Cyclophosphamide

By | 2010-07-25

Chemistry

A nitrogen-mustard derivative, cyclophosphamide occurs as a white, crystalline powder 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 be stored at temperatures less than 25°C. They may be exposed to temperatures up to 30°C for brief periods, but should not be exposed to temperatures above 30°C. Tablets should be stored in tight containers. The commercially available tablets (Cytoxan®) are manufactured in bi-level manner with a white tablet containing the cyclophosphamide found within a surrounding flecked outer tablet. Therefore, the person administering the drug need not protect their hands from cyclophosphamide exposure 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 bacteriostatic water for injection the product should be used within 24 hours if stored at room temperature and within 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 also compatible 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).

Pharmacology

While commonly categorized as an alkylating agent, the parent compound (cyclophosphamide) is not, but cyclophosphamide’s metabolites such as phosphoramide mustard do act as alkylating agents interfering with DNA replication, RNA transcription and replication, and ultimately disrupting nucleic acid function. The cytotoxic properties of cyclophosphamide are also enhanced by phosphorylating activity the drug possesses.

Cyclophosphamide has marked immunosuppressive activity and both white cells and antibody production 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 or the Protocols (at the end of this section), for more information. Cyclophosphamide has also been used as a chemical shearing agent in sheep.

Pharmacokinetics

While the pharmacokinetics of cyclophosphamide have not been detailed in dogs or cats, it is presumed that the drug is handled in a manner similar to humans. The drug is well absorbed 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 into milk and presumed to cross the placenta.

Cyclophosphamide is metabolized in the liver to several metabolites. Which metabolites account for which portion of the cytotoxic properties of the drug are a source of controversy. After IV injection, the serum half-life of cyclophosphamide is approximately 4-65 hours, but drug/metabolites can be detected up to 72 hours after administration. The majority of the drug is excreted as metabolites and unchanged drug in the urine.

Contraindications – Precautions – Reproductive Safety

There are no absolute contraindications to 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 whom immunosuppression may be dangerous (e.g., infected patients).

Because of the potential for development of serious adverse effects, cyclophosphamide should only 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 also effect red cell and platelet production. The nadir for leukocytes occurs generally between 7-14 days after dosing and may require up to 4 weeks for recovery.

Sterile hemorrhagic cystitis induced by cyclophosphamide is thought to be caused by the metabolite acrolein. Up to 30% of dogs receiving long-term (>2 months) cyclophosphamide can develop this problem. In cats, cyclophosphamide-induced-cystitis (CIC) is rare. Initial symptoms may present as hematuria and dysuria. Because bacterial cystitis is not uncommon in immune-suppressed patients, it must be ruled out by taking urine cultures. Diagnosis of CIC is made by a negative urine culture and inflammatory urine sediment found during urinalysis. Because bladder fibrosis and/or transitional cell carcinoma of the bladder is also associated with cyclophosphamide use, these may need to be ruled out by contrast radiography. It is believed that the incidence of cyclophosphamide-induced-cystitis may be minimized by increasing urine production and frequent voiding. The drug should be given in 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 drug slowly over several months and monitor for early signs of relapse. Rapid withdrawal can lead to a rebound 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, the animal should be hospitalized for supportive care.

Cyclophosphamide: Drug Interactions

Phenobarbital (or other barbiturates) given chronically may increase the rate of metabolism of cyclophosphamide via microsomal enzyme induction and increase the likelihood of 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) as potentiation 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 false negative skin test results to a variety of antigens, including tuberculin, Candida, and Trichophyton.

Cyclophosphamide: Doses

For more information, refer to the protocol references found in the appendix or other protocols found in numerous references, including: Handbook of Small Animal Practice; Handbook of Small Animal Therapeutics; Current Veterinary Therapy X: Small Animal Practice; and Textbook of Veterinary Internal Medicine, 3rd Edition.

Doses for dogs:

For susceptible neoplastic diseases:

a) 50 mg/m2 PO or IV 4 days/week.

b) 50 mg/m2 PO or IV 4 days/week or 200 mg/m2 IV weekly.

c) For multiple myeloma in patients refractory to melphalan: 1 mg/kg PO once daily.

For macroglobulinemia in patients refractory to chlorambucil: 1 mg/kg PO once daily.

As an immunosuppressant:

a) For adjunctive therapy for immune-mediated hemolytic anemia (probably should be reserved for dogs w/fulminant intravascular hemolysis, autoagglutination or those that require repeated transfusion or have persistant reticulocytopenia): Initially at 2 mg/kg/day IV or PO for 4 days; no treatment for 3 days and then repeat cycle.

b) For immune-mediated hemolytic anemia: 50 mg/m2 for 4 consecutive days per week. May be overtreatment; efficacy not proven.

c) For immune-mediated hemolytic anemia if glucocorticoids unsuccessful: Add cyclophosphamide at 2.2 mg/kg (50 mg/m2) PO or IV once daily for 4 consecutive days of each week. Discontinue CTX when PC V increases significantly and attempt to slowly reduce steroids dose and D/C eventually, if possible.

c) For immune-mediated hemolytic anemia: Usually steroids used initially, but cyclophosphamide (&/or azathioprine) may be indicated early in therapy for cases with severe hemolysis and agglutination. Cyclophosphamide 2 mg/kg PO once daily for 4 days, stop for 3 days, then repeat. Animals should receive steroids, CTX, and azathioprine if they exhibit massive agglutination and intravascular hemolysis (poor prognosis).

d) For immune-mediated thrombocytopenia: If corticosteroids ineffective, may use either vincristine, azathioprine or cyclophosphamide. CTX dose: 50 mg/m2 PO once daily for 3-4 days/week. May give initial doses IV. Decrease dose if renal or hepatic impairment exists. After 1-4 weeks, taper dose and discontinue after platelet count is >100,000/µl. Serious bleeding secondary to thrombocytopenia and hemorrhagic cystitis can occur; use cautiously.

e) For rheumatoid arthritis: In conjunction with a glucocorticoid (predniso(lo)ne); give CTX PO once daily in the AM for 4 consecutive days each week at 2.5 mg/kg if weighs <10 kg, 2 mg/kg if 10-35 kg, and 1.5 mg/kg if >35 kg. Discontinue: 1 month after remission of synovial inflammation (determined from joint tap), after 4 months of treatment, or if hemorrhagic cystitis develops. If cystitis develops, switch to azathioprine.

f) For polymyositis: In conjunction with steroids, if steroids alone are ineffective: 1 mg/kg PO once daily for 4 days, then off 3 days. Decrease concurrent prednisone dose to 1 mg/kg/day.

Doses for cats:

For susceptible neoplastic diseases:

a) For advanced mammary carcinoma: Doxorubicin: 30 mg/m2 IV every 3 weeks up to 4-8 treatments. Cyclophosphamide: 100 mg/ m2 PO once daily on days 3, 4, 5, and 6 after doxorubicin.

As an immunosuppressant:

a) Give 2.5 mg/kg once daily PO for 4 consecutive days out of 7 for up to 3 weeks. Alternatively, 7 mg/kg IV may be given once a week.

b) For immune-mediated hemolytic anemia: 50 mg/ m2 for 4 consecutive days per week. May be overtreatment; efficacy not proven.

c) For rheumatoid arthritis: In conjunction with a glucocorticoid (predniso(lo)ne); give CTX PO once daily in the AM for 4 consecutive days each week at 2.5 mg/kg. Discontinue 1 month after remission of synovial inflammation (determined from joint tap), after 4 months of treatment, or if hemorrhagic cystitis develops. If cystitis develops, switch to azathioprine.

Doses for sheep:

As a chemical defleecing agent:

a) 25 mg/kg PO once.

Monitoring Parameters

1) Efficacy. See the Protocol section or refer to the references from the Dosage section above for more information.

2) Toxicity, see Adverse Effects above. Regular hemograms and urinalyses are mandatory.

Client Information

Clients must be briefed on the possibilities of severe toxicity developing from this drug, including drug-related mortality. Clients should contact veterinarian should the animal exhibit any symptoms of abnormal bleeding and/or bruising.

Although no special precautions are necessary with handling intact tablets, direct exposure should be avoided to split or crushed tablets, oral elixir, or the animal’s urine or feces. Should exposure occur, wash the area thoroughly with soap and water.

Dosage Forms – Preparations – FDA Approval Status – Withholding Times

Veterinary-Approved Products:

None

Human-Approved Products:

Cyclophosphamide Tablets 25 mg, 50 mg; Cytoxan® (Mead Johnson Oncology); (Rx)

Cyclophosphamide Powder for Injection 100 mg, 200 mg, 500 mg, 1 g and 2 g vials; Cytoxan® (with sodium chloride) and Cytoxan® Lyophilized (with mannitol) (Mead Johnson Oncology) (Rx), Neosar® (Pharmacia & Upjohn) (Rx)