucan or 10 days with clotrimazole.
t Endoscopic cure results of a multicenter, prospective, randomized, double-
blind triaf comparing Diflucan 100 to 200 mglday; ketoconazole 200 to
400 mglday. Endoscopic cure means complete resolution of esophageal
lesions at end-of-cure endoscopic examination. Not all patients underwent
endoscopy at initiatiOn and completion of therapy.
t Open-label trial. Diflucan 100 to 200 mglday. "Overall" includes cases of
candidemia, disseminated candidiasis, peritonitis. urinary tract infections,
and pneumonia. The "urinary tract" data is a subset of the overall systemic
candidiasis efficacy data. Results reflect complete resolution (clinical cure)
or substantial (clinical) improvement of baseline Signs and symptoms of
infection.
iff
Open-label randomized trial. Results reflect cure (CSF culture negative
and either absence of disease, or disappearance or improving
signs/symptoms) and quiescent (CSF culture positive. stable or imprOVing
signs/symptoms). Diflucan, 400-mg loading dose on the first day and
200 mg thereafter or amphotericin B, at least 0.3 mglkglday. Three risk
factors that may predict a negative outcome for AIDS patients with
cryptococcal meningitis are abnormal mental status, CSF with antigen
titer >1:1024, and CSF WBC <20 cells per cubic millimeter.
II Multicenter comparative study. Results reflect successful maintenance
without culture-confirmed relapse and without toxicity necessitating
discontinuance as evaluated at a median of 279 days for Diflucan and
140 days for amphotericin B. Diflucan, 200 mglday; amphotericin B.
1 mg/l<g1week.
Please see briefsummary of prescribing information onlastpageof thisadvertisement.
DIFLUCAN(,8/M)
ketoconazole (wc>,)
DIFLUCAN(WJ8)
Cured Improved 26%
DIFLUCAN(IO,VIII)
amphotericin B(, 2nn
___ ESOPHAGEAL2t (endoscopic cures) P < .001c--__
URINARY TRACT2;
---
Excellent clinical success
in oropharyngeal, esophageal,
and systemic candidiasis,
and cryptococcal
meningitis
MAINTENANCE TO PREVENT RELAPSE 2,411 P < .001
--- - -
Extensive penetration to key tissues, organs,
and fluids
Distribution throughout the bodyapproximates that of total
bodywater after oral or IVdosing.' Oral bioavailability of
Diflucan is >90%and unaffected byagents that increase
gastric pH.
2
Overwhelming antifungal success
Excellent clinical safety
Inover 4,000 patients who received Diflucan for at least 7days, the
most common adverse events were nausea (3.7%) , headache (1.9%) , skin
rash (1.8%) , vomiting (1. 7%) , abdominal pain (1.7%) , and diarrhea (1.5%). 2
Rare incidents of serious hepatotoxicity have been reported, but the causal
relationship to Diflucan is uncertain. '
DIFLUCAN( 189/21'
Cured C>J%
OROPHARYNGEAL2 P < .001
DIFLUCAN(2121U1)
Cured III% Improved 1,%
clotrimazole nl'Jl )
CuredC>5'li, lmproved
OVERWHELMING ANTIFUNGAL SUCCESS
With once-daily dosing
for a wide range of patients
LOADING DAILY
INDICATI ON DOSE THERAPY
OROPHARYNGEAL
CANDIDIASIS 200mg 100mg
ESOPHAGEAL
CANDIDIASIS 200mg 100mg*
SYSTEMIC
CANDIDIASIS 400mg 200mg
CRYPTOCOCCAL
MENI NGITIS(acute) 400 mg 200mg*
CRYPTOCOCCAL
MENINGITIS (maintenance
toprevent relapse) 200 mg
Doses of upto 400 mg/day may beused. based on medical judgment of the patient's response
totherapy.
References: 1. Jarvis WR. Nati onal Nosocomial Infections Surveillance System. Predominant
pathogens in hospital infection. Presented at the 17th International Congress of Chemotherapy; June
23-28. 1991; Berlin. FRG. Abstract111. 2. Data available on request fromRoerig. 3. LaineL. Dretl er
RH. Conteas CN. et al. Fluconazole comparedwith ketoconazole for the treatment of candida
esophagitis in AIDS: a randomizedtrial. Anntntem Med. 1992; 117:655-660. 4. Saag MS, Powderly
WG, Cloud GA. et al. Comparisonof amphotericin 8 with fluconazole in thetreatment of acute AIDS-
associated cryptococcal meningitis. N Engl J Med. 1992;326:83-89. 5. Powderly WG. SaagMS.
Cloud GA. et al. Acontrolled trial of fluconazole or amphotericin Bto prevent relapse of cryptococcal
meningitis in patients withtheacquired immunodeficiency syndrome. NEngl J Med. 1992;326:793-
798.
Briel Summary
INDICATIONS AND USAGE
DIFLUCAN (fluconazole)is indicated for thetreatment of:
1. Oropharyngeal andesophageal candidiasis. DIFLUCANISalso effectivetor thetreatment ot senous
systemiccandldal infections, includingurinary tract mtecnon, pentomtis. andpneumonia
2. Cryptococcal meningitiS.
Specimens for fungal cultureandother relevant laboratorystudies(serology.histopathology) shouldbe
obtained prior totherapy toIsolateandIdenlifycausative organi sms. Therapymay beInstitutedbefore the
results of the cultures and other laboratory studies are known: however. once these results become
available, anti -ml ectivetherapy should beadjustedaccordingly.
CONTRAINDICATIONS
DIFLUCAN (fluconazole) iscontraindicatedmpatientswhohave shownhypersensitivitytofluconazoleorto
any of its excipients. There is noinformation regarding crosshypersensitivity between fluconazole and
other azotean!llungal agents. caunonshouldbeusedmprescnbingDIFLUCAN10patientsWi thhypersen-
sillvitytoother azoles
WARNINGS
Inrare cases. anaphylans has been reported.
Patients who developabnormal liverfunctiontests dunngDlfLUCANtherapy should be monitoredtorthe
developmentof moreseverehepatic injury, Although serioushepatic reactionshavebeenrareandthecausal
associationwithDIFWCANuncertain, if clinical signsand symptomsconsistent withliverdiseasedevelop that
maybeattnoutabletofluconazole, DIFLUCANshouldbediscontinued. (SeeAdverseReactions.)
lmrnunocomprorrused patients who developrashes during treatment With DIFLUCANshould be mono
ItoredcloselyandthedrugdiscontinuedIf lesionsprogress. (SeeAdverseBeacnons.)
PRECAUTIONS
DrugInteraclions (SeeClinical Pharmacology)
DIFLUCAN(fluconazole)increasedtheprothrombin time alter wartann administration. Careful monitoring
01prothrombinlimeinpatientsreceivinqDIFLUCANandcoumarin-typeanticoagulantsis recommended.
DIFLUCANincreasedtheplasmaconcentralions01phenyloin. Careful morutonnq 01phenytoinconcen-
trations in patientsreceivingDIFWCANandphenytoinisrecommended.
OIFLUCANhas been infrequently associatedwith anIncreasein cyclosporine concentrations in renal
transplantpatientswithor without Impairedrenal function. Careful monitoringof cvclosponne concentra-
tions inpatientsreceiving DIFWCANandcyclosporine is recommended
DIFLUCANincreased theplasmaconcentralionsandreducedthemetabol ism01tolbutamide. glyburide
andglipizide. When OIFLUCANis usedconcomitantly with theseor othersulfonylureaoral hypoglycemic
agents. blood glucose concentrations should becarefully momtored. and thedose of Ihe SUlfonylurea
should beadiustedas necessary.
Rlfampin enhances the metabol ismot concurrently administered DIFLUCAN. Depending on clinical
circumstances, considerationshouldbegiven10increasingthedoseof OIFWCANwhenit isadministered
Withntampm.
Physicians should be aware that drug-drugmteract ionstudiesWith other medications havenot been
conducted, butsuch interactionsmay occur.
Carcinogenesis, Mutagenesis andImpairment 01Fertilit y
Fluconazole showed noevidence01carcinogenicpotential inmiceand ratstreatedorallyfor 24months at
doses ot 2.5. 5 or 10mg/kglday(approximately 27xthe recommended human dose) Malerats treated
with5 and10mg/kg/ dayhadanIncreased incidence01hepatocellular adenomas.
Fluconazole. wilhor without metabolic acnvanon. wasnegative intests for mutagenicityin4 strainsof
S typhimurium. andin themouselymphoma L5178Ysystem. Cytogenellc studiesmVIVO (murine bone
marrowcells. follOWi ngoral adminrstrationot fluconazole) and in vitro(human Iymphocyles exposed to
fluconazoleat 1000fLg/ mL) showed noevidenceof chromosomal mutations.
Fluconazole didnotatlect the terlility of maleor femalerats treated orallywithdallydoses ot 5. 10 or
20 mg/kgor With parenteral doses of 5. 25 or 75 mg/kg. although theonset of parturuionwas slightly
delayed at 20 mg/kgp.o. Inanintravenous perinatal study in rats at S, 20and40 mg/ kg, dystocia and
prolonqation of parturitionwere observed Ina fewdams at 20 mg/ kg (approximately 5-15xtherecom-
mended human dose) and40mg/kg. but notat5 mg/kg. The disturbancesinparturition werereflectedby
a slight increase in Ihenumber of sll ilborn pups and decreaseof neonatalsurvival at thesedose levels.
The effects on parturition In rats areconsistent Wi th the species specific estroqen -loweri ng property
producedbyhighdosesof fluconazole. Suchahormonechange hasnotbeenobserved inwomentreated
With fluconazole. (See Clinical Pharmacology.)
Pregnancy
Teratogenfc Effects. Pregnancy CategoryC: Fluconazole wasadmini steredorallyto pregnant rabbits
duringorganogenesis in twostudies. at 5. 10and20 mg/kg andat 5, 25. and75 mg/kg respectively
Malernal weight gainwasimpairedat all dose level s. andabortionsoccurred at 75 mg/ kg(approXimately
20-60x Ihe recommended human dose); no adverse fetal ellects were detected. In several studiesin
whichpregnanl rats weretreated orallyWithfluconazoleduringorqancqenesrs, maternal weight gainwas
impairedand placental weightswereIncreased at 25mg/ kg. TherewerenoletaI effectsal5 or 10mg/kg;
increases infetal anatomical variants(supernumeraryribs, renal pelvisdilation) anddelaysinossi fication
were observed at 25 and 50 mg/kgandhigher doses. At doses ranging from80 mg/kg(approximately
2060x the recommended human dose) to 320 mg/kg embryolethalily in rats was increased and fetal
abnormalities Includedwavy ribs. cleft palateandabnormal cranio-facial ossnication. These effects are
consistent withtheinhibition of estrogen synthesisinratsandmay bearesult of knowneffectsof lowered
estrogenonpregnancy. organogenesisandparturition.
There are no adequateand well controlled studies in pregnant women. DIFLUCANshould beusedin
pregnancyonlyIf thepotential oenent [usuties thepossiblerisk tothetetus
Nursing Mothers
Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the useof
DIFLUCANInnursingmothers ISnotrecommended.
Podiatr ic Use
Efficacy01DIFLUCANhasnot been eslabli shed In children. A small number 01patients fromage 3 to
13years have been treated salely withDIFLUCANusmgdosesof 36 mg/kgdally
ADVERSE REACTIONS
Sixteen percenl ot over 4000 patients treated With DIFLUCAN(lluconazole) Inclinical trials 017 days or
moreexperiencedadverseevents. Treatment wasdiscontinuedin1.5%of patient sduetoadverseclinical
events andm1.3%ot patients dueto laboratorytest abnormalities.
In combined clinical tnals andtorelgnmarketing experiencepnor to US. marketing. patients wllh
senous underlying disease (predominantly AIDSor malignancy) rarelyhave developedserious hepatic
reactions or extohative skin disorders during treatment with DIFLUCAN (See Warnings). Two of these
neoancreactionsand oneexfoliativeskin disorder (Stevens-Johnson syndrome) were assoc.ateowith a
tarat outcome. Becausemost of thesepatients werereceivinq multipleconcomitantmedications. includ-
ing many knowntobe hepatotoxic or associatedwithexfoliativeskin disorders, thecausal associationof
thesereacnons withDIFLUCANtherapyis uncertain.
ClinicaladverseeventswerereportedmoretrequentlyInHIV infectedpatients(21%) IhaninnonHIVinfected
patients(13%);however,thepanernsinHIVintected and non-HIVintectedpatients weresimilar.Ihepropornons
ofpatientsdiscontinuingtherapy duetoclinical adverseevents wereSi milar Inthetwogroups(1.5%).
The follOWing neatment-relatedclinical adverseevents occurredat an incidence of 1%or greater in
4048patientsreceivingDIFLUCANtor 7or more daysinclinical trials: nausea 3.7%, headache1.9%. skin
rash1.8%, vomiting1.7%. abdominal pain 1.7%. anddiarrhea 1.5%.
Intwo comparative trials evaluating theetflcacyot DIFLUCANtor thesuppressi on ot relapseof cryp-
tococcal meni ngitis, a statisucallysiqruticant Increasewasobserved inmedian AST(SGOT) levels froma
baseline valueof 30 lUlL to 41lUl L In onetnat and34 lUlL to 66 lUlL Intheother. Theoverall rate of
serumtransarnmaseelevations of more than 8 times theupper limit of normal was approximately 1%in
fluconazole-treated patientsincnmcalr nals. Theseetevanonsoccurredinpatientswilhsevereunderlying
disease, predominantly AIDSor malignancies. most of whomwere recei vingmultipleconcomilant medi-
cations. mcluding many known 10 be hepatotoxic. The incidence 01 abnormally elevated serumtrans-
ammases was greater in patients taking OIFLUCAN concomitantly wllh one or more ot the following
medications: nfampin, phenytoin, isoniazi d, valproicacid, ororal sulfonylureahypoglycemicagents.
In rarecases, anaphylaxis hasbeen reported.
The tollowing adverseexperi ences occurred under conditions(e.g open trials. marketingexperience)
whereacausal association is uncertain:
Central NervousSystem: seizures.
Hemalopo,et,candLymphatIC: leukopenia. thrombocytopenia.
Hoer ig
1992. Pfizer Inc 704526-005 Issued May1992
The onlyanti-infective
with quinolonepower*
andone-a-daydosage...
'For its labeled indications.
Pleasesee references and brief summary of prescribing information
on last page of this advertisement.
qd compliance
bid compliance
ONLY

offersquinolonepower:..
Unsurpassed byamoxicillin tid and
cefaclor tid in acute bacterial exacerbation
of chronic bronchitis (ABECBY
Unsurpassed by norfloxacin bid
and trimethoprim/sulfamethoxazole
(TMP/SMX) bid in uncomplicated
urinary tract infection (UTIY
Unsurpassed by ciprofloxacin bid in
complicated UTI
1
with one-a-daydosing...
One-a-day dosing may improve compliance
in short-term antibiotic therapy]':'
95%
10..- .....
76%
10..- ....
tid compliance
Note: A patient was considered noncompliant if he or she
had deviated by more than 20% of the prescribed dose.
" For i ts labeled indications.
SEARLE
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n LABORATORI ES
Maxaquin is a reqistered trademark of G.D. Searle & Co.
1992 Searle
andit's the only
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Ouinolone Theophylline
Interaction
Maxaquin
None
(lomef/oxacin He/)
Ciprof/oxacin Yes
Of/oxacin Yes
Norf/oxacin Yes
Enoxecitv" Yes
Proven safety in over 6,000,000
prescriptions written worldwide'
' For its labeled indications.
Please see references and brief summary of prescribing information on
last page of thi s adver tisement.
"For its labeled indications.
Please see references and brief summary of prescribing information on last page
of this advertisement.
For acute bacterial exacerbation of
chronic bronchitis (ABECB) causedby
I.J Haemophilus influenzae 0 Moraxella catarrhalis
Maxaquin is not indicated for routine empiric treatment of
chronic bronchitis because Streptococcus pneumoniae exhibits
in vitro and in vivo resistance to lomefloxacin. For gram-stain-
guided empiric treatment, a pretreatment sputum specimen with
at least 25 PMNsILPF should confirm a predominance of only
gram-negative organisms.
For uncomplicated and complicated urinary
tract infection (UTI) caused by
In uncomplicated UTI...
o Escherichia col i
o Klebsiella pneumoniae
o Proteus mirabilis
[.] Staphylococcus saprophyticus
In complicated UTI...
U Escherichia coli 0 Pseudomonas aeruginosa
o Klebsiella pneumoniae 0 Citrobacter diversus
o Proteus mirabilis 0 Enterobacter cloacae
The safety and efficacy of lomefloxacin in treating patients
with Pseudomonas bacteremia have not been established.
o Maxaquin is well tolerated. The most frequently reported adverse
events (21 %) in patients in clinical studies with lomefloxacin in-
clude: nausea (3.7%), headache (3.2%), photosensitivity (2.4%),
dizziness (2.3%), and diarrhea (1 .4%).
o As with other quinolones, photosensitivity reactions have been
reported. Patients should be advised to avoid exposure to the sun
and artificial ultraviolet light.
o Like other quinolones, Maxaquin should be dosed at least 2 hours
before or 4 hours after taking sucralfate or magnesium- or
aluminum-based antacids. No reported significant interactions
with renitidine.:
cantly decreased the bioavailability (48%) of lomefloxacin. Separating the doses of antacid and
lomefloxacin minimizes this decrease in bioavailability; therefore. administration of these agents should
precede lomefloxacin dosing by 4 hours or follow lomefloxacin dosing by at least 2 hours.
Caffeine: One hundred mg of caffeine (equivalent to 1 to 3 cups of American coffee) was administered
to 16 normal, healthy volunteers who had achieved steady-state blood concentrations of lomefloxacin
after being dosed at 400 mg qd. This did not result in any statistically or clinically relevant changes in
the pharmacokinetic parameters of either caffeine or lomefloxacin. No data are available on potential
interactions in individuals who consume greater than 100 mg of caffeine per day or in those, such as

interference with the metabolism of caffeine, resulting in a reduced clearance, a prolongation of plasma
half-life, and an increase in symptoms that accompany high levels of caffeine.
Cimetidine: Cimetidine has been demonstrated to interfere with the elimination of other quinolones.
This interference has resulted in significant increases in half-life and AUC. The interaction between
lomeftoxacin and cimetidine has not been studied.
Cyclosporine: Elevated serum levels of cyclosporine have been reported with concomitant use of
cyclosporine with other members of the quinolone class. The interaction between lometloxacln and
cyclosporine has not been studied.
Nonsteroidal anti-inflammatory drugs (NSAIDs): Concomitant administration of the NSAID fenbufen
with some quinolones has been reported to increase the risk of CNS stimulation and convulsive
seizures. There was an increase in the incidence of in mice treated with fenbufen, when
fenbufen was administered to mice that had been concomitantly treated with a dose of lomefloxacin
equivalent to the recommended human dose on a mg/m
2
basis (10 times the recommended human
dose on a mg/kg basis). Fenbufen is not presently an approved drug in the U.S.
Probenecid: Probenecid slows the renal elimination of lomefloxacin. An increase of 63% in the mean
AUC and increases of 50% and 4%, respectively, in the mean Tmaxand mean Cm_. were noted in one
study of six individuals.
Warfarin: Quinolones may enhance the effects of the oral anticoagulant warfarin or its derivatives.
When these products are administered concomitantly, prothrombin or other suitable coagulation tests
should be monitored closely.
Carcinogenesis. mutagenesis. impairment of fertility: Carcinogenesis: Long-term carcinogenicity
studies of lomefloxacin in animals have not been performed. Mutagenesis: One in vitro mutagenicity
test (CHO/HGPRT assay) was weakly positive at lomefloxacin concentrations of ;;,; 226 Jlg/mL and
negative at concentrations < 226 Jlg/mL. Two other in vitro mutagenicity tests (chromosomal
aberrations in Chinese hamster ovary cells, chromosomal aberrations in human lymphocytes) and two
in vivo mouse micronucleus mutagenicity tests were all negative. Impairment of Fertility: Lomefloxacin
did not affect the fertility of male and female rats at oral doses up to 8 times the recommended human
dose based on mg/m
2
(34 times the recommended human dose based on mg/kg).
Pregnancy: Teratogenic Effects. Pregnancy Category C, Reproductive function studies have been
performed in rats at doses up to 8 times the recommended human dose based on mg/m
2
(34 times
the recommended human dose based on mg/kg). and no impaired fertility or harm to the fetus was
reported due to lomefloxacin. Increased incidence of fetal loss in monkeys has been observed at
approximately 3 to 6 times the recommended human dose based on mg/m
2
(6 to 12 times the
recommended human dose based on mg/kg). No teratogenicity has been observed in rats and monkeys
at up to 16 times the recommended human dose exposure. In the rabbit, maternal toxicity and
associated fetotoxicity, decreased placental weight, and variations of the coccygeal vertebrae occurred
at doses 2 times the recommended human exposure based on mg/m
2
. There are, however. no adequate
and well-controlled studies in pregnant women. Lomeftoxacin should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Nursing mothers: It is not known whether lomefloxacin is excreted in human milk. However, it is
known that other drugs of this class are excreted in human milk and that lomefloxacin is excreted in
the milk of lactating rats. Because of the potential for serious adverse reactions from lomefloxacin in
nursing infants, 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: The safety and effectiveness of lomefloxacin in children and adolescents below the age
of 18 years have not been established. Lomefloxacin causes arthropathy in juvenile animals of several
species. (See Wamings)
Geriatric use: Of the total number of patients in clinical studies of lomefloxacin, 26% were ;;,;65 years
of age. No overall differences in effectiveness or safety were observed between these patients and
younger patients.
ADVERSE REACTIONS
In clinical trials, most of the adverse events reported were mild to moderate in severity and transient
in nature. During these clinical investigations, 2.869 patients received Maxaquin. In 2.6%.of the patients,
lomefloxacin was discontinued because of adverse events, primarily involving the gastrointestinal
system (0.7%1. skin (1.0%), or CNS (0.5%1.
Adverse clinical ewnts: The events with the highest incidence (;;,;1%) in patients, regardless of
relationship to drug, were nausea (3.7%1, headache (3.2%1, photosensitivity (2.4%1. dizziness (2.3%).
and diarrhea (1.4%).
Additional clinical events reported in less than 1% of patients treated with Maxaquin, regardless of
relationship to drug, are: dry mouth, flushing. increased sweating. fatigue, back pain, malaise, asthenia,
chest pain, chills, allergic reaction, face edema, influenza-like symptoms, decreased heat tolerance,
hypotension. hypertension, edema. syncope, tachycardia, bradycardia, arrhythmia, extrasystoles,
cyanosis, cardiac failure, angina pectoris, myocardial infarction, pulmonary embolism. cerebrovascular
disorder. cardiomyopathy, phlebitis. convulsions, coma. hyperkinesia, tremor, vertigo, paresthesias,
abdominal pain, dyspepsia, vomiting. flatulence, constipation. gastrointestinal inflammation, dysphagia.
gastrointestinal bleeding, tongue discoloration, earache, tinnitus, thrombocytopenia, thrombocythemia,
purpura, lymphadenopathy, increased fibrinolysis. thirst. gout, hypoglycemia, leg cramps. arthralgia,
myalgia, abnormal vision, conjunctivitis, eye pain, somnolence, insomnia, nervousness, anorexia,
confusion. anxiety. depression, agitation. increased appetite, depersonalization, paroniria, vaginitis,
leukorrhea, intermenstrual bleeding. perineal pain, vaginal moniliasis, orchitis, epididymitis, dyspnea,
respiratory infection. epistaxis, respiratory disorder, bronchospasm. cough, increased sputum, stridor,
pruritus, rash, urticaria. eczema, skin exfoliation, skin disorder. taste perversion, dysuria, hematuria,
strangury, micturition disorder, anuria.
Adverse laboratory events: Changes in laboratory parameters, listed as adverse events, without
regard to drug relationship include: elevations of ALT (SGPT) (0.4%), AST (SGOT) (0.3%), bilirubin
(0.1%), alkaline phosphatase (0.1%); monocytosis (0.3%), elevated ESR (0.1%). elevated BUN (0.1%),
decreased potassium (0.1%).
Additional laboratory changes occurring in :s0.1 % in the clinical studies included: elevation of serum
gamma glutamyl transferase. decrease in total protein or albumin, prolongation of prothrombin time.
anemia, decrease in hemoglobin. leukopenia, eosinophilia, thrombocytopenia, abnormalities of urine
specific gravity or serum electrolytes, decrease in blood glucose.
Quinolone-class adverse events: Although not reported in completed clinical studies with Maxaquin.
a variety of adverse events have been reported with other quinolones.
Clinical adverse events include: anaphylactoid reactions, erythema nodosum, Stevens-Johnson
syndrome, exfoliative dermatitis, toxic epidermal necrolysis, hepatic necrosis, possible exacerbation of
myasthenia gravis. dysphasia, nystagmus, pseudomembranous colitis. painful oral mucosa. intestinal
perforation. hallucinations. manic reaction, ataxia. phobia, hyperpigmentation, diplopia, interstitial
nephritis, renal failure. renal calculi, polyuria, urinary retention, acidosis, cardiopulmonary arrest, cerebral
thrombosis, laryngeal or pulmonary edema, hiccough, dysgeusia, and photophobia.
Laboratory adverse events include: agranulocytosis, elevation of serum triglycerides. elevation of
serum cholesterol. elevation of blood glucose, elevation of serum potassium, albuminuria, candiduria,
and crystalluria. 3/2/92 P92MX7210V
ONE-A-DAY

References: 1. Data on file, Searle. 2. Cockburn J, Gibberd RW, Reid AL, et al.
Determinants of non-compliance with short term antibiotic regimens. BMJ. 1987;295:814-
818. 3. Takagi K, Hasegawa T, Yamaki K, et al. Interaction between theophylline and
enoxacin. Int J Clin Pharmacal Ther Toxicol. 1988;26:288-292. 4. Beckmann J, ElsaBer
W, Gundert-Remy U, et al. Enoxacin-a potent inhibitor of theophylline metabolism. Eur J
Clin Pharmacal. 1987;33:227-230. 5. Nix D, Schentag J. Lomefloxacin (L) absorption ki-
netics when administered with ranitidine (R) and sucralfate (S). Abstracts of the 29th
Interscience Conference on Antimicrobial Agents and Chemotherapy. Houston, Tex; 1989.
Abstract 1276.
BRIEF SUMMARY
INDICATIONS AND USAGE
TREATMENT: Maxaquin (Iomefloxacin HCI) is indicated for the treatment of adults with mild to
moderate infections caused by susceptible strains of the designated microorganisms in the conditions
listed below: Lower Respiratory Tract: Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB)
caused by Haemophilus influenzae or Moraxella (Branhamella) cetsrmeus: NOTE: MAXAQUIN IS NOT
INDICATED FORTHE EMPIRIC TREATMENT OF ABECB WHEN IT IS PROBABLE THAT STREPTOCOCCUS
PNEUMONIAE IS A CAUSATIVE PATHOGEN. S PNEUMONIAE EXHIBITS IN VITRO RESISTANCE TO
LOMEFLOXACIN, AND THE SAFETY AND EFFICACY OF LOMEFLOXACIN IN THE TREATMENT OF
PATIENTS WITH ABECB CAUSED BY S PNEUMONIAE HAVE NOT BEEN DEMONSTRATED. IF LOME-
FLOXACIN IS TO BE PRESCRIBED FOR GRAM-STAIN-GUIDED EMPIRIC THERAPY OF ABECB, IT
SHOULD BE USED ONLY IF SPUTUM GRAM STAIN DEMONSTRATES AN ADEQUATE QUALITY OF
SPECIMEN (>25 PMNs/LPF) AND THERE IS BOTH A PREDOMINANCE OF GRAM-NEGATIVE ORGAN-
ISMS AND NOT A PREDOMINANCE OF GRAMPOSITIVE ORGANISMS.
Urinary Tract Infections (UTls): Uncomplicated UTls (cystitis) caused by Escherichia coli, Klebsiella
pneumoniae, Proteus mirabilis. or Staphylococcus saprophyticus. Complicated UTls caused by E coli,
K pneumonise, P mirabilis. Pseudomonas aeruginosa. Citrobacter diversus: or Enterobacter cloacae..
!'JOTE: In clinical trials of complicated UTls due to P aeruginosa. 12 of 16 patients had the organism
eradicated from the urine after therapy with lomefloxacin. No patients had concomitant bacteremia.
Serum levels of lomefloxacin do not reliably exceed the MIC of Pseudomonas isolates. THE SAFETY
AND EFFICACY OF LOMEFLOXACIN IN TREATING PATIENTS WITH PSEUDOMONAS BACTEREMIA
HAVE NOT BEEN ESTABLISHED. 'Efficacy for this organism in this organ system was studied in fewer
than 10 infections. Appropriate culture and susceptibility tests should be performed before antimicrobial
treatment in order to isolate and identify organisms causing infection and to determine their susceptibility
to lomefloxacin. In patients with UTls. therapy with Maxaquin may be initiated before results of these
tests are known; once these results become available. appropriate therapy should be continued. In
patients with an ABECB, therapy should not be started empirically with lomefloxacin when there is a
probability the causative pathogen is S pneumoniae. Beta-Iactamase production should have no effect
on lomefloxacin activity.
PROPHYLAXIS: Maxaquin is indicated preoperatively to reduce the incidence of UTls in the early

not been established. Maxaquin, like all drugs for prophylaxis of transurethral surgical procedures,
for which prophylaxis is not indicated (eg.
CONTRAINDICATIONS
Lomefloxacin is contraindicated in patients with a history of hypersensitivity to lomefloxacin or to any
of the quinolone group of antimicrobial agents.
WARNINGS
THE SAFETY AND EFFICACY OF LOMEFLOXACIN IN CHILDREN ADOLESCENTS (UNDER THE
AGE OF 18 YEARS) PREGNANT WOMEN AND LACTATING WOMEN HAVE NOT BEEN
ESTABLISHED. (See PRECAUTIONS-Pregnancy; Nursing Mothers; and Pediatric Use.) The
oral administration of multiple doses of lomeftoxacin to juvenile dogs at 0.3 times and to rats at 5.4
times the recommended adult human dose based on mg/m
2
(0.6 and 34 times the recommended adult
human dose based on mg/kg, respectively) caused arthropathy and lameness. Histopathologic
examination of the weight-bearing joints of these animals revealed permanent lesions of the cartilage.
Other quinolones also produce erosions of cartilage of weight-bearing joints and other signs of
arthropathy in juvenile animals of various species.
The safety and efficacy of lomefloxacin in the treatment of ABECB due to S pneumonise have not
been demonstrated. This product should not be used empirically in the treatment of ABECB when it is
probable that S pneumoniae is a causative pathogen.
In clinical trials of complicated UTls due to P aeruginosa, 12 of 16 patients had the organism
eradicated from the urine after therapy with lomefloxacin. No patients had concomitant bacteremia.
Serum levels of lomefloxacin do not reliably exceed the MIC of Pseudomonas isolates. THE SAFETY
AND EFFICACY OF LOMEFLOXACIN IN TREATING PATIENTS WITH PSEUDOMONAS BACTEREMIA
HAVE NOT BEEN ESTABLISHED.
Serious and occasionally fatal hypersensitivity (anaphylactoid or anaphylactic) reactions, some
following the first dose, have been reported in patients receiving quinolone therapy. Some reactions
were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial
edema, dyspnea, urticaria, or itching. Only a few of these patients had a history of previous
hypersensitivity reactions. Serious hypersensitivity reactions have also been reported following
treatment with lomefloxacin. If an allergic reaction to lomefloxacin occurs, discontinue the drug. Serious
acute hypersensitivity reactions may require immediate emergency treatment with epinephrine. Oxygen,
intravenous fluids, antihistamines. corticosteroids, pressor amines, and airway management. including
intubation, should be administered as indicated.
Convulsions have been reported in patients receiving lomefloxacin. Whether the convulsions were
directly related to lomefloxacin administration has not yet been established. However, convulsions.
increased intracranial pressure, and toxic psychoses have been reported in patients receiving other
quinolones. Quinolones may also cause central nervous system (CNS) stimulation, which may lead to
tremors, restlessness, lightheadedness, confusion, and hallucinations. If any of these reactions occurs
in patients receiving lomefloxacin, the drug should be discontinued and appropriate measures instituted.
No evidence of an effect of lomefloxacin on the electrical activity of the brain has been demonstrated.
Lomefloxacin does not alter cerebral blood flow or cerebral glucose uptake in the CNS based on
positron emission tomography. However, until more information becomes available. lomefloxacin, like
all other quinolones, should be used with caution in patients with known or suspected CNS disorders.
such as severe cerebral arteriosclerosis, epilepsy, or other factors that predispose to seizures. (See
Adverse Reactions.)
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including
quinolones, and may range from mild to life-threatening in severity. Therefore, it is important to
consider this diagnosis in patients who present with diarrhea subsequent to the administration
of antibacterial agents. Treatment with broad-spectrum antibiotics alters the normal flora ofthe colon
and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile
is a primary cause of "antibiotic-associated colitis." After the diagnosis of pseudomembranous colitis
has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous
colitis usually respond to discontinuation of drug alone. In moderate to severe cases, consideration
should be given to management with fluid and electrolytes, protein supplementation, and treatment
with an antibacterial drug clinically effective against C difficile colitis.
PRECAUTIONS
General: Alteration of the dosage regimen is recommended for patients with impairment of renal
function (Cb < 40 mLlmin/1.73 m2) .
Moderate to severe phototoxicity reactions have been observed in patients exposed to excessive
sunlight or artificial ultraviolet light while receiving lomefloxacin or some other quinolones. Excessive
sunlight and artificial ultraviolet light should be avoided while takinglomefloxacin. Lomefloxacin therapy
should be discontinued if phototoxicity occurs.
Infonnation for patients: Patients should be advised to drink fluids liberally; that lomefloxacin can be
taken without regard to meals; that mineral supplements or vitamins with iron or minerals should not
be taken within the 2-hour period before or after taking lomefloxacin (see Drug Interactions); that
sucralfate or antacids containing magnesium or aluminum should not be taken within 4 hours before or
2 hours after taking lomefloxacin (see Drug Interactions); that lomefloxacin can cause dizziness and
lightheadedness and, therefore. patients should know how they react to lomefloxacin before they
operate an automobile or machinery or engage in activities requiring mental alertness and coordination;
that .Iomef!oxacin may be with hypersensitivity reactions. even following the first dose, and
to discontinue the drug at the first sign of a skin rash or other allergic reaction; and to avoid excessive
sunlight !"':ld artificial ultraviolet light while receiving lomefloxacin and to discontinue therapy if
phototoxicitv occurs.
Drug intl7ractions: Theophylline: In three pharmacokinetic studies including 46 normal, healthy subjects,
dearance and concentration were not significantly altered by the addition of lomefloxacin.
In chmcal studies I?atlents were on chronic theophylline therapy. lomefloxacin had no measurable
effect on the of theophylline concentrations or the mean estimates of theophylline
clearanc.e. individual theophylline levels fluctuated, there were no clinically significant symptoms
of drug Interaction.
Antacids anC! sucralfate: and antacids containing magnesium or aluminum form chelation
complexes.wlth and interfere with its bioavailability. Sucralfate administered 2 hours before
lornefloxacln resulted In a slower rate of absorption (mean Cm_. decreased by 30% and mean Tmax
Increased by 1 hour) a lesser extent of absorption (mean AUC decreased by approximately 25%).
Magneslum- and alummum-containing antacids. administered concomitantly with lomefloxacin. signifi-
SE4RLE
Address medical inquiries to:
G.D. Searle & Co.
Medica/ & Scientific Information
Depanment
4901 Searle Parkway
Skokie. IL 60077
P92MX7646T
Now
you canuse
fEUPOCE
(FILGRASTIJVJ)
A recombinant G-CSF
...tospedJiadlystimulate
neutrophil production after
myelosuppressive chemotherapyl
Promotes differentiation, maturation and production
of neutrophils
Shown to act specifically on both immature bone
marrow progenitor cells and mature, differentiated
neutrophils, in vivo
.. to decrease theinddence
ofinfectionbyreducingthe
duration ofneutropenia
1
Reduces the risk of infection as manifested by fever in
association with neutropenia*
Shown to reduce hospitalizations for fever in associa-
tion with neutropenia when compared to placebo

Well tolerated with minimal

adverse effects
1
Well tolerated - the majority of adverse effects re-
ported in clinical trials were attributed to the underlying
malignancy or chemotherapy
No reports of effects that mimic infection such as fever
or flu-like symptoms attributed to NEUPOGEN
Of adverse effects attributed to NEUPOGEN, only
medullary bone pain, usually mild to moderate and con-
trollable with non-narcotic analgesics, occurred at a rate
at least 5% greater than placebo
No antibody development reported
Contraindicated in patients with known hypersensitiv-
ity to E. coli-derived products
Formoreinformation...
Scientific or clinical information: Call your Amgen
Sales Representative at 1-800-28-AMGEN (Monday
through Friday, 6 AM-9 PM Pacific Time)
or
Amgen Professional Services Department at
1-800- 77-AMGEN (6 AM-6 PM Pacific Time - on call
24 hours)
Reimbursement information: General reimbursement
information can be obtained through your Amgen
Sales Representative. For case-by-case information,
please call the NEUPOGENReimbursement Hotline,
1-800-272-9376 (in Washington, D.C., 202-637-6698),
. Monday through Friday, 9 AM-5 PM Eastern Time.
AMGEN
Pioneers in Hematopoietic Growth Factors
*As manifested by febrile neutropenia (ANC <500
cells/mm-, temperature ~ 38.2 C)
Please see following page for brief summary of
prescribing Information.
NEUPOGEN@ (Filgrastim)
Brief Summary of Prescribing Information
INDICATIONS AND USAGE
NEUPOGEN'" is indicated to decrease the incidence of infection, as manifested by febrile
neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer
drugs associated with a significant incidence of severe neutropenia with fever. A complete blood
count and platelet count should be obtained prior to chemotherapy, and twice.per week (see
LABORATORY MONITORING) during NEUPOGEN'" therapy to aVOIdleukocytosis and to monitor
the neutrophil count. In Phase III clinical studies, NEUPOGEN'" therapy was discontinued when
the absolute neutrophil count (ANC) was after the expected chemotherapy-
induced nadir.
CONTRAINDlCATIONS
NEUPOGEN'" is contraindicated in patients with known hypersensitivity to b coli-derived
proteins.
WARNINGS
In cancer patients who have received NEUPOGEN'" to date, no serious adverse reactions that
would limit the use of the product have been reported.
PRECAUTIONS
General
Simultaneous Use with Chemotherapy
The safety and efficacy of NEUPOGEN'" given simultaneously wit.h cytotoxic chemotherapy have
not been established. Because of the potential sensmvrty of rapidly dividing myeloid cells to
cytotoxic chemotherapy, do not use NEUPOGEN'" in the period 24 hours before through 24
hours after the administration of cytotoxic chemotherapy (see DOSAGE AND
ADMINISTRATION).
The efficacy of NEUPOGEN'" has not been evaluated in patients receiving chemotherapy .
associated with delayed myelosuppression (e.g., nitrosoureas) or with rmtomycm C.or with
myelosuppressive doses of anti-metabolites such as s-fluorouracil or cytosine arabinoside.
Growth Factor Potential
NEUPOGEN'" is a growth factor that primarily stimulates neutrophils. However, the possibility
that NEUPOGEN'" can act as a growth factor for any tumor type, particularly myeloid
malignancies, cannot be excluded. Therefore, because of the possibility of tumor growth,
precaution should be exercised in using this drug in any malignancy with myeloid
characteristics.
Leukocytosis
White blood cell counts of I 00,OOO/mm'or greater were observed in approximately 2% of
patients receiving NEUPOGEN'" at doses above 5 meg/kg/day. There were no reports of adverse
events associated with this degree of leukocytosis. In order to avoid the potential
complications of excessive leukocytosis, a complete blood count (CBC) is recommended twice
per week during NEUPOGEN'" therapy (see LABORATORY MONITORING).
Premature Discontinuation of NEUPOGEN'" Therapy
A transient increase in neutrophil counts is typically seen I to 2 days after initiation of
NEUPOGEN'" therapy. However, for a sustained therapeutic response, NEUPOGEN'" therapy
should be continued until the post nadir ANC reaches 10,000/mm'- Therefore, the premature
discontinuation of NEUPOGEN'" therapy, prior to the time of recovery from the expected
neutrophil nadir, is generally not recommended (see DOSAGE AND ADMINISTRATION).
Chronic Administration
The safety and efficacy of chronic administration of NEUPOGEN'" have not been established..
Preliminary investigational studies with NEUPOGEN'" have been conducted in 224 patients With
severe chronic neutropenia, 13 of whom have been treated for up to three years. In these
patients, subclinical splenomegaly (detected by CT or MRI scanning) was the most frequently
observed adverse effect, occurring in approximately one third of patients receiving chronic
administration of NEUPOGEN"'; 3% of patients were noted to have clinical splenomegaly. Less
frequently observed adverse events included exacerbation of some pre-existing skin disorders
(e.g., psoriasis). alopecia, hematuria/proteinuria, thrombocytopenia (platelets less than
50,000/mm') and osteoporosis.
Other
In studies of NEUPOGEN'" administration following chemotherapy, most reported side effects
were consistent with those usually seen as a result of cytotoxic chemotherapy (see ADVERSE
REACTIONS). Because of the potential of receiving higher doses of chemotherapy (i.e., full
doses on the prescribed schedule), the patient may be at greater risk of thrombocytopenia,
anemia, and non-hematologic consequences of increased chemotherapy doses (please refer to
the prescribing information of the specific chemotherapy agents used). Regular monitoringof
the hematocrit and platelet count is recommended. Furthermore, care should be exercised in
the administration of NEUPOGEN'" in conjunction with other drugs known to lower the platelet
count. In septic patients receiving NEUPOGEN"', the physician should be alert to the theoretical
possibility of adult respiratory distress syndrome, due to the possible influx of neutrophils at the
site of inflammation. Cardiac events (myocardial infarctions, arrhythmias) have been reported In
II of 375 cancer patients receiving NEUPOGEN'" in clinical studies; the relationship to
NEUPOGEN'" therapy is unknown. However, patients with pre-existing cardiac conditions
receiving NEUPOGEN'" should be monitored closely.
Laboratory Monitoring
A CBC and platelet count should be obtained prior to chemotherapy, and at regular intervals
(twice per week) during NEUPOGEN'" therapy. Following cytotoxic chemotherapy, the
neutrophil nadir occurred earlier during cycles when NEUPOGEN'" was administered, and white
blood cell differentials demonstrated a left shift, including the appearance of promyelocytes and
myeloblasts. In addition, the duration of severe neutropenia was reduced, and was followed by
an accelerated recovery in the neutrophil counts. Therefore, regular monitoring of white blood
cell counts, particularly at the time of the recovery from the post chemotherapy nadir, is
recommended in order to avoid excessive leukocytosis.
Drug Interaction
No evidence of interaction of NEUPOGEN'" with other drugs was observed in the course of
clinical trials.
carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of NEUPOGEN'" has not been studied. NEUPOGEN'" failed to induce
bacterial gene mutations in either the presence or absence of a drug metabolizing enzyme
system. NEUPOGEN'" had no observed effect on the fertility of male or female rats, or on
gestation at doses up to 500 mcglkg.
Pregnancy category C
NEUPOGEN'" has been shown to have adverse effects in pregnant rabbits when given in doses 2
to I times the human dose. There are no adequate and well controlled studies in pregnant
women. NEUPOGEN'" should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
In rabbits, increased abortion and embryolethality were observed in animals treated with
NEUPOGEN'" at 80 meg/kg/day. NEUPOGEN'" administered to pregnant rabbits at doses of 100
meg/kg/day during the period of organogenesis ",,-,as associated with increased fetal resorption,
genitourinary bleeding, developmental abnormalities, and decreased body weight, live births,
and food consumption. External abnormalities were not observed in the fetuses of dams
treated at 100 meg/kg/day. Reproductive studies in pregnant rats have shown that NEUPOGEN'"
was not associated with lethal, teratogenic, or behavioral effects on fetuses when administered
by daily intravenous injection during the period of organogenesis at dose levels up to 575
meg/kg/day. . . .
In Segment III studies in rats, offspring of dams treated at >20 meg/kg/day exhibited a delay In
external differentiation (detachment of auricles and descent of testes) and slight growth
retardation, possibly due to lower body weight of females rearing and nursing.. Offspring
of dams treated at 100 meg/kg/day exhibited decreased body weights at birth, and a slightly
reduced four day survival rate.
1992 Amgen Inc.
NEUPOGEN<II (Filgrastim)
Nursing Mothers
It is not known whether NEUPOGEN<II is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised if NEUPOGEN<II is administered to a
nursing woman.
Pediatric Use
Although efficacy of NEUPOGEN<II has not been demonstrated in a pediatric population, safety
data indicate that NEUPOGEN<II does not exhibit any greater toxicity in children than in adults.
NEUPOGEN<II has been used to treat 128 pediatric severe chronic neutropenia patients; such
patients ranged in age from 3 months to 18 years and were treated with NEUPOGEN<II at 0.6-120
meg/kg/day for up to three years. Such doses were well tolerated, and the overall pattern of
adverse events in children and adults appeared to be similar. While subclinical increases in
spleen size detected by imaging studies (CT or MRI) were reported more often in children than
in adults, the clinical significance of these radiographic findings relative to normal growth and
development is not known. No hematologic abnormalities were noted which were unique to
children treated with NEUPOGEN<II. In addition, 12 pediatric patients with neuroblastoma have
received up to six cycles of cyclophosphamide, cisplatin, doxorubicin, and etoposide
chemotherapy concurrently with NEUPOGEN<II; in this population, NEUPOGEN<II was well
tolerated. There was one report of palpable splenomegaly associated with NEUPOGEN'"
therapy, however, the only consistently reported adverse event was musculoskeletal pain, which
is no different from the experience in the adult population.
ADVERSE REACTIONS
In clinical trials involving over 350 patients receiving NEUPOGEN<II following cytotoxic
chemotherapy, most adverse experiences were sequelae of the or
cytotoxic chemotherapy. In all Phase II and III trials, medullary bone pam, reported in 24% of
patients, was the only consistently observed adverse react.ion attributed to NEUPOGEN<II
therapy. This bone pain was generally reported to be of miid-to-moderate seventy, and could be
controlled in most patients with non-narcotic analgesics; infrequently, bone pam was severe
enough to require narcotic analgesics. Bone pain was reported more frequently in patients
treated with higher doses (20-100 meg/kg/day) administered intravenously, and less frequently
in patients treated with lower subcutaneous doses of NEUPOGENIlI> (3-10 meg/kg/day).
In the randomized, double-blind, placebo-controlled trial of NEUPOGEN<II therapy following
combination chemotherapy in patients (n = 207) with small cell lung cancer, the following
adverse events were reported during blinded cycles of study medication (placebo or NEUPOGEN<II
at 4 to 8 meg/kg/day). Events are reported as exposure adjusted since patients remained on
double-blind NEUPOGEN<II a median of three cycles versus one cycle for placebo.
% of Blinded Cycles with Events
NEUPOGEN<II Placebo
N =384 patient N =257 patient
Event cycles cycles
Nausea/vomiting 57 64
Skeletal Pain 22 1I
Alopecia 18 27
Diarrhea 14 23
Neutropenic Fever 13 35
Mucositis 12 20
Fever 12 II
Fatigue II 16
Anorexia 9 I 1
Dyspnea 9 I I
Headache 7 9
Cough 6 8
Skin Rash 6 9
Chest Pain 5 6
Generalized Weakness 4 7
Sore Throat 4 9
Stomatitis 5 10
Constipation 5 10
Pain (Unspecified) 2 7
In this study, there were no serious, life-threatening, or fatal adverse reactions attributed to
NEUPOGEN<II therapy. Specifically, there were no reports of flu-like symptoms, pleuritis,
pericarditis, or other major systemic reactions to NEUPOGEN"'. .
Spontaneously reversible elevations in uric acid, lactate dehydrogenase, and alkaline
phosphatase occurred in 27% to 58% of98 patients receiving blinded NEUPOGEN'" therapy
following cytotoxic chemotherapy; increases were generally mild to moderate. Transient
decreases in blood pressure 90/60 mmHg), which did not require clinical treatment, were
reported in 7 of 176 patients in Phase.III clinical studies following administration of
NEUPOGENIlI>.
No evidence of interaction of NEUPOGEN<II with other drugs was observed in the course of
clinical trials (see PRECAUTIONS- SIMULTANEOUS USEWITH CHEMOTHERAPY). To date,
there have been no reported allergic reactions or anaphylaxis attributed to NEUPOGENIlI>
administration in over 500 patients treated with NEUPOGENIlI> for a variety of conditions. In this
group of patients, including 33 who have received NEUPOGEN'" daily for almost two years, there
has been no evidence of the development of antibodies to NEUPOGEN<II or of a blunted or
diminished response over time.
OVERDOSAGE
The maximum tolerated dose of NEUPOGEN'" has not been determined. Twenty-seven patients
have been treated at NEUPOGENIlI> doses meg/kg/day. Of those, six patients have been
treated at liS meg/kg/day with no toxic effects attributable to NEUPOGEN<II. Efficacy has been
demonstrated using much lower doses. (Doses of 4 to 8 meg/kg/day showed efficacy In the
Phase III study.) Doses of NEUPOGEN'" which increase the ANC beyond 10,000/mm' may not
result in any additional clinical benefit. .
In NEUPOGEN<II clinical trials, white blood cell counts >IOO,OOO/mm' have been reported in less
than 5%of patients, but were not associated with any reported adverse clinical effects.
It is recommended, to avoid the potential risks of excessive leukocytosis, that NEUPOGEN'"therapy
should be discontinued if the ANC surpasses 10,OOO/mm' after the ANCnadir has occurred.
Discontinuation of NEUPOGENIlI> therapy usually results in a 50% decrease in circulating
neutrophils within I to 2 days, with a return to pretreatment levels in I to 7 days.
DOSAGE AND ADMINISTRATION
The recommended starting dose of NEUPOGENIlI> is 5 meg/kg/day. administered subcutaneously
or intravenously as a single daily injection. No data are currently available regarding
NEUPOGEN<II's stability or compatibility with infusion equipment or diluted in intravenous
solutions. A CBCand platelet count should be obtained before NEUPOGENIlI> therapy,
and monitored twice weekly during therapy. Doses may be increased m mcrernents of 5 mcglkg
for each chemotherapy cycle, according to the duration and severity of the ANC nadir.
NEUPOGEN<II should be administered no earlier than 24 hours after the administration of
cytotoxic chemotherapy. NEUPOGENIlI> should not be administered in the period 24 hours
before the administration of chemotherapy (see PRECAUTIONS). NEUPOGENIlI> should be
administered daily for up to two weeks, until the ANC has reached I O,OOO/mm' following the
expected chemotherapy-induced neutrophil nadir. The duration of NEUPOGEN therapy needed
to attenuate chemotherapy-induced neutropenia may be dependent on the myelosuppresslve
potential of the chemotherapy regimen employed. NEUPOGEN'" therapy should be discontinued
if the ANC surpasses I O,OOO/mm' after the expected chemotherapy-induced neutrophil nadir
(see PRECAUTIONS). In Phase III trials, efficacy was observed at doses of 4 to 8 meg/kg/day.
Manufactured by:

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Amgen Center
Thousand Oaks, California 91320-1789 Issue Date: 2/21/91
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