Introduction
Cyclophosphamide is a nitrogen mustard alkylating agent and immunosuppressive medication that has been a cornerstone of cancer chemotherapy and immunosuppressive therapy since its approval in 1959. As a prodrug requiring hepatic activation, cyclophosphamide belongs to the oxazaphosphorine class of chemotherapeutic agents and represents one of the most widely used cytotoxic drugs in clinical practice.
Mechanism of Action
Cyclophosphamide is a prodrug that undergoes hepatic metabolism via cytochrome P450 enzymes (primarily CYP2B6, CYP2C9, and CYP3A4) to form active metabolites, primarily phosphoramide mustard and acrolein. The active metabolite phosphoramide mustard forms covalent cross-links between DNA strands, primarily at the N-7 position of guanine, resulting in DNA alkylation. This interferes with DNA replication and transcription, ultimately leading to cell death, particularly in rapidly dividing cells.
The immunosuppressive effects occur through inhibition of both humoral and cellular immunity by reducing B and T lymphocyte proliferation and function.
Indications
FDA-Approved Indications:- Various malignant conditions including:
- Hodgkin's and non-Hodgkin's lymphoma - Multiple myeloma - Leukemias (chronic lymphocytic leukemia, acute lymphoblastic leukemia) - Mycosis fungoides - Neuroblastoma - Ovarian adenocarcinoma - Retinoblastoma - Breast carcinoma
- Severe rheumatologic conditions including:
- Systemic lupus erythematosus - Rheumatoid arthritis - Systemic vasculitis - Severe progressive rheumatoid arthritis unresponsive to conventional therapy
Off-label Uses:- Nephrotic syndrome
- Multiple sclerosis
- Aplastic anemia
- Solid organ transplantation rejection prophylaxis
- Various autoimmune disorders
Dosage and Administration
Oncologic Dosing:- Initial dose: 40-50 mg/kg IV in divided doses over 2-5 days
- Maintenance: 1-5 mg/kg orally daily or 10-15 mg/kg IV every 7-10 days
- High-dose therapy: 60 mg/kg IV daily for 2 days (with stem cell support)
- 500-1000 mg/m² IV monthly
- 1-2 mg/kg orally daily
- IV formulation: Reconstitute with sterile water or bacteriostatic water
- Administer IV over 30-60 minutes with adequate hydration
- Oral formulation: Administer on empty stomach to reduce nausea
- Renal impairment: Reduce dose by 25-50% for CrCl < 25 mL/min
- Hepatic impairment: Use with caution, consider dose reduction
- Elderly: Start at lower end of dosing range
- Pediatrics: Dose based on body surface area
Pharmacokinetics
Absorption: Oral bioavailability approximately 75% (range 60-90%) Distribution: Widely distributed throughout body tissues, Vd: 0.78 L/kg; crosses blood-brain barrier poorly Metabolism: Extensive hepatic metabolism via CYP450 system to active and inactive metabolites Elimination: Renal excretion (5-25% unchanged, remainder as metabolites); half-life: 3-12 hours Protein binding: <20%Contraindications
- Hypersensitivity to cyclophosphamide or any component of formulation
- Severe bone marrow suppression
- Active infections
- Pregnancy (Category D)
- Patients with urinary outflow obstruction
Warnings and Precautions
Black Box Warnings:- Severe bone marrow suppression
- Increased risk of malignancies with long-term therapy
- Severe immunosuppression leading to serious infections
- Infertility in both males and females
- Hemorrhagic cystitis and bladder fibrosis (require vigorous hydration and mesna protection)
- Cardiotoxicity (especially with high doses)
- Pulmonary toxicity including pneumonitis and pulmonary fibrosis
- Secondary malignancies including bladder cancer and acute myeloid leukemia
- Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
- Impaired wound healing
- Vaccination with live vaccines contraindicated during therapy
Drug Interactions
Major Interactions:- Allopurinol: Increased risk of bone marrow suppression
- CYP450 inducers (phenobarbital, rifampin): Increased activation to toxic metabolites
- CYP450 inhibitors (cimetidine, azole antifungals): Decreased efficacy
- Succinylcholine: Prolonged neuromuscular blockade
- Cardiotoxic drugs (anthracyclines): Increased cardiotoxicity risk
- Nephrotoxic drugs: Increased renal toxicity risk
- Live vaccines: Risk of vaccine-induced infection
Adverse Effects
Common (>10%):- Myelosuppression (leukopenia, thrombocytopenia, anemia)
- Nausea and vomiting (70-90%)
- Alopecia (50-90%)
- Anorexia
- Diarrhea
- Amenorrhea
- Sterility
- Hemorrhagic cystitis (5-40%)
- Secondary malignancies (5-17% with long-term use)
- Severe infections due to immunosuppression
- Cardiotoxicity (heart failure, pericarditis)
- Pulmonary fibrosis
- Hepatic veno-occlusive disease
- Anaphylaxis
- SIADH and hyponatremia
Monitoring Parameters
Baseline:- Complete blood count with differential
- Renal function (BUN, creatinine)
- Hepatic function (LFTs)
- Urinalysis
- Pregnancy test in women of childbearing potential
- Cardiac function assessment if high-dose therapy planned
- CBC weekly or more frequently during therapy
- Renal and hepatic function regularly
- Urinalysis for hematuria regularly
- Fluid balance and hydration status
- Signs of infection
- Pulmonary symptoms
- Cardiac monitoring with high doses
- Annual urinalysis and cytology for bladder cancer screening
- Regular cancer screening
- Fertility assessment if appropriate
Patient Education
Key Points to Discuss:- Importance of adequate hydration (2-3 L daily) to prevent bladder toxicity
- Signs of infection (fever, chills, sore throat) requiring immediate medical attention
- Nausea management strategies and antiemetic use
- Hair loss expectations and management options
- Contraception requirements during and after treatment (both genders)
- Infertility risks and fertility preservation options
- Avoidance of crowds and sick individuals
- Importance of not receiving live vaccines
- Signs of bleeding or bruising
- Urinary symptoms (hematuria, dysuria) requiring immediate attention
- Follow-up care and monitoring requirements
- Take oral dose on empty stomach if nausea occurs
- Maintain good oral hygiene to prevent mucositis
- Use sunscreen due to photosensitivity
- Report any new or worsening symptoms promptly
- Keep all follow-up appointments for monitoring
References
1. National Cancer Institute. Cyclophosphamide Monograph. Accessed 2023. 2. American Society of Health-System Pharmacists. AHFS Drug Information. 2023. 3. Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009;6(11):638-647. 4. Takamoto S, et al. Cyclophosphamide metabolism, pharmacokinetics, and pharmacodynamics in patients with lupus nephritis. Clin Pharmacol Ther. 2021;109(5):1294-1304. 5. FDA Prescribing Information: Cyclophosphamide. 2022. 6. Lexicomp Online. Cyclophosphamide Drug Monograph. Wolters Kluwer Clinical Drug Information. 2023. 7. American College of Rheumatology Guidelines for Cyclophosphamide Use in Rheumatic Diseases. 2020. 8. NCCN Guidelines: Hematopoietic Growth Factors. Version 2.2023. 9. McEvoy GK, ed. Cyclophosphamide. In: AHFS Drug Information. American Society of Health-System Pharmacists; 2023. 10. Flaggerty CM, et al. Management of cyclophosphamide-induced hemorrhagic cystitis. J Oncol Pharm Pract. 2019;25(5):1223-1230.
This monograph is intended for educational purposes only and should not replace clinical judgment. Always consult current prescribing information and clinical guidelines for specific patient care decisions.