Rev. Bras. Reumatol. vol.57 número6

ww w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Review

article

Cyclophosphamide

administration

routine

in

autoimmune

rheumatic

diseases:

a

review

夽

Kaian

Amorim

Teles

,

Patricia

Medeiros-Souza

,

Francisco

Aires

Correa

Lima

,

Bruno

Gedeon

de

Araújo

_,

_Rodrigo

_Aires

_Correa

_Lima

a_{UniversidadedeBrasília(UnB),DepartamentodeCiênciasdaSaúde,Brasília,DF,Brazil} b_{UniversidadeEstadualdeCampinas(Unicamp),Campinas,SP,Brazil}

c_{UniversidadedeBrasília(UnB),HospitalUniversitáriodeBrasília,Servic¸odeReumatologia,AmbulatóriodeColagenoses,Brasília,DF,}

Brazil

d_{HospitalUniversitáriodeBrasília(HuB),Brasília,DF,Brazil}

e_{UniversidadedeBrasília(UnB),HospitalUniversitáriodeBrasília,Servic¸odeReumatologia,Brasília,DF,Brazil}

f_{HospitaldeBasedoDistritoFederal,Servic¸odeReumatologia,AmbulatóriodeArtriteReumatoideInicial,Brasília,DF,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received2August2013 Accepted7April2016

Availableonline24October2016

Keywords:

Cyclophosphamide Antiemetics Chemotherapy Cystitis

a

b

s

t

r

a

c

t

Cyclophosphamideisanalkylatingagentwidelyusedforthetreatmentofmalignant neo-plasiaandwhichcanbeusedinthetreatmentofmultiplerheumaticdiseases.Medication administrationerrorsmayleadtoitsreducedefficacyorincreaseddrugtoxicity.Manyerrors occurintheadministrationofinjectabledrugs.Thepresentstudyaimedatstructuringa routineforcyclophosphamideuse,aswellascreatingadocumentwith pharmacotherapeu-ticguidelinesforthepatient.Theroutineisschematizedinthreephases:pre-chemotherapy, administrationofcyclophosphamide,andpost-chemotherapy,takingintoaccountthedrugs tobeadministeredbeforeandaftercyclophosphamideinordertopreventadverseeffects, includingnauseaandhemorrhagiccystitis.Adversereactionscanalterlaboratorytests; thus,thisroutineincludedclinicalmanagementforchangesinwhitebloodcells,platelets, neutrophils,andsodium,includingcyclophosphamidedoseadjustmentinthecaseof kid-neydisease.Cyclophosphamideisresponsibleforotherrare–butserious–sideeffects,for instance,hepatotoxicity,severehyponatremiaandheartfailure.Otheradversereactions includehairloss,amenorrheaandmenopause.Inthisroutine,wealsoenteredguidelines topost-chemotherapypatients.Thecompatibilityofinjectabledrugswiththevehicleused hasbeendescribed,aswellasstabilityandinfusiontimes.Theroutineaimedattherational useofcyclophosphamide,withpreventionofadverseeventsandrelapseepisodes,factors thatmayburdenthehealthcaresystem.

©2016ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

夽

StudyconductedattheServic¸odeReumatologia,HospitalUniversitário,UniversidadedeBrasília,Brasília,DF,Brazil. ∗ _{Correspondingauthors.}

E-mails:[email protected](K.A.Teles),[email protected](P.Medeiros-Souza). http://dx.doi.org/10.1016/j.rbre.2016.09.008

Rotina

de

administrac¸ão

de

ciclofosfamida

em

doenc¸as

autoimunes

reumáticas:

uma

revisão

Palavras-chave:

Ciclofosfamida Antieméticos Quimioterapia Cistite

r

e

s

u

m

o

Aciclofosfamidaéumagentealquilantevastamenteusadoparaotratamentodeneoplasias malignasepodeserusadonotratamentodediversasdoenc¸asreumatológicas.Oerrode administrac¸ãodemedicamentospodelevaràdiminuic¸ãodaeficáciaouaoaumentoda toxicidademedicamentosa. Diversoserrosocorremnaadministrac¸ãodemedicamentos injetáveis.Otrabalhoobjetivouaestruturac¸ãodeumarotinadousodeciclofosfamida,bem comoacriac¸ãodeumdocumentodeorientac¸õesfarmacoterapêuticasparaopaciente.A rotinafoiesquematizadaemtrêsfases,apré-quimioterapia,aadministrac¸ãoda ciclofos-famidaeapós-quimioterapia,quelevaramemconsiderac¸ãoosmedicamentosquedevem seradministradosantesedepoisdaciclofosfamidaparaprevenc¸ãoaosefeitosadversos, incluindo náusea ecistite hemorrágica. Asreac¸õesadversas podemalterar os exames laboratoriaisearotinaincluiumanejoclínicoparaalterac¸ãoclínicadosleucócitos,das plaquetas,dosneutrófilosedosódioincluindooajustededosedeciclofosfamidaemcaso deinsuficiênciarenal.Aciclofosfamidaéresponsávelporoutrasreac¸õesadversasraras, massérias,comohepatotoxicidade,hiponatremiaseveraefalênciacardíaca.Outrasreac¸ões adversasincluemperdadecabelo,amenorreiaemenopausa.Arotinafoicomposta tam-bémpororientac¸õesaopacientepós-quimioterapia.Acompatibilidadedosmedicamentos injetáveiscomoveículofoidescrita,bemcomootempodeestabilidadeeotempodeinfusão. Arotinavisouaousoracionaldaciclofosfamidaeprevenirosefeitosadversoseosepisódios derecidiva,osquaispodemonerarosistemadesaúde.

©2016ElsevierEditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCC BY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Cyclophosphamide(CPM)isanalkylatingagentwidelyused for the treatment of malignancies such as breast cancer,1 multiplemyeloma,2_{renaldiseasesincludingnephrotic}

syn-drome refractory to corticosteroid and focal segmental

glomerulonephritis,andthis drugcanbeusedinthe treat-mentofmultiplerheumaticdiseases,3–5 _{includingcicatricial}

pemphigoid (also called pemphigoid mucous membrane),4

rheumatoid arthritis,5 _{juvenile dermatomyositis,}6 _systemic sclerosis,7,8 _{interstitial lung disease,}7 _{lupus vasculopathy,}9

systemic vasculitis, and refractory treatment of

lupus-associatedthrombocytopenicpurpura.10_{Inadditiontoother}

indications of cyclophosphamide, the treatment of

neu-romyelitisopticacanalsobeincluded.11

In children, cyclophosphamide may be used in the

treatment of nephrotic syndrome and systemic lupus

erythematosus.12,13

Cyclophosphamidecanbeadministeredbyoralor

intra-venous route.14 _{The intravenous administration is more}

frequentin the field ofrheumatology, taking into account studies showing an efficacy similar to that of oral treat-ment, but with less toxicity, for example, a decrease in premature ovarianfailure, less severe infection, and lower overall exposure of the urinary tract to acrolein, a toxic

metabolite of cyclophosphamide.15 _{Cyclophosphamide is}

orallyadministeredQD(24–24h),whiletheintravenousroute isadministeredinpulses,andthedoseisadjustedaccording tohematologicandrenaltoxicities.16

Theadministration ofcyclophosphamideinpulses may

follow a weekly or monthly basis, in combination with

a corticosteroid and other chemotherapeutic agents, pro-vided that the attending physician takes into account the

minimum blood count (NADIR) for the administration of

cyclophosphamide.16–18_{Cyclophosphamidemaycausesome}

adverseevents,andwhentheseeffectsarerelatedtothedrug, areclassifiedasanadversedrugreaction.19_{Theadversedrug} reactioncanbeconceptualizedasanunintendedandharmful reactionintothebody,occurringinthoseroutinelyuseddoses inhumansforprophylaxis,diagnosis,diseasetherapy,orfor changesofphysiologicalfunctions.19

Areactionthatoccursinasmallpercentageofthe popu-lation,butthat,ifnotavoided,maycauseirreversibledamage tothepatient,suchasdeath,congenitalabnormalities,birth defectsorconditionsthatrequirepermanenthospitalization, isclassifiedas“severereaction”.19

Someadverse reactionsrelated totheadministrationof

cyclophosphamide are bone marrow suppression,

suscep-tibility to infections, sterility and amenorrhea,18 _{as well} as nephrotoxicity and cystitis,18,19 _{and also cardiovascular} complications, for instance, sinus bradycardia, pericarditis, myocarditis and heart failure.20 _{Children and adolescents} treatedwithhighdosesofcyclophosphamidearemorelikely to develop dental disorders and a decreased salivary flow. Cyclophosphamideisalsoteratogenic.21_{Alongtermreaction} ofcyclophosphamideismalignacies.18 _{Onecanobserve an} increaseintheincidenceofbladdercancerandesophageal

and lung adenocarcionoma, which customarily occur after

Inadditiontoadversedrugreactionsofcyclophosphamide, itiscriticalthatthephysicianadoptallprecautionary meas-ures,becausetheseadversereactionsmaybemoreimportant

in cases where cyclophosphamide is administered

intra-venously,giventhat, withthis routeofadministration,the drug isnotabsorbed, the onset ofits actionisfaster and, becausethedrugdoesnotundergofirst-passmetabolism,the bioavailability, i.e.the bioavailableconcentrationtoexert a pharmacologicalaction,becomesproportionallyhigher ver-sus oral administration of cyclophosphamide.22,23 _Another importantaspecttoconsiderconcernstheerrorsassociated withtheadministrationofinjectabledrugs.24

It is known that the use of injections is often associ-ated with medication errors classified as serious events.22 Intravenous-route administrationerrors represent 21.1% of all errors, with possible risk of errors of contamination, administration rate, and dilution.25 _{Such parenteral drug} administrationerrors,especiallythosebyintravenousroute, cancauseanadversedrugreaction.19

Inadditiontohealth-relatedproblems,itisrequiredthat thecostsresultingfromdrugadministrationerrorsaretaken intoaccount. InBrazil,it isestimatedthattheannual cost withthe use of chemotherapeutic drugsexceed 1.1billion reais,andthisvaluecanincreaseincasesofinjectabledrug administrationerrors.24

Thus,onemustbearinmindthatthesecostsmaybe mag-nifiedbytheoccurrenceofadverseevents.26_{Anadverseevent} isanyuntowardmedicaloccurrencethataffectsthepatient beingmedicated,butwithoutadirectcausalrelationshipwith his/hertreatment.19

Thus,itisimportanttostandardizetheadministrationof parenteraldrugsandprovidetheirrationaluse,whichcanbe definedasthepatient’sneedtoreceivetheappropriatedrug inthecorrectdosageforanadequatelengthoftimeandwith thelowestcost.27

Takingintoaccounttherationaluseofdrugs,itis impor-tanttostandardizerulesfortheparenteraladministrationof cyclophosphamide.Theobjectivesofthisstudyareproposing acyclophosphamideadministrationroutineinRheumatology units, andthe creation ofadocumentcontaining pharma-cotherapeuticguidelinesforthepatient,inordertomaximize theefficiencyoftreatmentbasedonaliteraturereview.

Methods

Cyclophosphamideroutine

Aninfusionroutineforcyclophosphamidewasdevelopedin ordertoincreasethebioavailability(effectiveness)ofthisdrug whileminimizingadversereactions,thusrenderingthe treat-mentmoretolerableforthepatient.Theprotocolwasdivided intostagestofacilitatethecomprehensionofthehealthstaff andthereplicationofthecyclophosphamidedosing sched-ule. The drugs of the first (pre-ChT) and third (post-ChT) stepscorrespondtotheadministrationofpharmaceuticalsin ordertopreventthemainadversereactionsresultingfromthe administrationofcyclophosphamide(secondphase), includ-ingnausea,vomiting,andhemorrhagiccystitis.Theclinical

management of adverse reactions that change laboratory

testswas described,aswellasthe clinicalmanagementof cyclophosphamide in renal failure. The rare, but serious, adversereactionswerealsohighlighted.

The most common adverse reactions were emphasized

sothattheattendingphysiciancouldprovideguidancewith respecttothemaincarethatthepatientshouldtakeinhis/her home,afteradministrationofcyclophosphamide.These pre-cautionsareessentialtopreventorminimizeadverseeffects andincreasetreatmentadherence.

Inaddition,thecompatibilityoftheseinjectabledrugswith thevehicle,stabilitytime,andinfusiontimewasascertained. Thesequenceofadministrationofthesedrugshasbeen pre-paredinordertoincreasetheefficacyofcyclophosphamide and diminish the onset of adverse reactions to the drugs administered.

Results

Theroutineadministrationofcyclophosphamidewas

devel-oped in three phases: pre-ChT, cyclophosphamide

admin-istration, and post-ChT. With a view to the prevention of hemorrhagiccystitis,intravenoushydrationwithablood vol-umeexpander(acrystalloid:0.9%saline)wasstandardized.28 In addition,the drugadministrationsequence,the amount ofdiluent,theneed(orotherwise)fordilution,infusionand administrationtimes,and laboratorytestswhichshouldbe monitoredbeforeandaftertheinfusionofcyclophosphamide wereindicated,aswellastheguidelinestothepatient.

Fig. 1 3,5,20,29–42_{, lists the routine data, and Fig. 2} 44–50 describestheguidelinesforthepatient.Severeand

uncom-mon adverse reactions which should be monitored are

hepatotoxicity,3_hyponatremia45_{(inthiscase,serumsodium} level=135mmol/L [sodium is an univalent element; thus, 1mmol/L=1mEq/L)],45 _{and cardiovascular failure due to} cyclophosphamidecardiotoxicity.36

Other adverse reactions from cyclophosphamide are

amenorrhea,18_{earlymenopause,}46_andhairloss.3

Discussion

Drug administration errors can decrease the effectiveness

of the pharmacological treatment and increase both the

occurrence of adverse reactions and the financial costs of treatment.24_{Aretrospectivestudyconductedinhospitalsin} Spainbetween2008and2010evaluatedtheincidenceofcost and adverse event. 245,320 episodes were identified, with anoverallcostof1,308,791.97euros.Approximately6.8%of patients experiencedadverse events,representinga riseof 16.2%incosts.Sixofthe tenadverseeventsthatburdened moresignificantlythehospitalsystemoccurredinthe oper-atingroom,correspondingtoanincreaseofexpensesaround 6.7%tothehealthsystem.26

A prospective study conducted between August and

November 1999 and between January and May 2000

Cyclophosphamide administration routine in autoimmune rheumatic diseases

Pre-chemotherapy administration scheme

Hydration with saline (S)

In the case of congestive heart failure, hypertension, acute/chronic kidney disease, use glucose solution. The infusion time must be 3h.

Specified dose: 1000 mL/S 0.9%a

Dexamethasoneb,c

Dose:

Specified infusion: 1 hour/S 0.9%a

Specified time: 1 hour before cyclophosphamide

Time: 1/2 hour prior to cyclophosphamide

The use of mesna is controversial; it may be replaced by a suitable hydration.a

The administration of cyclophosphamide is carried out immediately after pre-QT phase, with a dose between 0.5 and 1 g/m2 _{body surface,}f,g diluted into 100-200 ml saline,h with an infusion time of 60-120 minutes.h

Mesna

The use of mesna is controversial; it may be replaced by a suitable hydration.a

Suggestion to interrupt cyclophosphamide treatment, according to hematological parameters

Precautions and clinical management of cyclophosphamide with respect to genitourinary system

Kidney failure - clearance <10 mL/min: Reduce the dose by 25%; supplementation with 50% after dialysis.m

Urinalysis - obtain a urinalysis every 4 weeks after administration of cyclophosphamide because of the risk of hemorrhagic cystitis;n watch for signs of hematuria, proteinuria, and leukocyturia.o

Mesna

Specified dose: 20 mg

Specified dose: 20% of the dose of cyclophosphamidee Dilution: 20 ml of Sd

Specified dose: 20 mg

Specified Infusion: 1-2 minute bolus

Specified time: immediately after cyclophosphamide

Time: 4 and 8 hours for IV use, or 2 and 6 hours for POe

Specified dose: 20% of the dose of cyclophosphamide (IV) or 40% of the PO dosee

Dilution: 20 mL S in the case of IVd Infusion: 15-30 minutes

Specified dose: 8 to 16 mg (VO) Time: 6 and 14h after cyclophosphamide

Platelets <100 000/mm3k

Absolute neutrophil count <1500 cells/µL l

White blood cell count <3500/mm3k Infusion: 15-30 minutese

Time: 15 minutes prior to cyclophosphamidee

Dose:

Infusion: 10 minutes Dilution: 20 ml of S 0.9%d

Dose: Dilution used:

Dose:

Dose: Dilution used: Infusion time:

Administration time:

Infusion time:

Ondansetronj

Noninvasive and invasive laboratory tests must be monitored in patients receiving cyclophosphamide according to the severity of their condition.

Noninvasive methods - echocardiography, assessment of cardiac function (systolic ejection and diastolic function, diastolic peak velocity and atrial and valve function, electrocardiograms, electrocardiography, 24-hour Holter ECG).

Serious and uncommon adverse reactions should be monitored:

Hepatotoxicityq_{and hyponatremia. Serum sodium concentration in this} case is 135 mmol/L (sodium is an univalent element; thus, 1 mmol/L=1 mEq/L).r _{Cardiovascular failure due to cyclophosphamide cardiotoxicity.}

Other adverse reactions from cyclophosphamide:

Amenorrhea,k premature menopause,g and hair loss.q

Invasive methods - magnetic resonance imaging, myocardial biopsy.p Administration time:

Dose:

Administration time: Infusion time:

Dosage scheme after chemotherapy

Furosemidei

Administration time: Dilution used:

Infusion time: Infusion time:

Administration time:

Administration time:

Fig.1–Cyclophosphamideadministrationroutineinautoimmunerheumaticdiseases.

Sources:a_{Shepherdetal.}29_;b_Hawthorn;e_Cunningham30_;c_Jordanetal.31_;d_Turneretal.32_;e_Trissel33_;f_Haubitzetal.34_;

g_{Mardeganetal.}35_;h_DiLisietal.36_;i_Salidoetal.37_;j_{Calixto-Limaetal.}38_;k_Lotanetal.20_;l_Zahnetal.39_;m_Milman40_;n_Mota

Water intake - the physician should instruct the patient to drink at least two liters of water a day unless in the presence of a kidney condition; thus, the amount of water to be consumed should be individualized. Imprensa electrolytes in the blood.a

Instructions for preventing mucositis - cyclophosphamide can cause mucositis; some precautions are advisable and these should be taken by the patient to minimize risks, including brushing adequately his/her teeth after a meal, using a soft brush and a non-abrasive toothpaste (for children), avoiding alcohol and cigarettes, avoiding too much salt, choosing soft foods, giving preference to food in the form of puddings, porridges, vitamins, gelatin, and caloric-, protein-rich meat, chicken or fish soup.b,c

Clinical management for symptoms of nausea - the patient should eat before getting hungry, with small, frequent (2-2 hours), slowly eaten meals because hunger can increase nausea; also, should avoid very spicy, fatty and sweet food and hot food and drinks. On the other hand, the patient should avoid drinking liquids during meals and should stay away from the kitchen during food preparation, eating in a ventilated and pleasant environment.b

Guidelines for patients with anemia - the patient should consume foods of animal origin such as chicken, fish and especially red meat, and should consume legumes and dark green vegetables such as kale, broccoli and spinach, pea beans and other grains, and combine vegetables with sources of vitamin C (orange, mandarin [tangerine], lemon, acerola). Milk, cheese, cottage cheese, yogurt and other dairy products should be avoided during or close to lunch or dinner time.d,e

Guidelines for disposal of urine and faeces - on the appointed day to take cyclophosphamide and on the next two days, when using the toilet the patient should flush three times with the cover closed. If someone else is responsible for the cleaning of the patient’s excreta, this person should wear gloves and use disposable material. The cleaning procedure must be done in a outside-inside manner; and all content should be placed in two plastic bags, which will then be tightly closed. Cleaning should be completed with bleach.f,g

Guidelines for bathing - the patient must first wash his/her hands, then the face and head. Next, the stomach, back, arms and the catheter (if in use of one of these devices).

Fig.2–Guidelinesforthepatienttakingcyclophosphamide.

Sources:a_{InstitutoEstadualdeHematologiaArthurdeSiqueira}44_;b_{Bruiningetal.}45_;c_{Gonzálezetal.}46_;d_OteroLópez47_;

e_{Medeiros-Souzaetal.}48_;f_Mesna49_;g_{Taketomoetal.}50_.

(3.3%) were due to intoxication. According to the criteria (modified)ofSchumock andTornton,68.4% ofdrug-related problemsareconsideredaspreventable.47

Thecyclophosphamidedosingscheduletookintoaccount

the most common adverse reactions, the administration’s

strategyinthe caseofkidney failure, andthe sequence in theadministrationofpre-ChTdrugs,cyclophosphamide,and post-ChT drugs; tothis end, the dosageofall medications used,theirdilutionandinfusiontimealsowereincluded.

Themainclinicalstrategiesinthefaceofadversereactions

from cyclophosphamide use included the care of

hemor-rhagiccystitis,nausea,andvomiting.18_{Theadministrationof} thesedrugscorrespondstowhatisdefinedasaqualitative polypharmacy, whereinthe administrationofamedication

is performed to correct the adverse reaction of another

medication.48

Several clinical strategies have been proposed to avoid hemorrhagic cystitis, including increased hydration of the patientandtheadministrationofmesnaandfurosemide.28,29 Inthosecasesinwhichthepatientsuffersofaseverekidney impairment,itispreferabletoadministermesnainplaceof hydration,duetothepatient’swaterrestriction.20,29

For the prevention of hemorrhagic cystitis, mesna

is administered in a dose equivalent to 60% of

cyclophosphamide, divided into three doses – 20%

15min before the administration of cyclophosphamide,

20% after cyclophosphamide, and 20% 4 or 8h after

cyclophosphamide.28 _{Mesnareducesthedepositofacrolein}

(a metabolite of cyclophosphamide) in the bladder, thus

preventinghemorrhagiccystitisandbladdercancer.18 Inordertodecreasetheexposureoftheurinarytractto acrolein,thepatientshouldbewellhydratedbefore,during andaftertheadministrationofcyclophosphamide.Thus,at the time ofhis/her admission, the patient should receive, throughavenousaccess,1Lofabloodvolumeexpander(a crystalloid:saline0.9%)for1h,60minbeforethe administra-tionofcyclophosphamide.51

Cyclophosphamidepersecanbeadministeredatanytime. Inturn,theinfusionofmesnadependsontheadministration ofcyclophosphamide.28_{Mesnamaybeadministeredbyoral} orparenteral(subcutaneousorintravenous)route.28

mesna would havealsothe advantageofa likelydecrease

in expenses, due the lower bed occupancy time and less

workloadofthenursingteam.51_{Stillinthiscontext,another} possibledisadvantageisthepatient’snon-compliance;thus, onecannotbesurethatthepatienthastaken,orotherwise, thelastdoseofmesnaPO.52

TheadvantageoftheuseIVmesnaisthatthereisnoneed ofabsorption,andtheonsetofactionofthisdrugisfaster, comparedwithoraladministration.22,23,53_{Thedisadvantage} oftheparenteralrouteisthegreaterriskofcontamination, administrationerrors,lessdosingconvenience,andincrease ofthepatient’shospitalstay.23,53

However,mesna administrationwitha viewto the pre-ventionofhemorrhagiccystitisinpatientsusing

cyclophos-phamide in therapeutic doses for rheumatic diseases is

controversial; thus, mesna may be replaced by a suitable hydrationwith6Lofwaterperday,plusadiureticdrug,or theuseofhydrationwithavolumeof3L/m2_perday.54

Furosemideisadministeredaftercyclophosphamide infu-sionatadoseof20mg,inordertostimulatediuresisthat, insynergismwithmesna,decreasestheexposureof urothe-liumtotheactionofacrolein.55_{Themaximumconcentration} offurosemideis10mg/mLadministeredinbolus,achieving atherapeuticconcentrationof10mg/mLperminute.55 _The

second dose ofmesna (20% of cyclophosphamidedose) is

administeredintheintervalbetween15and30minafterthe administrationofcyclophosphamide.28

Nauseaandvomitingareconsideredascommonadverse

reactions in chemotherapy, and this also occurs with

cyclophosphamide31 _{which, in turn, participates of many} chemotherapeuticregimens.Inthiscase,aroutinehasbeen proposed forthe treatment of rheumaticdiseases. Nausea causedbytheexclusiveadministrationofcyclophosphamide (withoutatherapeuticscheme)isclassified asalate-onset nausea.56_{Thus,ondansetronwasnotrequiredtopreventthis} effect.56_{Adecreaseineffectivenessisanotherreasonfornot} usingondansetronpriortocyclophosphamide.57

Thisreductioninefficacyoccursbecauseondansetronisan inhibitorofCYP2B.58_{Thisoccursbecausecyclophosphamide} isaprodrug thatmust beactivatedby CYP2B,resulting in

4-hydroxycyclophosphamide and aldophosphamide. These

metabolitesaretransportedtothesiteofaction,wherethey

undergo spontaneous cleavage, producing phosphoramide

mustard,responsible forthe pharmacologicaleffectsofthe drug.58

Moreover,dexamethasonewasaddedpriorto chemother-apy,asaprophylacticagenttoanaphylacticshockandalso as an antiemetic.59 _{Preferably, dexamethasone should be} administered so that its peak coincides with the peak of physiologicalcorticosteroids,whichnormallyoccursat8a.m. and16p.m.58 _{Apeakindexamethasoneplasma} concentra-tionoccurswithin60min,anditsactionbeginsin30min.55,60 Thus,theadministrationofdexamethasoneshouldbestarted inthemorning,30minbeforetheadministrationof cyclophos-phamide,preferablyat7:30a.m.58

Afterthe emesiscausedbycyclophosphamidewas clas-sified as a delayed-type,56 _{and in view of the decrease of}

cyclophosphamide efficacy when ondansetron is

adminis-teredpriortothischemotherapeuticagent,ondansetron(8mg PO31,61 _{administered at 6 and 14 or 8 and 16h post-ChT,}

andwithamaximumdoseof16mgafterchemotherapy,not exceeding32mgperday)wasthelastdrugusedforthe pro-phylaxisofemesiscausedbycyclophosphamide.31

Other important adverse effects of

cyclophos-phamide include hematologic toxicity,18 _{kidney failure,}20 hyponatremia,45,62_{neurologicalimpairment,}45_amenorrhea,18 early menopause,46 _{hair loss,}3 _{hepatotoxicity (rare),}3 _and

late-onset cancer.18 _{The dose of cyclophosphamide for}

the treatment of systemic lupus erythematosus, including

those patients with neuropsychiatric and/or hematologic

disorders, with class IV lupus nephritis, and with other

serious manifestations of systemic lupus erythematosus,

is 0.5–1g/m2 _{IV monthly,}5,62 _{with dosage adjustment in} patientswithhematological toxicityandkidneyfailure.20,63 Adversehematologicreactionscausedbycyclophosphamide are classified as serious,as theycause high morbidity.19,64

NADIRistheminimumhematologiccountingthatmustbe

observed tosee if the patient may or may notembark on

another chemotherapeuticcycle.65 _{Themainhematological} tests include platelets, neutrophils, white blood cells and neutrophil counts.Neutropenia isdefined asadecrease in absoluteneutrophilcount<1500cells/␮L.65Themaincauses

ofneutropeniaincludehematologicdisorders,autoimmune diseases,infection,adversedrugreaction,chemotherapy,and radiotherapy.65_{Thrombocytopeniaoccurs whentheplatelet} countis<100,000/mm3_.65 _{Inapatientwithaplateletcount} <81,000/mm3 _{concomitantly experiencing leukopenia, the}

treatment should be discontinued until the platelet count increase to99,000/mm3_.65 _{However, cyclophosphamidecan}

be used in the treatment of refractory thrombocytopenic

purpura,andinthiscase,amongthehematologicdisorders,

thrombocytopenia,andmicroangiopathichemolyticanemia

are included.Leukopenia10 _{isdefinedasawhite cellcount} <3500/mm3_.65

Hepatotoxicityisanadversereactioncausedby

cyclophos-phamide that normally occurs at high doses.3 _When

hepatotoxicityoccursatlowdoses,thereactionisclassifiedas arare,butserious,event.19,64_{Acuteliverfailurewithlow-dose} cyclophosphamide (200mg) was described ina casereport ofamaleChineseaged48 yearswithprogressive glomeru-lonephritissecondarytoWegener’sgranulomatosis,24hafter the administrationofcyclophosphamide.3 _{Thediagnosisof} granulomatosiswithpolyangiitis wasestablishedby

patho-logical examination and c-ANCA.3 _{The patient was being}

treated with high-dose methylprednisolone,

plasmaphere-sis,intermittenthemodialysisandlowintravenousdosesof cyclophosphamide.3 _{Other factors that may be associated} withhepatotoxicityhavebeen excluded,including antifun-gals, HIV, and hepatitis B and C.3 _{Alanine transaminase} increasedfrom41U/Lto336U/Latthedayofadministration of200mgofcyclophosphamide; inthenext day, apeakof 566U/Lwasreached.3_{Twoweekslater,thepatientwastreated} withanotherpulseof200mgofcyclophosphamide(second dose),andtheconcentrationofalaninetransaminasereached 1253U/L.3_{Aliverbiopsywasnotpossible,becausethepatient} hadaclottingdisorder.3_{Anotherlaboratoryparametertobe} monitoredissodiumconcentration.Hyponatremiais consid-eredasanelectrolytedisorderidentifiedinclinicalpractice.45

Although many cases are mild or relatively symptomatic,

withhighmorbidityandmortality.Neurologicalsymptomsof hyponatremiaoccuratsodiumlevels<125mmol/L.66_Among thecomplicationsofhyponatremia,onecanmentioncentral nervoussystemdisorderssuchasseizures,andevena per-manentdamagetothecentralnervoussystem,anddeath.66 Syndrome of inappropriate antidiuretic hormone secretion (SIADH)wasdescribedinacasereportinwhichthissyndrome wasassociatedwiththeuseofIVcyclophosphamideinadose of500–1000mg/m2_{,withaserumsodiumlevel<120mmol/L}

inapatientpresentingneurologicalcomplications.62

Cyclophosphamide may also cause cardiotoxicity.

Rou-tinely, echocardiography, a noninvasive method, is used

to monitor cardiovascular function in patients treated

with immunosuppressants.36 _{Other non-invasive methods}

most widely used are electrocardiography and 24-h (ECG)

Holtermonitoring.36_{Invasivemethodssuchasscintigraphy,}

magnetic resonance imaging and cardiac biopsy are also

procedures that can beused incases ofadverse reactions classifiedasserious.36

Other adverse reactions caused by cyclophosphamide

include amenorrhea, menopause, and late-onset cancer,

includingesophageal,lungandbladderadenocarcinoma.18,46

Cyclophosphamide was administered at a dose of

750–1000mg/m2 _{body surfaceinLUMINA(Lupusin}

minori-ties,natureversusnurture),amulticenterstudyperformed including567womenagedunder51 years.46 _{Adecrease in} gonadalfunctionwasfound,andgonadalfailurewasdefined astheoccurrenceofamenorrheaformorethansixmonths withoutahistoryofhysterectomy.46_{Cyclophosphamidehas} alsobeenassociatedwithteratogenicity.18

Astocyclophosphamidedoseadjustmentinpatientswith kidneyfailure,thisisonlydoneinseverecases,thatis,with acreatinineclearance<10mL/min.Thetherapeuticregimen ofcyclophosphamideshouldbemodified,itsdoseshouldbe reducedby25%,andsupplementedwith50%afterdialysis.34

Thedilutionofthedrugsusedincyclophosphamide rou-tinewascarriedoutwiththegoalofmaintainingthehighest possibleconcentrationofthedruginitsnon-ionizedform.58 Thus,twoparametersweretakenintoaccount:drug compat-ibilitywiththevehicle(saline,dextroseorringerlactate)and itsstabilitytimeinthevehicle;preferencewasgiventothose drugswhosestabilitytimewaslonger,inordertoensurea moreeffectivetreatment.33

Whenthedrugsusedhaveprovedcompatibleandstable withthesamevehicle,preferencewasgiventothechoiceof thesame vehicle,asthisfacilitatestheiradministrationby thenursingstaffandpreventspharmacokineticinteraction, whichwouldcauseionizationofthedrugsandadecreasein theirefficacy.67

Anotherimportantaspectthatshouldbeaddressedisthe educationofthepatientonthetreatmenttowhathe/sheis beingsubmitted.AstudyinthecityofNatalwith40women diagnosedwithsystemiclupuserythematosusattheHospital Onofrehasshownthatpatientsshowinggreateradherence werethosewhounderstoodcorrectlythetreatmentandalso thedisease;thus,thesewomensatisfactorilyunderstoodthe adverseeventsandtheclinicalmanagement,inorderto min-imizetheseadversedrugreactions.68

Publications on adverse events are important tools for drug safety monitoring after their release for marketing

purposes bythe health authorities of each country.69 _This reviewofmedicationadministrationintendedtostandardize the administrationof cyclophosphamide by health profes-sionals,inordertominimizethe adverseeventscausedby drugs,theso-calledadversedrugreaction.19

Conclusion

Theroutinewasdevelopedinordertoincreasetheareaunder thecurve(AUC)forcyclophosphamide,andtoattainan

appro-priate clinical management to minimize the adverse drug

reactions that, if not properly prevented, will cause dam-age tothe patient,forinstance,anincreasedprevalenceof vomiting,andacroleindepositioninthebladder.Theclinical managementofadversereactionsthatalterlaboratorytests wasdescribedinordertoguidetheapplicationofthesetests. Adversereactions,evenbeingrare,werehighlightedbecause theseeventscancausehighmorbidity.Thus,therationaluse ofcyclophosphamideincreasesthe safety ofthe treatment and reducesthecostofadministrationofthis chemothera-peuticagent,sinceourgoalistoavoiderror.

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