CYCLOPHOSPHAMIDE

Chemistry - A nitrogen-mustard derivative, cyclophosphamide occurs as a white, crystallinepowder that is soluble in water and alcohol. The commercially available injection has pH of 3 to 7.5.
Cyclophosphamide may also be known as CPM, CTX or CYT.

Storage, Stability, Compatibility

Cyclophosphamide tablets and powder for injection should bestored at temperatures less than 25°C. They may be exposed to temperatures up to 30°C for briefperiods, but should not be exposed to temperatures above 30°C. Tablets should be stored in tightcontainers. The commercially available tablets (Cytoxan®) are manufactured in bi-level manner witha white tablet containing the cyclophosphamide found within a surrounding flecked outer tablet.
Therefore, the person administering the drug need not protect their hands from cyclophosphamideexposure unless the tablets are split or crushed.
Cyclophosphamide injection may be dissolved in aromatic elixir to be used as an oral solution.
When refrigerated, it is stable for 14 days.
After reconstituting the powder for injection with either sterile water for injection or bacteriostaticwater for injection the product should be used within 24 hours if stored at room temperature andwithin 6 days if refrigerated.
Cyclophosphamide is reportedly compatible with the following intravenous solutions and drugs:
Amino acids 4.25%/dextrose 25%, D5 in normal saline, D5W, sodium chloride 0.9%. It is alsocompatible in syringes or at Y-sites for brief periods with the following: bleomycin sulfate, cisplatin, doxorubicin HCl, droperidol, flurouracil, furosemide, heparin sodium, leucovorin calcium, methotrexate sodium, metoclopramide HCl, mitomycin, vinblastine sulfate, and vincristine sulfate.
Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.
It is suggested to consult specialized references for more specific information (e.g., Handbook on
Injectable Drugs by Trissel; see bibliography).

Pharmacology - CYCLOPHOSPHAMIDE

While commonly categorized as an alkylating agent, the parent compound(cyclophosphamide) is not, but cyclophosphamide's metabolites such as phosphoramide mustarddo act as alkylating agents interfering with DNA replication, RNA transcription and replication, andultimately disrupting nucleic acid function. The cytotoxic properties of cyclophosphamide are alsoenhanced by phosphorylating activity the drug possesses.
Cyclophosphamide has marked immunosuppressive activity and both white cells and antibodyproduction are decreased, but the exact mechanisms for this activity have not been fully elucidated.
Uses, Indications - In veterinary medicine, cyclophosphamide is used primarily in small animals, both as an antineoplastic agent and an immunosuppressant. Refer to the Dosages section below orthe Protocols (at the end of this section), for more information. Cyclophosphamide has also beenused as a chemical shearing agent in sheep.

Pharmacokinetics - CYCLOPHOSPHAMIDE

While the pharmacokinetics of cyclophosphamide have not been detailed indogs or cats, it is presumed that the drug is handled in a manner similar to humans. The drug is wellabsorbed after oral administration with peak levels occurring about 1 hour after dosing.
Cyclophosphamide and its metabolites are distributed throughout the body, including the CSF(albeit in subtherapeutic levels). The drug is only minimally protein bound and is distributed intomilk and presumed to cross the placenta.
Cyclophosphamide is metabolized in the liver to several metabolites. Which metabolites accountfor which portion of the cytotoxic properties of the drug are a source of controversy. After IVinjection, the serum half-life of cyclophosphamide is approximately 4-65 hours, butdrug/metabolites can be detected up to 72 hours after administration. The majority of the drug isexcreted as metabolites and unchanged drug in the urine.

Contraindications, Precautions, Reproductive Safety

There are no absolute contraindicationsto the use of cyclophosphamide, but it must be used with caution in patients with leukopenia, thrombocytopenia, previous radiotherapy, impaired hepatic or renal function, or in those for whomimmunosuppression may be dangerous (e.g., infected patients).
Because of the potential for development of serious adverse effects, cyclophosphamide shouldonly be used in patients who can be adequately and regularly monitored.
Cyclophosphamide's safe use in pregnancy has not been established and it is potentially teratogenic and embryotoxic. Cyclophosphamide may induce sterility (may be temporary) in male animals.

Adverse Effects, Warnings

Primary adverse effects in animals associated with cyclophosphamide are myelosuppression, gastroenterocolitis (nausea, vomiting, diarrhea), alopecia (especially in breeds where haircoat continually grows, e.g., Poodles, Old English Sheepdogs), and hemorrhagic cystitis.
Cyclophosphamide's myelosuppressant effects primarily impact the white cells lines, but may alsoeffect red cell and platelet production. The nadir for leukocytes occurs generally between 7-14 daysafter dosing and may require up to 4 weeks for recovery.
Sterile hemorrhagic cystitis induced by cyclophosphamide is thought to be caused by themetabolite acrolein. Up to 30% of dogs receiving long-term (>2 months) cyclophosphamide candevelop this problem. In cats, cyclophosphamide-induced-cystitis (CIC) is rare. Initial symptomsmay present as hematuria and dysuria. Because bacterial cystitis is not uncommon in immunosuppressed patients, it must be ruled out by taking urine cultures. Diagnosis of CIC is made by anegative urine culture and inflammatory urine sediment found during urinalysis. Because bladderfibrosis and/or transitional cell carcinoma of the bladder is also associated with cyclophosphamideuse, these may need to be ruled out by contrast radiography. It is believed that the incidence of CICmay be minimized by increasing urine production and frequent voiding. The drug should be givenin the morning and animals should be encouraged to drink/urinate whenever possible.
Recommendations for treatment of CIC include discontinuation of the cyclophosphamide, furosemide, and corticosteroids. Refractory cases have been treated by surgical debridement, 1%formalin or 25% DMSO instillation in the bladder.
Other adverse effects that may be noted with CTX therapy include pulmonary infiltrates and fibrosis, depression, immune-suppression with hyponatremia, and leukemia.
In recovering dogs with immune-mediated hemolytic anemia, taper the withdrawal of the drugslowly over several months and monitor for early signs of relapse. Rapid withdrawal can lead to arebound hyperimmune response.

Overdosage, Acute Toxicity

There is only limited information on acute overdoses of this drug.
The lethal dose in the dogs has been reported as 40 mg/kg IV. If an oral overdose occurs, theanimal should be hospitalized for supportive care.

Drug Interactions

Phenobarbital (or other barbiturates) given chronically may increase the rateof metabolism of cyclophosphamide via microsomal enzyme induction and increase the likelihoodof toxicity development.
Allopurinol and thiazide diuretics may increase the myelosuppression caused by cyclophosphamide.
The absorption of orally administered digoxin tablets and elixir may be decreased when cyclophosphamide is also being given. This effect may even occur several days after the cyclophosphamide was administered.
Succinylcholine metabolism may be slowed with resulting prolongation of effects, as cyclophosphamide may decrease the levels of circulating pseudocholinesterases.
Use caution when using cyclophosphamide with other cardiotoxic agents (e.g., doxorubicin) aspotentiation of cardiotoxicity may occur.
Drug/Laboratory Interactions - Uric acid levels (blood and urine) may be increased after cyclophosphamide use. The immunosuppressant properties of cyclophosphamide may cause falsenegative skin test results to a variety of antigens, including tuberculin, Candida, and Trichophyton.