No

Antineoplastic Agent, Alkylating Agent

Treatment of Hodgkin's and non-Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, chronic granulocytic leukemia, AML, ALL, mycosis fungoides, breast cancer, multiple myeloma, neuroblastoma, retinoblastoma, rhabdomyosarcoma, Ewing's sarcoma; testicular, endometrium and ovarian, and lung cancer, and as a conditioning regimen for BMT; prophylaxis of rejection for kidney, heart, liver, and BMT transplants, severe rheumatoid disorders, nephrotic syndrome, Wegener's granulomatosis, idiopathic pulmonary hemosideroses, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, autoimmune hemolytic anemia, idiopathic thrombocytic purpura, macroglobulinemia, and antibody-induced pure red cell aplasia

D

Hypersensitivity to cyclophosphamide or any component

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Possible dosage adjustment needed for renal or hepatic failure; use with caution in patients with bone marrow suppression.

>10%:

Dermatologic: Alopecia is frequent, but hair will regrow although it may be of a different color or texture; alopecia usually occurs 3 weeks after therapy

Endocrine & metabolic: Fertility: May cause sterility; interferes with oogenesis and spermatogenesis; may be irreversible in some patients; gonadal suppression (amenorrhea)

Gastrointestinal: Nausea and vomiting occur more frequently with larger doses, usually beginning 6-10 hours after administration; also seen are anorexia, diarrhea, stomatitis; mucositis

Emetic potential:

Oral: Low (<10%)

<1 g: Moderate (30% to 60%)

greater than or equal to 1 g: High (>90%)

Time course of nausea/vomiting: Onset: 6-8 hours; Duration: 8-24 hours

Hepatic: Jaundice seen occasionally

1% to 10%:

Central nervous system: Headache

Dermatologic: Skin rash, facial flushing

Hematologic: Myelosuppressive: Thrombocytopenia occurs less frequently than with mechlorethamine, anemia

WBC: Moderate

Platelets: Moderate

Onset (days): 7

Nadir (days): 10-14

Recovery (days): 21

<1%: High-dose therapy may cause cardiac dysfunction manifested as congestive heart failure; cardiac necrosis or hemorrhagic myocarditis has occurred rarely, but is fatal. Cyclophosphamide may also potentiate the cardiac toxicity of anthracyclines.

Dizziness, darkening of skin/fingernails, hyperglycemia, hypokalemia, distortion, hyperuricemia, SIADH has occurred with I.V. doses >50 mg/kg, stomatitis, acute hemorrhagic cystitis is believed to be a result of chemical irritation of the bladder by acrolein, a cyclophosphamide metabolite. Acute hemorrhagic cystitis occurs in 7% to 12% of patients, and has been reported in up to 40% of patients. Hemorrhagic cystitis can be severe and even fatal. Patients should be encouraged to drink plenty of fluids (3-4 L/day) during therapy, void frequently, and avoid taking the drug at nighttime. If large I.V. doses are being administered, I.V. hydration should be given during therapy. The administration of mesna or continuous bladder irrigation may also be warranted.

Hepatic toxicity, renal tubular necrosis has occurred, but usually resolves after the discontinuation of therapy, nasal congestion occurs when given in large I.V. doses via 30-60 minute infusion; patients experience runny eyes, nasal burning, rhinorrhea, sinus congestion, and sneezing during or immediately after the infusion; interstitial pulmonary fibrosis with prolonged high dosage has occurred; secondary malignancy has developed with cyclophosphamide alone or in combination with other antineoplastics; both bladder carcinoma and acute leukemia are well documented; rare instances of anaphylaxis have been reported

Symptoms of overdose include myelosuppression, alopecia, nausea, vomiting

Treatment is supportive; cyclophosphamide is moderately dialyzable (20% to 50%)

CYP2B6, 2D6, and 3A3/4 enzyme substrate

Increased toxicity:

Allopurinol may cause increase in bone marrow depression and may result in significant elevations of cyclophosphamide cytotoxic metabolites

Anesthetic agents: Cyclophosphamide reduces serum pseudocholinesterase concentrations and may prolong the neuromuscular blocking activity of succinylcholine; use with caution with halothane, nitrous oxide, and succinylcholine

Chloramphenicol results in prolonged cyclophosphamide half-life to increase toxicity

Cimetidine inhibits hepatic metabolism of drugs and may decrease or increase the activation of cyclophosphamide

Doxorubicin: Cyclophosphamide may enhance cardiac toxicity of anthracyclines

Phenobarbital and phenytoin induce hepatic enzymes and cause a more rapid production of cyclophosphamide metabolites with a concurrent decrease in the serum half-life of the parent compound

Tetrahydrocannabinol results in enhanced immunosuppression in animal studies

Thiazide diuretics: Leukopenia may be prolonged

Store intact vials of powder at room temperature (25°C to 35°C)

Reconstitute vials with SWI to a concentration of 20 mg/mL as follows below; reconstituted solutions are stable for 24 hours at room temperature (25°C) and 6 days at refrigeration (5°C)

100 mg vial = 5 mL

200 mg vial = 10 mL

500 mg vial = 25 mL

1 g vial = 50 mL

2 g vial = 100 mL

Further dilutions in D₅W or NS are stable for 48 hours at room temperature (25°C) and 28 days at refrigeration (5°C)

Maximum concentration of cyclophosphamide is limited to 20 mg/mL due to solubility of cyclophosphamide

Standard I.V. push dilution: Dose up to 500 mg/30 mL syringe

Maximum syringe size for IVP is a 30 mL syringe syringe should be less than or equal to 75% full

Standard IVPB dilution:

May further dilute in D₅W or NS after initial reconstitution with SWI

Doses up to 2 g/250 mL volume

Doses up to 4 g/500 mL volume

Interferes with the normal function of DNA by alkylation and cross-linking the strands of DNA, and by possible protein modification; cyclophosphamide also possesses potent immunosuppressive activity; note that cyclophosphamide must be metabolized to its active form in the liver

Absorption: Completely from the GI tract (>75%)

Distribution: V_d: 0.48-0.71 L/kg; well distributed; crosses the placenta; appears in breast milk; does cross into the CSF, but not in concentrations high enough to treat meningeal leukemia

Protein binding: 10% to 56%

Metabolism: In the liver into its active components, one of which is 4-HC

Bioavailability: >75%

Half-life: 4-6.5 hours

Time to peak serum concentration: Oral: Within 1 hour

Elimination: In the urine as unchanged drug (<10%) and as metabolites (85% to 90%); most of which are inactive

Refer to individual protocols

Children:

SLE: I.V.: 500-750 mg/m² every month; maximum dose: 1 g/m²

JRA/vasculitis: I.V.: 10 mg/kg every 2 weeks

Children and Adults:

Oral: 50-100 mg/m²/day as continuous therapy or 400-1000 mg/m² in divided doses over 4-5 days as intermittent therapy

I.V.:

Single Doses: 400-1800 mg/m² (30-50 mg/kg) per treatment course (1-5 days) which can be repeated at 2-4 week intervals

MAXIMUM SINGLE DOSE WITHOUT BMT is 7 g/m² (190 mg/kg) SINGLE AGENT THERAPY

Continuous daily doses: 60-120 mg/m² (1-2.5 mg/kg) per day

Autologous BMT: IVPB: 50 mg/kg/dose x 4 days or 60 mg/kg/dose for 2 days; total dose is usually divided over 2-4 days

Nephrotic syndrome: Oral: 2-3 mg/kg/day every day for up to 12 weeks when corticosteroids are unsuccessful

Dosing adjustment in renal impairment: A large fraction of cyclophosphamide is eliminated by hepatic metabolism

Some authors recommend no dose adjustment unless severe renal insufficiency (Cl_cr <20 mL/minute)

Cl_cr >10 mL/minute: Administer 100% of normal dose

Cl_cr <10 mL/minute: Administer 75% of normal dose

Hemodialysis: Moderately dialyzable (20% to 50%); administer dose posthemodialysis or administer supplemental 50% dose

CAPD effects: Unknown

CAVH effects: Unknown

Dosing adjustment in hepatic impairment: Some authors recommend dosage reductions (of up to 30%); however, the pharmacokinetics of cyclophosphamide are not significantly altered in the presence of hepatic insufficiency. Cyclophosphamide undergoes hepatic transformation in the liver to its 4-hydroxycyclophosphamide, which breaks down to its active form, phosphoramide mustard.

Tablets should be administered during or after meals

CBC with differential and platelet count, BUN, UA, serum electrolytes, serum creatinine

May cause dizziness

May cause myelosuppression; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

Tablets may be taken during or after meals to reduce GI effects. Maintain adequate fluid balance (2-3 L/day of fluids unless instructed to restrict fluid intake). Void frequently and report any difficulty or pain with urination. May cause hair loss (reversible after treatment) or sterility or amenorrhea (sometimes reversible). If you are diabetic, you will need to monitor serum glucose closely to avoid hypoglycemia. You may be more susceptible to infection; avoid crowds and unnecessary exposure to infection. Report unusual bleeding or bruising; persistent fever or sore throat; blood in urine, stool (black stool), or vomitus; delayed healing of any wounds; skin rash; yellowing of skin or eyes; or changes in color of urine or stool. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during or for 1 month following therapy. Male: Do not cause a female to become pregnant. Male/female: Consult prescriber for instruction on appropriate barrier contraceptive measures. This drug may cause severe fetal defects. Do not breast-feed.

Encourage adequate hydration and frequent voiding to help prevent hemorrhagic cystitis

Powder for injection: 100 mg, 200 mg, 500 mg, 1 g, 2 g

Powder for injection, lyophilized: 100 mg, 200 mg, 500 mg, 1 g, 2 g

Tablet: 25 mg, 50 mg

A 2 mg/mL oral elixir was stable for 14 days when refrigerated when made as follows:

Keep in refrigerator (Store in amber glass)

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