Cyclophosphamide

Medicines used to treat cancer can have a number of side-effects, some of which can be delayed for several days or weeks after taking the medicine. Most chemotherapy medicines can lower the number of white cells in your blood, which increases the risk of you getting an infection. While you are taking cyclophosphamide you should take precautions to reduce the risk of getting an infection - you can do this by avoiding being with people who you know have an infection. If you think you are getting a sore throat or if you have a high temperature, please let your doctor know as soon as possible so that you can get some treatment straightaway.

Your doctor will discuss with you the possibility of unwanted side-effects from your treatment with cyclophosphamide, although not everyone experiences these. The table below contains some of the side-effects associated with cyclophosphamide. You will find a full list in the manufacturer's information leaflet supplied with your medicine. Please let your doctor know if you experience any of the following:

If you experience any other symptoms which you think may be due to cyclophosphamide, please speak with your doctor or pharmacist for further advice.

GENERIC AVAILABLE: Yes

Side effects of cyclophosphamide include:

• Hair loss
• Nausea
• Vomiting
• Diarrhea
• Mouth sores
• Weight loss
• Stomach pain
• Rash
• Mouth sores (stomatitis)
• Skin pigmentation
• Nail changes
• Sterility
• Jaundice

Cyclophosphamide causes kidney failure, and it also may affect the heart and lungs. Cyclophosphamide suppresses production of blood cells from the bone marrow, including white blood cells (leukopenia), red blood cells (anemia) and platelets (thrombocytopenia). Leukopenia reduces the ability of the body to fight infection, thrombocytopenia impairs the ability of blood to clot, and anemia reduces the ability of blood to carry oxygen. Cyclophosphamide suppresses the immune system which may result in serious and sometimes fatal infections. Severe allergic reactions also may occur. Cyclophosphamide may cause inflammation of the urinary bladder with bleeding (hemorrhagic cystitis). This can result in lower abdominal pain from the bladder, problems urinating due to blood clots, and anemia due to loss of blood.

Only an appropriately trained health care professional can administer cyclosphosphamide, since it's injected into your veins.

Your doctor will determine how much cyclophosphamide you should receive based on your weight and the condition for which you are being treated.

Cyclophosphamide Overdose

Because cyclophosphamide can only be administered in a hospital or clinical setting, you shouldn’t have to worry about overdosing.

However, if you think you have been given too much cyclophosphamide, contact an emergency room at 911 or a poison control center at (800) 222-1222 right away.

Missed Dose of Cyclophosphamide

Because cyclophosphamide can only be administered in a hospital or clinical setting, you should be given the drug as scheduled.

However, contact your doctor immediately if you miss your appointment.

Before receiving cyclophosphamide, tell your doctor about all of your medical conditions including if you:

• have low levels of white blood cells (a condition known as neutropenia)
• have low levels of platelets (thrombocytopenia)
• have bone marrow tumors
• have previously been treated with other chemotherapy medicines or x-ray therapy
• have liver or kidney disease
• are allergic to cyclophosphamide or any other medication
• have an infection or have recently been vaccinated
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

• Store tablets at or below 77°F (25°C).
• Store capsules at 20°C to 25°C (68°F to 77°F).
• Keep this and all medicines out of the reach of children.
• Keep all doctor and laboratory appointments.

Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve cross-linking of tumor cell DNA.

Cyclophosphamide is well absorbed after oral administration with a bioavailability greater than 75%. The unchanged drug has an elimination half-life of 3 to 12 hours. It is eliminated primarily in the form of metabolites, but from 5% to 25% of the dose is excreted in urine as unchanged drug. Several cytotoxic and noncytotoxic metabolites have been identified in urine and in plasma. Concentrations of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous dose. Plasma protein binding of unchanged drug is low but some metabolites are bound to an extent greater than 60%. It has not been demonstrated that any single metabolite is responsible for either the therapeutic or toxic effects of Cyclophosphamide. Although elevated levels of metabolites of Cyclophosphamide have been observed in patients with renal failure, increased clinical toxicity in such patients has not been demonstrated.

General

Special attention to the possible development of toxicity should be exercised in patients being treated with Cyclophosphamide if any of the following conditions are present:

Laboratory Tests

During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression. Urine should also be examined regularly for red cells which may precede hemorrhagic cystitis.

Drug Interactions

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 treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of succinylcholine chloride.

If a patient has been treated with Cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.

Adrenalectomy

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.

Wound Healing

Cyclophosphamide may interfere with normal wound healing.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

See WARNINGS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.

Pregnancy

See WARNINGS.

Nursing Mothers

Cyclophosphamide is excreted in breast milk. Because of the potential for serious adverse reactions and the potential for tumorigenicity shown for Cyclophosphamide in humans, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety profile of Cyclophosphamide in pediatric patients is similar to that of the adult population (see ADVERSE REACTIONS).

Geriatric Use

Insufficient data from clinical studies of cyclophospamide for malignant lymphoma, multiple myeloma, leukemia, mycosis fungoides, neuroblastoma, retinoblastoma, and breast carcinoma are available for patients 65 years of age and older to determine whether they respond differently than younger patients. In two clinical trials in which Cyclophosphamide was compared with paclitaxel, each in combination with cisplatin, for the treatment of advanced ovarian carcinoma, 154 (28%) of 552 patients who received Cyclophosphamide plus cisplatin were 65 years or older. Subset analyses (<65 versus >65 years) from these trials, published reports of clinical trials of Cyclophosphamide-containing regimens in breast cancer and non-Hodgkin’s lymphoma, and postmarketing experience suggest that elderly patients may be more susceptible to Cyclophosphamide toxicities. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and adjusting as necessary based on patient response (see DOSAGE AND ADMINISTRATION: Treatment of Malignant Diseases).

Treatment of Malignant Diseases

Oral Cyclophosphamide dosing is usually in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Many other regimens of intravenous and oral Cyclophosphamide have been reported. Dosages must be adjusted in accord with evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage. Transient decreases in the total white blood cell count to 2000 cells/mm3 (following short courses) or more persistent reduction to 3000 cells/mm3 (with continuing therapy) are tolerated without serious risk of infection if there is no marked granulocytopenia.

When Cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of Cyclophosphamide, as well as that of the other drugs.

Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. Patients with compromised renal function may show some measurable changes in pharmacokinetic parameters of Cyclophosphamide metabolism, but there is no consistent evidence indicating a need for Cyclophosphamide dosage modification in patients with renal function impairment.

Treatment of Nonmalignant Diseases

An oral dose of 2.5 to 3 mg/kg daily for a period of 60 to 90 days is recommended. In males, the incidence of oligospermia and azoospermia increases if the duration of Cyclophosphamide treatment exceeds 60 days. Treatment beyond 90 days increases the probability of sterility. Adrenocorticosteroid therapy may be tapered and discontinued during the course of Cyclophosphamide therapy (see PRECAUTIONS: Laboratory Tests).

Preparation and Handling of Solutions

Extemporaneous liquid preparations of Cyclophosphamide for oral administration may be prepared by dissolving Cyclophosphamide for injection in Aromatic Elixir, N.F. Such preparations should be stored under refrigeration in glass containers and used within 14 days.

• Antineoplastic Agent, Alkylating Agent
• Antineoplastic Agent, Alkylating Agent (Nitrogen Mustard)
• Antirheumatic Miscellaneous
• Immunosuppressant Agent

US labeling: Hypersensitivity to cyclophosphamide or any component of the formulation; urinary outflow obstruction

Canadian labeling: Hypersensitivity to cyclophosphamide or its metabolites, urinary outflow obstructions, severe myelosuppression, severe renal or hepatic impairment, active infection (especially varicella zoster), severe immunosuppression

Refer to adult dosing; adjust for renal clearance.

There are no dosage adjustments provided in the manufacturer’s labeling (use with caution; elevated levels of metabolites may occur).

The following adjustments have also been recommended:

Aronoff 2007: Children and Adults:

Clcr ≥10 mL/minute: No dosage adjustment required.

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

Hemodialysis: Moderately dialyzable (20% to 50%); administer 50% of normal dose; administer after hemodialysis

Continuous ambulatory peritoneal dialysis (CAPD): Administer 75% of normal dose.

Continuous renal replacement therapy (CRRT): Administer 100% of normal dose.

Janus 2010: Hemodialysis: Administer 75% of normal dose; administer after hemodialysis

Hematopoietic stem cell transplantation (Bodge 2014):

Moderate impairment: No dosage adjustment necessary.

Moderate to severe impairment: Consider dosage reduction.

Hemodialysis: Administer after hemodialysis. Cyclophosphamide is 20% to 50% dialyzed.

International Myeloma Working Group (IMWG) Recommendations: The International Myeloma Working Group (IMWG) recommendations suggest that cyclophosphamide may be administered without dosage adjustment in multiple myeloma patients with renal impairment, including those on dialysis. The IMWG recommends the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (preferred) or the Modification of Diet in Renal Disease (MDRD) formula to evaluate renal function estimation in multiple myeloma patients with a stable serum creatinine (Dimopoulos 2016).

Cyclophosphamide is associated with a moderate to high emetic potential (depending on dose, regimen, or administration route); antiemetics are recommended to prevent nausea and vomiting (Basch 2011; Dupuis 2011; Roila 2016).

IV: Infusion rate may vary based on protocol (refer to specific protocol for infusion rate). Administer by direct IV injection (if reconstituted in NS), IVPB, or continuous IV infusion

Bladder toxicity: To minimize bladder toxicity, increase normal fluid intake during and for 1 to 2 days after cyclophosphamide dose. Most adult patients will require a fluid intake of at least 2 L/day. High-dose regimens should be accompanied by vigorous hydration with or without mesna therapy. Morning administration may be preferred to ensure adequate hydration throughout the day.

Hematopoietic stem cell transplant: Approaches to reduction of hemorrhagic cystitis include infusion of 0.9% NaCl 3 L/m2/24 hours, infusion of 0.9% NaCl 3 L/m2/24 hours with continuous 0.9% NaCl bladder irrigation 300 to 1000 mL/hour, and infusion of 0.9% NaCl 1.5 to 3 L/m2/24 hours with intravenous mesna. Hydration should begin at least 4 hours before cyclophosphamide and continue at least 24 hours after completion of cyclophosphamide. The daily mesna dose (as a percentage of cyclophosphamide dose) may vary; refer to protocol and/or primary literature for mesna dose. Mesna can be administered as a continuous 24-hour intravenous infusion or be given in divided doses every 4 hours. Mesna should begin at the start of treatment, and continue at least 24 hours following the last dose of cyclophosphamide.

Oral: Tablets are not scored and should not be cut, chewed, or crushed. Swallow capsules whole; do not open, crush, or chew. To minimize bladder toxicity, increase normal fluid intake. Morning administration may be preferred to ensure adequate hydration throughout the day; do not administer tablets/capsules at bedtime. Avoid exposure to broken capsules; if contact occurs, wash hands immediately and thoroughly.

CBC with differential and platelets, BUN, UA, serum electrolytes, serum creatinine; monitor for signs/symptoms of hemorrhagic cystitis or other urinary/renal toxicity, pulmonary, cardiac, and/or hepatic toxicity