Compendium November 1999

Compendium November 1999

20TH ANNIVERSARY

Small Animal/Exotics

PHARM PROFILE

CYCLOPHOSPHAMIDE Ravinder S. Dhaliwal, DVM All Care Animal Referral Center, Fountain Valley, California Barbara E. Kitchell, DVM, PhD University of Illinois

C

yclophosphamide (CTX) is an alkylating agent that is often used by veterinarians for neoplastic and nonneoplastic (autoimmune) diseases in dogs and cats. The systemic anticancer effects of alkylating agents were first identified during World War II.1 Several alkylating agents are used in veterinary medicine today, of which CTX, chlorambucil, and melphalan are the most common.

PHARMACOLOGY Cyclophosphamide acts by dissociating a positively charged, electrophilic alkyl group capable of attacking negatively charged, electron-rich, nucleophilic centers on DNA, protein, and such small molecules as glutathione.2 The most common site of DNA alkylation is the N-7 position of the nucleotide guanine. Alkylating agents are cell-cycle dependent but not cell-cycle phase specific.2 They damage both proliferating and resting cells, but cycling cells are more sensitive than those that are resting.2 CTX is a prodrug that is converted by hepatic microsomal enzymes to 4-hydroxycyclophosphamide (4-HC).2,3

Spontaneous breakdown of 4-HC results in production of phosphoramide mustard and acrolein, both of which damage DNA (Figure 1). The cytotoxic action of CTX is thought to result from phosphoramide mustard– induced DNA crosslinking.3 Acrolein is capable of depleting glutathione.2 DNA alkylation occurs when these CTX metabolites crosslink DNA. The clinical efficacy of CTX in treating immune-mediated hemolytic anemia (IMHA) is based on subjective evaluation. The exact mechanisms by which CTX is immunosuppressive are not completely defined. Leukocyte numbers and antibody production are generally decreased. CTX is considered more effective in treating aberrant humoral immune responses than in suppressing cell-mediated immune responses.4 Antibody production by B lymphocytes is suppressed in a dose- and antigen-specific manner. Because of the cell-cycle phase nonspecific nature of CTX cytotoxicity, CTX is capable of affecting immune response either before or after antigenic challenge.4 Cyclophosphamide can be administered either orally or intravenously

(IV). Metabolism is similar in dogs and humans. Bioavailability is greater than 75% after oral administration. Up to 90% of the parent drug and metabolites are excreted in urine with IV administration. Although elevated plasma levels of CTX have been observed in humans with renal failure, increased toxicity in such patients has not been demonstrated. The plasma half-life of CTX is 2.5 to 5.5 hours.3

INDICATIONS Lymphocytes appear to be highly sensitive to the cytotoxic effect of CTX, and thus CTX is commonly used to treat neoplasms of lymphoid origin (lymphosarcoma). Table One lists the neoplastic and nonneoplastic pathologic conditions for which CTX is recommended and has been administered. In general, IMHA is a regenerative anemia; nonregenerative forms of IMHA or pure red-cell aplasia can also be treated with CTX, but careful monitoring of the thrombon and leukon is required. Because pancytopenia associated with IMHA is usually caused by other myeloid disorders, further marrow suppression by CTX should be avoided. If pancy-

Pharm Profile introduces drugs that are new to the veterinary market as well as new indications for existing drugs. If you would like Pharm Profile to cover a particular agent, please contact column editor GiGi Davidson, BS, RPh, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606; phone 919-821-9500 • fax 919-829-4225 • email [email protected].

Small Animal/Exotics

20TH ANNIVERSARY

CTX

Hepatic activation

4-HC

4-HC reenters the circulation to enter the peripheral and tumor tissues

Phosphoramide mustard

Acrolein

Figure 1—The mechanism of action of cyclophosphamide (CTX). After conversion to 4-hydroxycyclophosphamide (4-HC) in the hepatic cells, CTX reenters the circulation and finally is taken up by the peripheral and tumor tissues, where it decomposes to phosphoramide mustard and acrolein.

topenia is noted, other causes for marrow suppression should be investigated. To the best of our knowledge, no studies strongly suggest that CTX is useful in treating IMHA.

CAUTIONS Because CTX is activated in the liver and is excreted renally, caution should be practiced when using this drug in patients with compromised renal and/or hepatic function. CTX is contraindicated in patients with cystitis, urinary bladder neoplasia, and myelosuppression. TOXICITY Myelosuppression secondary to cytotoxic therapy is almost always reversible with routine medical management. A routine complete blood count should be obtained. Patients with neutrophil counts above 2000 cells/µl are usually afebrile and otherwise asymptomatic. If the segmented neutrophil count is below 1000 to

1500 cells/µl, prophylactic oral antibiotic therapy can be initiated using oral trimethoprim–sulfadiazine (15 mg/ kg twice daily). These patients should be monitored closely for signs of sepsis (e.g., fever, lethargy, anorexia), but life-threatening sepsis rarely occurs with a neutrophil count above 1000 cells/µl. Neutropenia with signs of sepsis must be treated as a medical emergency. Blood and urine cultures should be obtained along with cultures of other probable sites of sepsis that were discovered on careful physical examination. Animals in septic shock should be treated with IV fluid therapy and parenteral combination antibiotic therapy. The clinical management of septic shock is beyond the scope of this column, and readers should seek an appropriate reference for further information. The other most frequent adverse effect associated with CTX therapy in humans is hemorrhagic cystitis, which may progress to bladder fibrosis. Transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, and sarcomas of the urinary bladder have all been associated with chronic CTX therapy in humans.5,6 Hemorrhagic cystitis and transitional cell carcinoma of the urinary bladder secondary to CTX therapy have also been reported in dogs.1,5–9 In one report, the rates of CTX-induced hemorrhagic cystitis were 23.95% and 3.75% in dogs and cats, respectively; female dogs appeared to be at the highest risk (18.75%) and male cats at the least risk (1.25%).7 Hemorrhagic cystitis caused by CTX therapy results from interactions of acrolein in the bladder mucosa. Acrolein causes mucosal ulceration, edema, and necrosis; of the urinary system epithelia, the bladder epithelium is most susceptible to these effects.5,8 Because of the possibility of CTX-induced hemorrhagic cystitis and transitional cell carcinoma in veterinary patients, precautions

Compendium November 1999

should be taken even when CTX is being administered intermittently. Acute development of hemorrhagic cystitis (within 24 hours) has been reported in dogs after IV administration.5 Clinical signs noted with CTX-induced cystitis include macrohematuria, stranguria, and pollakiuria. Several measures can be used to decrease the frequency and severity of CTX-induced cystitis. Concurrent administration of prednisone may decrease the rate of hemorrhagic cystitis because it induces diuresis and inhibits activation of CTX by hepatic microsomal enzymes.6,8,9 Treatment of CTX-induced cystitis should initially include discontinuing the drug and using an alkylating agent (e.g., chlorambucil) instead. When CTX is administered, diuresis should be encouraged. Bactericidal antibiotics should be used in patients with gross hematuria because of the associated compromised bladder mucosa. In most cases, hematuria will resolve after CTX is discontinued. If hematuria persists, such methods as intravesicular instillation of N-acetylcysteine,9 which inactivates acrolein, should be considered. The free-radical scavenger sodium 2mercaptoethane sulfonate (MESNA)3 and prostaglandin E1 (PGE1; which has shown significant protective effects in rats) can also be helpful to treat CTX-induced cystitis.7 Both MESNA and PGE1 are commercially available, but controlled veterinary clinical trials are lacking. Intravesicular administration of 50% dimethyl sulfoxide has been used in humans and dogs to treat CTX-induced cystitis.5,8,9 Other toxicities seen with CTX administration are myelosuppression, gastroenteritis, and delayed wound healing.1,9

DRUG INTERACTIONS The rate of CTX activation from prodrug increases when it is given concurrently with such drugs as barbiturates, which induce microsomal enzyme activity.9 Thus, the dose of CTX

Compendium November 1999

20TH ANNIVERSARY

Small Animal/Exotics

TABLE ONE Clinical Indications for Cyclophosphamide Diseases Neoplastic Lymphosarcoma, lymphocytic leukemia

Dosage

Remarks

50 mg/m2 PO every other day a OR 200 mg/m2 IV once/wka

Schedule depends on the combination chemotherapy regimen used

Acute nonlymphocytic leukemia

100 mg/m2 PO for 4 consecutive daysa

Used in combination with doxorubicin in dogs11

Mast-cell tumor

50 mg/m2 PO on days 3, 4, 5, and 6a,b

Used in combination with doxorubicin and vincristine in dogs and cats

Mammary carcinoma

50 mg/m2 PO on days 3, 4, 5, and 6 a,b

Used in combination with doxorubicin and 5-fluorouracil in dogs

Hemangiosarcoma

100–150 mg/m2 IV on day 1,b 50 mg/m2 PO on days 3, 4, 5, and 6a,b

Used in combination with doxorubicin and vincristine in dogs12,13

Malignant histiocytosis

50 mg/m2 PO every other daya

Used in combination with prednisone and vincristine in dogs14

Lymphomatoid granulomatosis

2 mg/kg PO at 4 days/wka

Used in combination with prednisone and vincristine in dogs15

Tonsillar squamous cell carcinoma

50 mg/m2 PO on days 3, 4, 5, and 6 a,b

Used in combination with doxorubicin in dogs16

Initially at 2 mg/kg/day IV or PO for 4 days, no treatment for 3 days, and then repeat cyclea

Prednisone and other supportive measures (e.g., fluid therapy, blood transfusion) should be used concurrently

Immune-mediated thrombocytopenia

50 mg/m2 PO 3–4 days/wka

May give initial dose IV; after 1–4 wk, taper dose and discontinue if platelet count >100,000/L

Systemic lupus erythematosus

1.5–2.5 mg/kg/day or 50 mg/m2 IV or PO until the disease is controlled OR 2 mg/kg/day IV or PO for 4 days, no treatment for 3 days, until the disease is controlled

CTX should be reserved for acute episodes only; clinicians must try immunosuppression with corticosteroids and azathioprine first17,18

Pemphigus vulgaris

0.45 mg/kg or 50 mg/m2 PO for 4 consecutive days each wk for 14–21 days

Used in combination with prednisone; CTX should not be the first approach— clinicians must try corticosteroids and azathioprine first19

Rheumatoid arthritis

2.5 mg/kg if <10 kg, 2 mg/kg if 10–35 kg, 1.5 mg/kg if >35 kg PO in the morning for 4 consecutive days each wk; discontinue 1 mo after remission

Nonneoplastic Immune-mediated hemolytic anemia

a

Duration of treatment varies. Days refer to days of the combination therapy schedule. CTX = cyclophosphamide; IV = intravenously; PO = orally. b

Small Animal/Exotics

20TH ANNIVERSARY

Client Counseling Information ■ Cyclophosphamide (CTX) is used to treat cancer in dogs and cats. Procedures for proper handling of anticancer drugs must be followed. CTX can be very toxic to humans if improperly handled. Clients handling tablets at home should wear gloves when administering pills as well as when cleaning up any animal waste for 48 hours after the last dose is given. Your veterinarian may also choose to administer the drug intravenously or may recommend that pills be given in a small amount of food. ■ Do not handle CTX if you are pregnant, breast-feeding, or trying to conceive. ■ Because CTX interacts with many drugs, your veterinarian must be informed of all medications your pet is currently taking. ■ CTX suppresses the immune system. If your animal shows any signs of lethargy, fever, or infection, contact your veterinarian immediately. ■ Keep CTX out of the reach of children and other pets. should be tapered in patients being treated concurrently with phenobarbital. Glucocorticoids inhibit activation by hepatic microsomal enzymes, thereby decreasing CTX metabolism.6,9 Review of human medical literature reveals that such drugs as MESNA, other alkylating agents, synthetic prostaglandins, and misonidazole can interact with CTX.10 Caution should also be exercised when using CTX in combination with other myelosuppressive agents to avoid additive marrow toxicity.

DOSAGE AND ADMINISTRATION In canine lymphoma induction protocols, CTX can be administered orally at the dose of 50 mg/m2 every other day or 4 days on/3 days off for 6 to 8 weeks. The same dosage can be used for other neoplastic diseases. It has recently been shown that the current tablet form of CTX is not designed for splitting or crushing. The CTX tablet consists of a core of active ingredient sealed within a compression coating, which does not facilitate even or predictable dose division. When tablets are crushed, the distribution of the active ingredient in the powder may not be uniaPersonal communication: Bambarola F, Bristol-Meyers Squibb, Oncology Products Division, Princeton, NJ, 1995.

form.a When fractions of the 25- or 50-mg tablet are required for the actual calculated dose, the dose can be rounded up or down. We have used doses as high as 65 mg/m2. When using doses higher than 50 mg/m2, we have increased the treatment interval to every 72 hours instead of every other day. We have found this to be well tolerated by most veterinary patients; we have not observed any change in clinical response or remission duration in these patients compared with those that received exactly 25 or 50 mg. Another option for lymphoma induction protocol is to administer CTX at 200 mg/m 2 IV once a week (Table One).

PREPARATIONS Cytoxan® (Bristol-Meyers Squibb, Princeton, NJ) and Neosar® (Pharmacia & Upjohn, Kalamazoo, MI) are supplied as lyophilized CTX in tablet and injectable forms, respectively. Injection should be prepared by adding sterile water to the vial and shaking to dissolve. The quantity of diluent needed varies with the dose strength required (e.g., 5 ml for 100 mg, 10 ml for 200 mg, 20 to 25 ml for 500 mg, 50 ml for 1 g, 80 to 100 ml for 2 g). Cytoxan® is sold in bottles of 100 25-mg tablets and 100 and 1000 50-mg tablets; price per

Compendium November 1999

tablet is $1.69 and $2.79, respectively, for the 25- and 50-mg tablets. Neosar® injectable costs $3.46 per 100 mg. Tablets should not be split or crushed, but an oral solution can be compounded from the injectable form using aromatic elixir as the diluent; at a concentration of 25 mg/ml, this solution is stable for 14 days in the refrigerator.a

STORAGE AND HANDLING Reconstituted lyophilized CTX for injection is clinically and physically stable for 24 hours at room temperature or for 6 days in the refrigerator. Storage below 77˚F (25˚C) is recommended for tablets, with a shelf life of 3 years. REFERENCES 1. Stanton ME, Legendre AM: Effects of cyclophosphamide in dogs and cats. Topics in drug therapy. JAVMA 188:1319–1322, 1986. 2. Berger NA: Alkylating agents: Anticancer drugs, in DeVita VT, Hellman S, Rosenberg SA, et al (eds): Cancer: Principles and Practice of Oncology, ed 4. Philadelphia, JB Lippincott, 1993, pp 400–409. 3. Teicher BA: Antitumor alkylating agents: Pharmacology of cancer chemotherapy, in DeVita VT, Hellman S, Rosenberg SA, et al (eds): Cancer: Principles and Practice of Oncology, ed 5. Philadelphia, JB Lippincott, 1997, pp 405–415. 4. Miller E: The use of cytotoxic agents in the treatment of immune-mediated diseases of dogs and cats. Semin Vet Med Surg (Small Anim) 12:157–160, 1997. 5. Peterson JL, Couto CG, Hammer AS, et al: Acute sterile hemorrhagic cystitis after a single intravenous administration of cyclophosphamide in three dogs. JAVMA 201:1572–1574, 1992. 6. Macy DW, Withrow SJ, Hoopes J: Transitional cell carcinoma of bladder associated with cyclophosphamide administration. JAAHA 19:965–968, 1983. 7. Henness AM: Treatment of cyclophosphamide induced cystitis (Letter). JAVMA 187:4–5, 1985. 8. Laing EJ, Miller CW, Cochrane SM: Treatment of cyclophosphamide induced hemorrhagic cystitis in five dogs. JAVMA 193: 233–236, 1988. 9. Crow SE, Theilen GH, Madewell BR, et al: Cyclophosphamide induced cystitis in the dog and cat. JAVMA 171:259–262, 1977. 10. Connors TA: Alkylating agents, nitro-

Compendium November 1999

11. 12.

13.

14. 15. 16.

17.

20TH ANNIVERSARY

sureas and alkyltriazenes. Cancer Chemotherap Biolog Resp Mod Annu 9:23–35, 1987. Hamlin RH, Duncan RC: Acute nonlymphocytic leukemia in a dog. JAVMA 196:110–112, 1990. Sorenemo KU, Jeglum KA, Helfand SC: Chemotherapy of canine hemangiosarcoma with doxorubicin and cyclophosphamide. J Vet Intern Med 7:370–376, 1993. Hammer AS, Couto CG, Flippi J, et al: Efficacy and toxicity of VAC chemotherapy in dogs with hemangiosarcoma. J Vet Intern Med 5:160–166, 1991. Uno Y, Momoi Y, Watari T, et al: Malignant histiocytosis with multiple skin lesions in a dog. J Vet Med Sci 55:1059–1061, 1993. Postorino NC, Wheeler SL, Park RD, et al: A syndrome resembling lymphomatoid granulomatosis in the dog. J Vet Intern Med 3:15–19, 1989. Brooks MB, Matus RE, Leifer CE, et al: Chemotherapy versus chemotherapy plus radiotherapy in the treatment of tonsillar squamous cell carcinoma in the dog. J Vet Intern Med 2:206–211, 1988. Drazner FH: Systemic lupus erythematosus in the dog. Compend Contin Educ Pract Vet 2(3):243–254, 1980.

Small Animal/Exotics

18. Haliwell REW, Gorman NT: Autoimmune blood diseases, in Haliwell REW, Gorman NT (eds): Veterinary Clinical Immunology. Philadelphia, WB Saunders Co, 1989, pp 308–336. 19. Ackerman LJ: Canine and feline pemphigus and pemphigoid. Part II. Pemphigoid. Compend Contin Educ Pract Vet 7(4):281–286, 1985.

ABOUT THE AUTHORS Dr. Dhaliwal is affiliated with the All Care Animal Referral Center, Fountain Valley, California, and Dr. Kitchell is affiliated with the Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, Illinois. Both authors are Diplomates of the American College of Veterinary Internal Medicine (Dhaliwal, Oncology; Kitchell, Oncology and Internal Medicine).