Cyclonex

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Cyclophosphamide monohydrate 53.5 mg equivalent to 50 mg cyclophosphamide
Available from:
CARSL Consulting
INN (International Name):
Cyclophosphamide monohydrate 53.5 mg
Dosage:
50 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Cyclophosphamide monohydrate 53.5 mg equivalent to 50 mg cyclophosphamide Excipient: Croscarmellose sodium Isopropyl alcohol Lactose monohydrate Magnesium stearate Microcrystalline cellulose Opadry Pink Purified water
Units in package:
Bottle, plastic, 40ml, 50 tablet pack, 50 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Orion Corporation
Therapeutic indications:
Latest Regulatory Activity
Product summary:
Package - Contents - Shelf Life: Blister pack, Al/PA/Al/PVC - 50 tablets - 18 months from date of manufacture stored at or below 25°C protect from light
Authorization number:
TT50-3935
Authorization date:
1985-08-15

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DATA SHEET

CYCLOBLASTIN ®

Presentations

Cycloblastin is supplied in tabletscontaining 50 mgofcyclophosphamide for oraladministration.

Cycloblastin tabletscontain the followinginactiveingredients: lactose monohydrate, sucrose, maize

starch, titaniumdioxide E171, pregelatinisedstarch, erythrosine E127, sodium stearyl

fumaratelactose, talc, microcrystallinecellulose,indigocarmine E132, magnesiumstearate sodium

benzoate E211, gelatin, calciumcarbonate, macrogol 6000, carnaubawax, povidone

Uses

Actions

Cyclophosphamide is asynthetic antineoplastic drugchemically related to the nitrogen mustards. The

drug undergoes activation to alkylating metabolitesby the mixed function microsomal oxidase systems

in the liver. These metabolites interferewith the growth of susceptible, rapidly proliferating malignant

cells via cross linking of DNA strands, alteration ofDNA replication and RNA transcription, yielding to

the disruptionof nucleicacidfunction. The drugalso exhibits phosphorylating properties(enhancing

its cytotoxicity), potent immunosuppressant effectsand a persistent inhibition ofpseudocholinesterase

activity.

Pharmacokinetics

Absorption:Cyclophosphamide is well absorbedfromthe gastrointestinal tract after oral

administration, with a reported bioavailability averaging 74%. Peakserum levelsare attained within

about 1 hourafter oral dosing.

Distribution:The drug andits metabolites are widely distributed intissues, including the brainand

CSF. It is assumed that cyclophosphamide crosses the placenta.Thedrug is distributed into milk.

Plasma protein bindingis low (0-10%), but somemetabolites are bound to an extent greaterthan 60%.

Volume of distribution is 0.78 L/kg.

Metabolism:Cyclophosphamide is biotransformedinthe liver to the initial metabolites 4-

hydroxycyclophosphamideand its acylictautomer, aldophosphamide, which bothundergo further

metabolism; aldophosphamide may undergonon-enzymaticconversion to active phosphoramide

mustard. Acrolein, the derivative responsiblefor bladder toxicity, is also produced.

Excretion:The eliminationhalf-life after IV administration of cyclophosphamide is in the range3-12

hrs; however,the drug and/or its metabolites can be detected in theserum up to 72 hrs after drug

administration. The half-life of phosphoramide mustard is approximately 9 hrs. Total body clearance

averages 4.4L/h. Cyclophosphamide andits metabolites areexcretedprincipally in urine, withabout

36-99% of a dose beingeliminated within48 hrs; about 5-30% of the amount excretedis unchanged

drug.

In patients withrenal failurethe half-life is prolonged and elevated levels of metabolites have been

found.

Indications

Cyclophosphamide is indicated, usually in combination chemotherapy regimens,for the treatment of

the followingsolid tumors and hematologic malignancies:

Breast

Cancer

Lung

Cancer

Ovarian Cancer

Neuroblastoma

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Retinoblastoma

Osteosarcomaand Soft Tissue Sarcoma

Leukemias(acute and chronic)

Lymphomas

(non-Hodgkin Lymphomasand Hodgkin’s Disease)

Multiple

Myeloma

Dosage & Administration

The dosageofcyclophosphamide, as for all cytotoxic drugs, is usuallybased onthe patient’s body

surfacearea(m 2

) or body weight (kg).

If the patient is obese or has severe fluidretention, dosage

should be based onthe estimated idealbody weight.

Cyclophosphamide dosages need alsoto be tailoredto the individual requirements of the patient,

depending on:

the disease being treated;

the therapeuticsetting(induction,maintenance, palliation, adjuvant);

the conditionof the patient (includingage and state ofbone marrow);

the concomitant use of other cytotoxicdrugs, radiotherapy, supportive therapy.

Therapeutic doses of cyclophosphamidein cancerpatients may thusvary considerably: conventional

cyclophosphamide doses are usually in the range of 80to 2000 mg/m 2 (2 - 50 mg/kg). Higherdoses

should be used only at the discretion ofphysicians experienced incytotoxic chemotherapy.

Contraindications

Cyclophosphamide is toxic to the uropoietic systemand to the bone marrow, and the drug isa potent

immunosuppressant,thus major contra-indications to its use are thefollowings:

evidence of hemorrhagiccystitis, acutesystemicor urinary infection, drug- or radiation-induced

urothelial toxicity

severe bone marrow impairment, the presence ofinfections(as aresult of immunosuppression

induced by the cytotoxic treatment)which could leadto fatal complications.

Warnings & Precautions

The administration of cyclophosphamideshould becarriedout under the supervision of physicians

fully trained in the use of cytotoxic drugs. Careful monitoring for toxicity is necessary, particularly when

high drug dosages are employed.

Although toxic effects are likely to be related (in frequency and severity) to dose and/or frequency of

drug administration, toxicity can occur atall doses.

Patients should be fully informed by the attending physician of the risk of toxicity before undergoing

cyclophosphamide treatment.

Routine baseline assessment should include a complete blood cell count, hepaticand renal function

tests.

Special warnings and precautionsapply to the following areas:

Urinarysystem:Sterile hemorrhagic cystitis is a severe adverse reactionthat has been reported with

cyclophosphamide therapy. To prevent this toxiceffect the patient needsto be adequately hydrated

with frequent voiding of urine. Patients should beinstructed to increase their fluidintake for 24hrs

before, duringand for at least 24 hrs after receiving cyclophosphamide and to void frequently for 24

hrs after receiving the drug.A further prophylacticmeasure is theconcomitant use of Mesna(see

Interactions). Urine also should be examined regularly for the presence of red cells, which may

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precede hemorrhagic cystitis. Since this complicationcan besevere and even fatal, the drug should

be discontinued in patients who developthis complication. In severe cases, blood replacement may be

needed.

Hematopoieticsystem:The patient’s hematologic status mustbe carefully monitored throughout each

cycle of treatment. Cyclophosphamide-induced leukopenia/neutropenia are dose-related and can be

usedas a guide to adjustingthe drug dosage. Full recovery from leukopenia is usually achieved within

28 days fromdosing.

Infections:Sincecyclophosphamide therapy has immunosuppressive activity which can potentially

lead to serious or even fatal infections, the patientshould be carefully monitored for any sign/symptom

of infection (such as, e.g., fever, sore throat orunusualbleeding orbruising). Interruption orreduction

of cyclophosphamide dosage should beconsideredfor patientswho develop bacterial, fungal,

protozoan, helmintic or viralinfections, especially thosepatients whoare receivingor who have

recentlyreceived corticosteroid therapy.

Heart disorders:Since cardiotoxicity hasbeen reported- albeit rarely- in patients receiving

cyclophosphamide, a monitoring of the cardiac functions isrecommended in patients with pre-existing

cardiac disturbances or impairments. In addition, special attention isrequired when using

cyclophosphamide in combination with other potentiallycardiotoxic drugs (such as, e.g.,

anthracyclines and fluorouracil).

Secondarytumors:Cytotoxic drugs have been reported associatedwith an increased risk of

development of secondary tumors in humans.Somepatients receiving cyclophosphamide have

developed secondary malignancies, most frequently urinary bladder, myelo- and lymphoproliferative

malignancies.Secondary malignancies haveoccurredmainly in patients who have been treated with

cyclophosphamide for primary haematologic malignancies or primary non-malignant diseasesin which

immune processes are believed to be involved. Insome cases, the secondarymalignancy was not

detected untilseveral years after discontinuance of cyclophosphamide therapy.

Microsomal enzymes: Since cyclophosphamide is converted intoits active metabolitesprimarily within

the liver the drug has to beadministeredwith cautionincombination with compounds that induce liver

microsomal enzymes (such as, e.g., barbiturates): such combinations may result in an increased

pharmacologic effect and increased toxicityof cyclophosphamide (see Interactions).

Hyperuricemia:As a resultof extensive purine catabolism which may follow rapid cell lysis

hyperuricemiamay occur insome patients receivingcyclophosphamide; this effect may be minimized

by adequate hydration, alkalinization of the urine and/or administration of allopurinol. A monitoring of

the patient for cyclophosphamide toxicity should follow the allopurinol administration (see Interactions).

Diabetes mellitus:Caution should be used when treating patients with diabetesmellitus, since

cyclophosphamide can interactwith insulin andother hypoglycaemic agents(seeInteractions).

Cyclophosphamide treatment may be unsafe in patients with acuteporphyria since the drug has been

shown to beporphyrinogenic in animals.

Pregnancy and Lactation: Cyclophosphamide crosses the placenta and can cause fetal toxicity when

administeredto pregnant women. Abnormalities (missing fingers and/or toes, cardiac defects, hernias)

have occurredin infants born to womentreated withthe drugduringthe pregnancy. If the drug is

administeredduring pregnancy or if thepatient becomes pregnantwhile receiving cyclophosphamide,

information onthe potential hazard to the fetus should be provided. Women of childbearing potential

should not receive the druguntil pregnancy isexcluded andshouldbe advisedto use a reliable

contraceptivemethod duringand until about 3monthsafter discontinuation of thedrug.

Cyclophosphamide is distributed into milk. Becauseofthe potential for serious adversereactions in

nursing infants, breast-feeding is not recommended duringcyclophosphamide therapy.

Effects on theAbility to Drive and Use Machines: There have beenno reports explicitly relatingto

effects of cyclophosphamide treatment onthe abilityto drive or usemachines. However, on the basis

of reported adverse reactions, the drugis presumed tobe potentially dangerous.

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ADVERSEEFFECTS

Adverse reactions to cyclophosphamide, as reportedfor the various organ systems, are asfollows.

Haematologic Effects:One of the major (and dose-limiting)toxicity of cyclophosphamide is bone

marrowsuppression. Leukopenia and neutropenia(granulocytopenia) are expected to occurfollowing

therapeutic doses of the drug,and they may be severe. The maximum depression(nadir) of

WBC/neutrophils counts isusually seen1 to 2 weeksfollowinga single dose, withrecovery usually

seenin 3 to 4 weeks. Thrombocytopenia is lesscommon, with nadirs occurring10-15 days after

administration of the drug.Anemia, particularly after large doses orprolonged therapy, has also been

reported.

Secondary leukemias have been reported in patients treated withcyclophosphamide-containing

regimens.

Gastrointestinal andHepatic Effects:Nausea (oftendelayed) andvomiting commonly occur while

under cyclophosphamide treatment. Anorexia and,less frequently, abdominal discomfort orpain,

diarrhea, hemorrhagic colitis, mucosal irritation and oral ulcerationmay also occur. Rarely, stomatitis,

enterocolitisand hepatotoxicity as evidenced by jaundice and hepatic dysfunction have beenreported.

Genitourinary Effects:Sterile hemorrhagic cystitis hasbeen reportedto occur inup to 40% of patients

(especially children)on long-term therapy, however thisis rarely severe or fatal. The cystitis appears

to result fromchronic inflammation leading to fibrosisand teleangiectasia of thebladder epithelium,

and hemorrhage may become life-threatening if drugadministration is continued. Hematuriausually

resolvesspontaneously within a few days afterdiscontinuance of therapy, but symptoms have been

reported to occur up to 6months after drug discontinuation. Further information is given inWarnings&

Precautions.

Nephrotoxicity, including hemorrhagic urethritisand renal tubular necrosis, aswell as fibrosisof the

bladder, withor without cystitis,has also occurred. Such lesions reportedly resolve in most instances

followingdiscontinuation of the drug.

Cyclophosphamide treatment has beenreported tobeassociatedwith the development of bladder

carcinoma.

Cardiac Effects:Cardiac toxicity has been reported inpatients receiving cyclophosphamide, generally

as a part of an intensive,multiple-drug antineoplastic regimen or with bone marrow transplant

procedures. In a few instances severe- and sometimes fatal - congestive heart failure has occurred

within days after the first dose; histopathologic examination has primarily shown hemorrhagic

myocarditis.Deathshavealso been reported fromdiffuse hemorrhagic myocardial necrosis and from a

syndrome ofacute myopericarditis. Hemopericardiumand pericarditis have also been reported.

Pulmonary Effects:Pulmonary toxicity has been reported in cyclophosphamide-treated patients,

mostly with high doses of the drugor inpatients receiving combination chemotherapy. The onset of

pulmonary toxicity may occurweeksto yearsafter therapy. Pulmonary events are mostly in the form of

interstitial pulmonary fibrosis.

Dermatologic and HypersensitivityEffects:Alopeciaoccurs frequently, generally beginning about 3

weeks after initiation of therapy. Skin hyperpigmentation and nailchanges (transverse ridging,

retarded growth and/orpigmentation offingernails) may also occur. Facial flushing, skin rash and

anaphylacticreactions have also been reported, andone instanceof possiblecross-sensitivity with

other alkylating agents has been described. An erythematouspruritic rash, similar to the palmar-

plantarsyndrome seen withother antineoplastics,but occurring on the dorsalsurfacesof the hands

and feet, hasbeen reported.

ReproductiveSystem:Cyclophosphamide interfereswith oogenesisand spermatogenesis. The drug

may cause sterility in both sexes, depending upon thedose of cyclophosphamide, the durationof the

therapy and the state of gonadal functionat the time of treatment. Long-term effects include

azoospermia,oligospermiaand ovarian failure. Libidoand sexual capability areusually not affected.

Azoospermiamay be reversible butrecovery is usually slow and often incomplete. Irregular menses

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and amenorrhea associated with decreased oestrogen and increased gonadotropin secretion may be

permanent in some patients.

Metaboliceffects:Hyperuricemia, asa component of theso-called ‘rapid tumor lysissyndrome’, may

occur(especially in non-Hodgkin’s lymphoma and leukemia patients). The effect can be minimized by

adequate hydration, alkalinization of theurine and/oradministration of allopurinol.

A syndrome of inappropriate antidiuretic hormonesecretion (SIADH) has also been reported.

Hyponatremia associatedwith weight gain without oedema may result from impaired excretion of

water(‘waterintoxication’); this event can be particularly severe in cyclophosphamide-treatedpatients

given the common practice to increase fluid intaketoprevent chemical cystitisand the formation of

uric acidcalculi.

Other Adverse Effects:Other reactions associatedwith the use of cyclophosphamide include

headache, dizziness, myxedema, astenia/fatigue,diaphoresis, decreasedserumcholinesterase

concentrations, interference with normalwound healing, hypoprothrombinemia,positive direct

antiglobulin (Coombs’)test results, hemolytic anemiaand recurrenttransient myopia.

Interactions

Cyclophosphamide is often usedin combinationwith othercytotoxic drugs orimmunosuppressant

agents having similar pharmacologic effects. Underthese circumstancesadditive toxicity may be

expected andshould be taken into account, especiallywith regardto bone marrow

depression/fostering of infection, gastrointestinal, kidney and heart toxicity.

Mesna(sodium2-mercaptoethanesulfonate) is asyntheticsulfhydryl compoundthat can chemically

interact with urotoxic metabolites of cyclophosphamide (e.g. acrolein) thought to be principally

responsible for drug-induced hematuria andhemorrhagic cystitis.Theconcomitant administration of

Mesna not only contributesto thedetoxification fromthese metabolitesbut also exerts uroprotective

activity.

An increasedincidence of bone-marrow depression has been described in patients receiving

allopurinol plus cyclophosphamide. Thiseffect is probably due toa prolonged cyclophosphamide half-

life.

The concomitant administration of corticosteroids, such asprednisone, may also inhibit the activation

of cyclophosphamide; thiseffect has howeverbeenreported as temporary since after long-term

treatment therate of activation has beenincreased.

Barbituratesand other drugs which induce liver microsomal enzymes may resultin an increased

pharmacologic effect and increased toxicity of cyclophosphamide becauseofincreased conversion of

the drug to active (alkylating) metabolites.

Conversely, the concurrentuse of inhibitors of microsomal enzyme activity in theliver, suchas

chloramphenicol, sulphaphenazole, chloroquine, imipramine, phenothiazines, potassium iodideand

vitamin A may decrease the effects of cyclophosphamide.

Possible interaction between cyclophosphamide anddigoxin yielding to cardiac arrhythmias has been

reported during combinationchemotherapy in apatient with atrial fibrillation previously well controlled

with digoxin.

Cyclophosphamide may decrease plasma concentrations of pseudocholinesterase, thereby enhancing

or prolongingthe neuromuscular blockadeby succinylcholine. Although the clinical importancehas not

been established, it has been suggestedthat succinylcholine be administeredwith caution in patients

receiving cyclophosphamide and that succinylcholineor cyclophosphamide be avoided in patients with

substantially depressedpseudocholinesterase concentrations. Theanesthesiologist should bealerted

before general anesthesiais administered if a patient has receivedcyclophosphamide withinthe

previous10 days.

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There is a report of acute, life-threateningwater intoxication in a patient given low-dose

cyclophosphamide concomitantly with indomethacin.

Cyclophosphamide also interacts with anticoagulants, insulin and other hypoglycaemicagents and

suxamethonium.

Laboratory valueswhich can be altered bycyclophosphamide in addition to those mentioned above

are theskin tests for Candida, mumps, Trichophyton and tubercolin(which may give false-negative

results) andPapanicolau test (whichmay give false-positive results).

Overdosage

Myelosuppression (particularly neutropenia) and hemorrhagic cystitis are the most serious

consequencesof cyclophosphamide overdosage. Formyelotoxicity, administration of broad-spectrum

antibiotics and colony stimulating factors (G-CSF, CM-CSF) are advisable. Transfusion of whole-

blood, platelets or white cells arerarely necessary. For the urotoxiceffects, IV Mesna may be

beneficial when used withinthe first24-48 hrs. Normal supportivemeasuressuch asanalgesics and

maintenance of fluid balance should beinstituted. If despite thesemeasures thecystitis doesnot

resolve, moreintensive treatment may be necessary and a urological opinionshould besought. No

furthercourses should begiven until the patient has fully recovered. .

Pharmaceutical Precautions

Shelf Life:

3

years

Special Precaution for Storage:

Cyclophosphamide tablets should be stored protected fromlight, in a dry place, at or below 25°C; the

preparation will withstand brief exposure to temperatures up to 30°C, but should beprotected from

temperaturesexceeding this value. Cyclophosphamide tablets should be storedin closedcontainers.

Medicine Classification

Prescription Medicine.

Package Quantities

50 mg tablets: brownsugar coated, diameter 7 mm.

Packaging: 50

Further Information

Preclinical Safety Data:

The LD50oforalcyclophosphamide is160 mg/kg forratsandapproximately 44mg/kgfordogs.The

LD50 ofthecompoundfollowingintravenous administrationis160-182mg/kgforratsandabout40mg/kg

fordogs.

Themaintargetsaftera singledosearethe hemolymphopoietic systemandG.I.tract.

Thetoxiceffects afterrepeatedadministrationofcyclophosphamidewereinvestigatedinmice,and rats,

hamsters, dogs andmonkeys.Themaintargetsofcyclophosphamideintheaboveanimalspecies arethe

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hemolymphopoieticsystem, G.I. tract,heart, liver,kidney,urinary bladder andmalereproductiveorgans.

Diffusehemorrhages wereseeninseveral organs,includingthebrainandtheheart.

Cyclophosphamidewasgenotoxicinmostoftheinvitroandin vivotests performed.Oralandintravenous

cyclophosphamideis toxic to thereproductiveorgans, and embryotoxicand teratogenicinmice,rats and

rabbits. Cyclophosphamide,likeothercytotoxic drugs,is carcinogenic inmiceandrats.

Name and Address

Pfizer New Zealand Ltd

PO Box 3998

Auckland

New Zealand

Toll FreeNumber: 0800 736 363

Date of Preparation

27 July 2010

(Ref. CDS 6.97)

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