Action And Clinical Pharmacology: Although it is classified generally as an alkylating agent, cyclophosphamide itself is not an alkylating agent. It appears to be inactive in vitro when tested on cultures of human leukocytes or carcinomatous cells of human origin. It appears active metabolites of the drug exhibit the alkylating action.
Cyclophosphamide’s metabolism is initiated by the mixed function oxidase enzymes of the liver microsomes, which produce several metabolites the principal active one being 4-hydroxycyclophosphamide. Because of their highly polar nature and lability during isolation procedures, their identification has been difficult and the knowledge of cyclophosphamide’s metabolic pathway is still incomplete. It appears that the metabolite 4-hydroxycyclophosphamide, is in equilibrium with its acyclic tautomeric form, aldophosphamide which when further oxidized, results in the known metabolite: carboxyphosphamide. Aldophosphamide to a lesser extent is metabolized to phosphoramide mustard and acrolein, both highly cytotoxic, and which might be the active metabolites of cyclophosphamide.
The rate of cyclophosphamide’s metabolism is much more variable among humans, than in other species. The plasma half-life of the unchanged drug does not appear to be influenced by: age, race, degree of sensitivity to the drug, condition treated or dosage.
Plasma cyclophosphamide half-life in patients without prior drug exposure has been found to be 6.5 hr., after i.v. administration. A maximum of 20% of injected cyclophosphamide was excreted intact in the urine, irrespective of the dose used. 68% of the injected drug was excreted in the urine when administered for 5 successive days; its half-life was shorter and peak alkylating concentrations were constantly higher on the fifth day than on the first day.
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 millimicron 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 proportions of unchanged drug metabolites were 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 immunosuppressive 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 humans, cyclophosphamide is absorbed from the gastrointestinal tract and from parenteral sites. It appears to be absorbed also when it is applied topically to neoplastic tissues situated on the body surface.
In humans, a generally higher proportion of the administered dose is excreted in the urine as metabolites. Recovery after i.v. administered 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 administered dose.
Indications And Clinical Uses: A. Frequently responsive myeloproliferative and lymphoproliferative disorders: malignant lymphomas (Stages III and IV, Peter’s Staging System) – Hodgkin’s disease, follicular lymphoma, lymphocytic lymphosarcoma, reticulum cell sarcoma, 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: Cyclophosphamide is a potent drug and should be used only by physicians experienced with cancer-chemotherapeutic drugs (see Precautions). Periodic monitoring of peripheral blood should be done. Renal function must be conducted prior to and during therapy.
The rate of metabolism of cyclophosphamide reportedly is 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.
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. To avoid the risk of prolonged apnea, the dose of succinylcholine should be reduced when administered concomitantly with cyclophosphamide.
Cyclophosphamide has been reported to have oncogenic activity in rats and mice. The possibility that it may have oncogenic potential in humans should be considered. Cyclophosphamide may interfere with normal wound healing.
Pregnancy and Lactation: 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.
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 on 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. Since cyclophosphamide has been reported to be more toxic in adrenalectomized dogs, adjustment of the doses of both replacement steroids and cyclophosphamide may be necessary for the adrenalectomized patient.
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.
Gonadal suppression, resulting in amenorrhea or azoospermia, has been reported and appears to be related to dosage and duration of therapy. This side effect, possibly irreversible, should be anticipated in patients treated with cyclophosphamide. It is not known to what extent cyclophosphamide may affect prepuberal gonads. Ovarian fibrosis following cyclophosphamide therapy has been reported also.
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.
Miscellaneous: headache, dizziness, hypoprothrombinemia, diabetes mellitus, hyponatremia.
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. tag_DosageDosage
Dosage And Administration: Chemotherapy with cyclophosphamide, as with other drugs used in cancer chemotherapy, is potentially hazardous and fatal complications can occur.
Cyclophosphamide should be administered only by physicians aware of the associated risks. 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 administered i.v. This dose can be given at the rate of 10 to 20 mg/kg/day for 2 to 5 days according to the patient’s tolerance. In patients having received other treatments (radiation therapy, other cytotoxic drugs) which might affect the functional capacity of the bone marrow or in patients with bone marrow neoplastic infiltration, the initial loading dose should be reduced by 30 to 50%.
The above mentioned doses are usually followed by a marked leukopenia. Recovery begins usually after 7 to 10 days. The white blood cell count should be monitored carefully during induction therapy.
If the treatment is started orally, a dose of 1 to 5 mg/kg/day should be administered, according to the patient’s tolerance.
Maintenance therapy: The initial chemotherapeutic effect must be maintained in order to obtain suppression, reduction or retardation of neoplastic growths.
Various maintenance therapy schedules have been used: orally: 1 to 5 mg/kg daily; i.v.: 10 to 15 mg/kg, repeated every 7 to 10 days; i.v.: 3 to 5 mg/kg, twice a week.
It is advisable to give the largest maintenance dose that can be tolerated by the patient. The total WBC count should be used as an objective indication to determine the maintenance dose. Usually, a leukopenia of 3 000 to 4 000 cells/mmis relatively safe to avoid serious infections or other complications.
Cyclophosphamide should be administered in the morning and followed by a fluid intake of 2 000 to 3 000 mL to ensure the prompt excretion of the active metabolites. The bladder must be emptied frequently to avoid the development of a cyclophosphamide cystitis.
Preparation and Handling of Solutions: As with most anti-neoplastic agents, care should be exercised in the preparation of solutions. Protective wear – i.e., gloves (unpowdered surgical latex gloves), safety glasses, disposable gown and mask – is recommended, as is the use of a vertical laminar flow hood (Biological Safety Cabinet – Class II), when possible. Personnel regularly handling these agents should have biannual blood examinations.
After use, all disposable materials which have come into contact with the agent should be segregated and incinerated at above 1 000°C.
Prepare Procytox solutions for parenteral use by adding Sterile Water for Injection, USP, or Bacteriostatic Water for Injection, USP (paraben or benzyl alcohol preserved) to the vial and shaking until dissolution. pH: 5.1 to 5.9. Extreme caution should be exercised with solutions containing benzyl alcohol in very young children. Use of sterile water for injection is recommended.
Heating should not be used to facilitate dissolution.
Procytox solutions may be injected i.v., i.m., intraperitoneally or intrapleurally or they may be infused i.v. in Dextrose Injection USP (5% dextrose and 0.9% sodium chloride).
Solutions prepared with Bacteriostatic Water for Injection may be stored under refrigeration (4°C) if used within 6 days. Use solutions prepared with Sterile Water for Injection for single dose administration and discard any unused solution.
Extemporaneous liquid preparations of Procytox for oral administration may be prepared by dissolving Procytox for Injection in Aromatic Elixir USP. These solutions when kept under refrigeration (4°C) should be used within 14 days.
Availability And Storage: Injection: Each vial contains: cyclophosphamide 200, 500,1 000 or 2 000 mg. Nonmedicinal ingredients: sodium chloride. Gluten-, lactose- and tartrazine-free. Single vials and boxes of 10.
Tablets: 25 mg: Each white, coated, deeply convex and round tablet contains: cyclophosphamide 25 mg. Nonmedicinal ingredients: calcium carbonate, calcium phosphate, cellulose, gelatin, glycerin, lactose, magnesium stearate, polyethylene glycol, polysorbate, povidone, silicon dioxide, starch (corn), sucrose, talc, titanium dioxide and wax. Energy: 2.1 kJ (0.5 kcal). Gluten-, sodium- and tartrazine-free. Bottles of 100.
50 mg: Each white, coated, deeply convex and round tablet contains: cyclophosphamide 50 mg. Nonmedicinal ingredients: calcium carbonate, calcium phosphate, cellulose, gelatin, glycerin, lactose, magnesium stearate, polyethylene glycol, polysorbate, povidone, silicon dioxide, starch (corn), sucrose, talc, titanium dioxide and wax. Energy: 2.1 kJ (0.5 kcal). Gluten-, sodium- and tartrazine-free. Bottles of 30, 100 and 1 000.
Store injectables (before reconstitution) and tablets at room temperature; injectables after reconstitution must be refrigerated. (Shown in Product Recognition Section)
PROCYTOX® Carter Horner Cyclophosphamide Antineoplastic