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CYTOXAN®
Bristol
Cyclophosphamide
Antineoplastic Agent
 
Action And Clinical Pharmacology: Cyclophosphamide is activated by metabolism in the liver by the mixed-function oxidase system of the smooth endoplasmic reticulum. The hepatic cytochrome P-450 mixed-function converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in a steady state with the acyclic tautomer, aldophosphamide. The drug and its metabolites are distributed throughout the body including the brain.

Cyclophosphamide, which is biologically relatively inactive, is eliminated from the body very slowly. The activated metabolites alkylate the target sites in susceptible cells in an all-or-none type of reaction or are detoxicated by formation of inactive metabolites that are rapidly excreted by the kidneys.

Cyclophosphamide is absorbed from the gastrointestinal tract and from parenteral sites. It appears to be absorbed also when it is supplied topically to neoplastic tissues, situated on the surface of the body.

Cyclophosphamide is metabolized in the body initially by the mixed function oxidase enzymes of the liver microsomes; several toxic metabolites have been identified.

There is much more variability in the rate of metabolism of cyclophosphamide among different human subjects than there is in non-human species. The plasma half-life of the unchanged drug is apparently independent of age, nationality, sensitivity or resistance to the drug, diagnosis, or dosage. In patients who had received no drug therapy known to affect microsomal metabolic rates, the apparent average half-life of unchanged cyclophosphamide was between 5.0 and 6.5 hours after i.v. administration of C14-labeled cyclophosphamide.

Peak plasma concentrations of metabolites have been found to be almost proportional to the administered dose, but relatively wide individual variations have been reported. Peak plasma alkylating metabolite levels generally are reached at 2 to 3 hours after administration of the drug.

The average plasma alkylating metabolite concentration at 8 hours after i.v. administration of the drug was about 77% of the peak level when studied in 12 patients without prior drug exposure.

Cyclophosphamide does not bind to human plasma proteins in appreciable amounts, but with single i.v. doses about 12 to 14% of the total dose was bound to plasma proteins at plasma cyclophosphamide concentrations of 10 and 200 mµ moles/mL. Repeated doses increased the amount bound to plasma proteins. Following 5 doses of 40 mg/kg, about 56% of the dose was bound.

The tissue distribution of cyclophosphamide has been examined in cancer patients following i.v. administration. It was found that both unchanged drug and metabolites pass the blood-brain barrier. Cerebral tissue contained drug levels in a concentration range similar to that found in blood.

Biopsies performed 2 hours after administration of the drug revealed that about 30% more drug was present in lymph nodes than in muscle, adipose tissue, or skin, but the relative proportion of unchanged drug metabolites was not established.

In experimental animals, cyclophosphamide inhibits immune phenomena, inflammatory processes, delayed hypersensitivity reactions, experimental allergic inflammatory disease, and body defenses to infectious microorganisms. Although immuno- suppressive and anti inflammatory actions for cyclophosphamide have not been demonstrated conclusively in humans, they may be associated with the therapeutic use of the drug.

In man, a generally higher proportion of the administered dose is excreted in the urine as metabolites. Recovery of radioactivity after i.v. administered labeled cyclophosphamide ranged from 37% to 82%, with 20% to 45% of that recovered attributable to the unchanged drug. The total urinary excretion of unchanged cyclophosphamide ranged from 3% to 30% of the dose with most cases in the upper half of the range.

Indications And Clinical Uses: A. Frequently responsive myeloproliferative and lymphoproliferative disorders: malignant lymphomas Stages II to IV: Hodgkin's disease, mixed-cell type lymphoma, lymphocytic lymphoma, histiocytic lymphoma, lymphoblastic lymphosarcoma, Burkitt's lymphoma; multiple myeloma; leukemias: chronic lymphocytic leukemia, chronic granulocytic leukemia (it is ineffective in acute blastic crises), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia in children (cyclophosphamide given during remission is effective in prolonging its duration); mycosis fungoides (advanced disease). B. Frequently responsive solid malignancies: neuroblastoma (in patients with disseminated disease), adenocarcinoma of the ovary, retinoblastoma. C. Infrequently responsive malignancies: carcinoma of the breast, malignant neoplasms of the lung.

Contra-Indications: Sensitivity to cyclophosphamide or to any components of its dosage forms, severe leukopenia, thrombocytopenia, hepatic or renal dysfunction. tag_WarningWarnings

Manufacturers' Warnings In Clinical States: Caution: Cyclophosphamide is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs (see Precautions). In those patients who develop bacterial, fungal, or viral infections, modification of dosage should be considered. Blood counts should be taken at regular intervals.

Since cyclophosphamide is an inhibitor of serum cholinesterase, patients receiving the drug may exhibit an increased sensitivity to neuromuscular blocking agents such as succinylcholine. If a patient receiving cyclophosphamide is to undergo surgery, advise the anesthesiologist.

The rate of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic administration of high doses of phenobarbital. The physician should be alert for possible combined drug actions, desirable or undesirable, involving cyclophosphamide even though cyclophosphamide has been used successfully concurrently with other drugs, including other cytotoxic drugs.

Cyclophosphamide has been reported to have oncogenic activity in rats and mice. The possibility that it may have oncogenic potential in man should be considered. Cyclophosphamide may interfere with normal wound healing.

Pregnancy: Cyclophosphamide can be teratogenic or cause fetal resorption in experimental animals. It should not be used in pregnancy, particularly in early pregnancy, unless the potential benefits outweigh the possible risks. Cyclophosphamide is excreted in breast milk and breast-feeding should be terminated prior to institution of cyclophosphamide therapy.

Patients, male or female, capable of conception, ordinarily should be advised of the mutagenic potential of cyclophosphamide. Adequate methods of contraception appear desirable for such patients receiving cyclophosphamide.

Since cyclophosphamide has been reported to be more toxic in adrenalectomized dogs, adjustment of the dose of both replacement steroids and cyclophosphamide may be necessary for the adrenalectomized patient.

Precautions: Administer cautiously to patients with any of the following conditions: leukopenia, thrombocytopenia, tumor cell infiltration of bone marrow, previous x-ray therapy, previous therapy with other cytotoxic agents, impaired hepatic or renal function.

Because cyclophosphamide may exert a suppressive action in immune mechanisms, consider the interruption or modification of dosage for patients who develop bacterial, fungal or viral infections. This is especially true for patients receiving concomitant steroid therapy and perhaps those with a recent history of steroid therapy, since infections in some of these patients have been fatal. Varicella- zoster infections appear to be particularly dangerous under these circumstances.

It is recommended that patients being considered as candidates for long-term therapy have their renal function monitored prior to treatment. Urine should also be examined regularly for red cells which may precede hemorrhagic cystitis.

Adverse Reactions: Hematopoietic: Leukopenia is an expected effect and ordinarily is used as a guide to therapy. Thrombocytopenia or anemia may occur in a few patients. These effects are almost always reversible when therapy is interrupted.

Gastrointestinal: Anorexia, nausea, or vomiting are common and related to dose as well as individual susceptibility. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy.

Genitourinary: Sterile hemorrhagic cystitis can result from cyclophosphamide administration. This can be severe, even fatal, and is probably due to metabolites in the urine. Nonhemorrhagic cystitis and/or bladder fibrosis also have been reported to result from cyclophosphamide administration. Atypical epithelial cells may be found in the urinary sediment. Ample fluid intake and frequent voiding help to prevent the development of cystitis, but when it occurs it is ordinarily necessary to interrupt cyclophosphamide therapy. Hematuria usually resolves spontaneously within a few days after cyclophosphamide therapy is discontinued, but may persist for several months. In severe cases, replacement of blood loss may be required. Electrocautery to telangiectatic areas of the bladder and diversion of urine flow has been successfully used in treatment of protracted cases. Cryosurgery has also been used. Nephrotoxicity, including hemorrhage and clot formation in the renal pelvis, has been reported. Hemorrhagic ureteritis and tubular necrosis have been reported in patients treated with cyclophosphamide.

Girls treated with cyclophosphamide during prepubescence generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged cyclophosphamide treatment in late prepubescence has been reported. Girls treated with cyclophosphamide during prepubescence subsequently have conceived.

Men treated with cyclophosphamide may develop oligospermia or azoospermia associated with increased gonadotropin but normal testosterone secretion. Sexual potency and libido are unimpaired in these patients. Boys treated with cyclophosphamide during prepubescence develop secondary sexual characteristics normally but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Men temporarily rendered sterile by cyclophosphamide have subsequently fathered normal children.

Integument: It is ordinarily advisable to inform patients in advance of possible alopecia, a frequent complication of cyclophosphamide therapy. Regrowth of hair can be expected although occasionally the new hair may be of a different color or texture. The skin and fingernails may become darker during therapy. Nonspecific dermatitis has been reported to occur with cyclophosphamide.

Pulmonary: Interstitial pulmonary fibrosis has been reported in patients receiving high doses of cyclophosphamide over a prolonged period. There have been reported cases of cyclophosphamide-induced pneumonitis which may continue for one or more months after discontinuation of therapy.

Cardiac Toxicity: Cardiotoxicity has been observed in some patients receiving high doses of cyclophosphamide ranging from 120 to 270 mg/kg administered over a period of a few days, usually as a portion of an intensive antineoplastic multi-drug regimen or in conjunction with transplantation procedures. In a few instances with high doses of cyclophosphamide, severe and sometimes fatal, congestive heart failure has occurred within a few days after the first cyclophosphamide dose. Histopathologic examination has primarily shown hemorrhagic myocarditis.

No residual cardiac abnormalities as evidenced by electrocardiogram or echocardiogram appear to be present in patients surviving episodes of apparent cardiac toxicity associated with high doses of cyclophosphamide.

Cyclophosphamide has been reported to potentiate doxorubicin-induced cardiotoxicity.

Carcinogenesis: Second malignancies have developed in some patients treated with cyclophosphamide used alone or in association with other antineoplastic drugs and/or modalities. Most frequently, they have been urinary bladder, myeloproliferative or lymphoproliferative malignancies. Second malignancies most frequently observed were detected in patients treated for primary myeloproliferative or lymphoproliferative malignancies or nonmalignant disease in which immune processes are believed to be involved pathologically. In some cases, the second malignancy developed several years after cyclophosphamide treatment had been discontinued. Urinary bladder malignancies generally have occurred in patients who previously had hemorrhagic cystitis. One case of carcinoma of the renal pelvis was reported in a patient receiving long-term cyclophosphamide therapy for cerebral vasculitis. The possibility of cyclophosphamide-induced malignancy should be considered in any benefit-to-risk assessment for use of the drug.

Adverse reactions in addition to those mentioned have been noted with cyclophosphamide: They include headache, dizziness, hypoprothrombinemia and diabetes mellitus. Also, the possibility of anaphylactic reaction to cyclophosphamide should not be excluded.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No specific antidote. Institute general supportive measures to sustain the patient through any period of toxicity that might occur.

Concurrent administration of the uroprotective agent Mesna will aid largely in the prevention of bladder toxicity.

Dosage And Administration: Chemotherapy with cyclophosphamide, as with other drugs used in cancer chemotherapy, is potentially hazardous and fatal complications can occur. Only physicians aware of the associated risks should administer cyclophosphamide. Therapy may be aimed at either induction or maintenance of remission.

Induction Therapy: The usual initial loading dose for patients with no hematologic deficiency is 40 to 50 mg/kg, usually given i.v. This can be given at the rate of 10 to 20 mg/kg/day for 2 to 5 days depending on patient tolerance.

Patients with any previous treatment that may have compromised the functional capacity of the bone marrow, such as x-ray or cytotoxic drugs, and patients with tumor infiltration of the bone marrow may require reduction of the initial loading dose by one-third to one-half.

A marked leukopenia is usually associated with the above doses, but recovery usually begins after 7 to 10 days. Monitor the white blood cell count closely during induction therapy.

If initial therapy is given orally, a dose of 1 to 5 mg/kg/day can be administered depending on patient tolerance.

Maintenance Therapy: It is frequently necessary to maintain chemotherapy in order to suppress or retard neoplastic growth. A variety of schedules has been used: (1) 1 to 5 mg/kg orally, daily; (2) 10 to 15 mg/kg i.v., every 7 to 10 days; (3) 3 to 5 mg/kg i.v., twice weekly.

Unless the disease is unusually sensitive to cyclophosphamide, the patient should be given the largest maintenance dose that can be reasonably tolerated. The total leukocyte count is a good objective guide for regulating the maintenance dose. Ordinarily, a leukocyte count of 3 000 to 4 000 cells/mmcan be maintained without undue risk of serious infection or other complications.

Preparation and Handling of Solutions: Prepare Cytoxan for Injection for parenteral use by adding Sterile Water for Injection USP or Bacteriostatic Water for Injection USP (paraben preserved only) to the vial and shaking to dissolve to produce a clear colorless solution. Heating should not be used to facilitate dissolution.

Solutions of Cytoxan for Injection may be injected i.v., i.m., intraperitoneally or intrapleurally or they may be infused i.v. in Dextrose Injection USP (5% Dextrose, 5% Dextrose and 0.9% Sodium Chloride) Dextrose 5% and Ringers Injection, Lactated Ringers Injection USP, Sodium Chloride Injection USP (0.45% sodium chloride) and Sodium Lactate Injection USP (1/6 molar sodium lactate). Reconstituted Cytoxan for Injection is chemically and physically stable at room temperature for 24 hours and for 6 days in the refrigerator. For solutions further diluted for i.v. infusion, it is recommended that the solutions be used within 24 hours at room temperature or 72 hours under refrigeration. Solutions prepared with Sterile Water for Injection should be used for single dose administration and any unused solution discarded.

As with all parenteral drug products, i.v. drug admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit.

Extemporaneous liquid preparations of Cytoxan for oral administration may be prepared by dissolving Cytoxan for Injection in Aromatic Elixir USP. Store such preparations under refrigeration and use within 14 days.

Handling and Disposal: Preparation of cyclophosphamide should be done in a vertical laminar flow hood (Biological Safety Cabinet - Class II). Personnel preparing cyclophosphamide should wear PVC gloves, safety glasses, disposable gowns and masks. All needles, syringes, vials and other materials which have come in contact with cyclophosphamide should be segregated and incinerated at 1 000°C or more. Sealed containers may explode. Intact vials should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport. Personnel regularly involved in the preparation and handling of cyclophosphamide should have biannual blood examinations.

Availability And Storage: Injection: Each lyophilized vial contains: cyclophosphamide USP 1 000 or 2 000 mg. Nonmedicinal ingredients: mannitol. Cartons of 6.

Tablets: 25 mg: Each white tablet with blue specks contains: cyclophosphamide USP 25 mg. Nonmedicinal ingredients: acacia, cornstarch, D&C yellow No. 10, FD&C blue No. 1, lactose, magnesium stearate, stearic acid and talc. Energy: 4.2 kJ (1 kcal). Bottles of 100.

50 mg: Each white tablet with blue specks contains: cyclophosphamide USP 50 mg. Nonmedicinal ingredients: acacia, cornstarch, D&C yellow No. 10, FD&C blue No. 1, lactose, magnesium stearate, stearic acid and talc. Energy: 8.4 kJ (2 kcal). Bottles of 100. (Shown in Product Recognition Section)