Cyclophosphamide
cyclophosphamide (formerly Cytoxan)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Malignant lymphomas (Hodgkin’s, NHL, Burkitt’s) | Adults & paediatrics | Mono or combination chemo | FDA Approved |
| Leukaemias (CLL, CML, AML, ALL) | Adults & paediatrics | Combination chemo | FDA Approved |
| Multiple myeloma | Adults | Combination chemo | FDA Approved |
| Breast, ovarian carcinoma; neuroblastoma; retinoblastoma; mycosis fungoides | Adults (& paediatrics where applicable) | Combination chemo | FDA Approved |
| Minimal change nephrotic syndrome (steroid-resistant/intolerant) | Paediatrics only | Oral monotherapy | FDA Approved |
Cyclophosphamide was first approved in 1959 and remains one of the most important cytotoxic immunosuppressants in medicine. While FDA-approved exclusively for malignancies and paediatric nephrotic syndrome, cyclophosphamide is extensively used off-label for severe autoimmune diseases, particularly lupus nephritis and ANCA-associated vasculitis, where it has been a cornerstone of treatment for decades. Notably, the FDA PI explicitly states that safety and effectiveness for nephrotic syndrome in adults or other renal disease has not been established.
Lupus nephritis (Class III/IV): First-line induction option, either as Euro-Lupus low-dose IV protocol or NIH high-dose IV protocol. Recommended by 2024 ACR, 2023 EULAR, and KDIGO 2024 guidelines alongside MMF. Evidence quality: High.
ANCA-associated vasculitis (GPA/MPA) — induction: Standard induction alongside rituximab. CYCLOPS trial established pulse IV dosing. Evidence quality: High.
Systemic sclerosis (diffuse cutaneous, ILD): Used for severe skin disease and interstitial lung disease. Evidence quality: Moderate.
Severe SLE (non-renal): Reserved for organ-threatening manifestations (cerebritis, pneumonitis, severe cytopenias). Evidence quality: Moderate.
Interstitial lung disease (CTD-ILD): Used across connective tissue diseases for progressive ILD. Evidence quality: Moderate.
Cyclophosphamide Dosing
Off-Label: Autoimmune Dosing (Primary Clinical Use)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Lupus nephritis — Euro-Lupus low-dose IV | 500 mg IV q2wk × 6 doses | Switch to MMF for maintenance | 3 g total course | Fixed dose, no weight adjustment Euro-Lupus Nephritis Trial (ELNT); now preferred by most guidelines due to equivalent efficacy and lower toxicity |
| Lupus nephritis — NIH high-dose IV | 0.5–1 g/m² IV monthly × 6 | Then q3mo × 6–8 doses or switch to MMF | 1 g/m²/dose | Adjust for WBC nadir (target nadir >2,500/mm³) Historical NIH protocol; higher gonadotoxicity than Euro-Lupus |
| ANCA vasculitis — pulse IV (CYCLOPS) | 15 mg/kg IV q2wk × 3, then q3wk | Until remission (typically 3–6 mo), then switch to AZA or rituximab | 1.2 g/dose | Reduce for age >60 and renal impairment CYCLOPS: pulse IV non-inferior to daily oral with less cumulative exposure |
| ANCA vasculitis — daily oral | 2 mg/kg/day PO | Continue until remission (3–6 mo), then switch to maintenance | 200 mg/day | Higher cumulative dose and bladder toxicity risk Reduce to 1.5 mg/kg/day if age >60 or CrCl <30 |
| Systemic sclerosis (ILD/skin) | 500–750 mg/m² IV monthly | 6–12 monthly pulses | 1 g/m²/dose | Scleroderma Lung Study I protocol Now often replaced by MMF (SLS II showed equivalent efficacy) |
FDA-Approved: Oncology Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Malignancy — IV monotherapy | 40–50 mg/kg IV over 2–5 days | Regimen-dependent | Regimen-dependent | Alternative: 10–15 mg/kg q7–10d or 3–5 mg/kg twice weekly Adjust for myelosuppression per protocol |
| Malignancy — oral | 1–5 mg/kg/day PO | 1–5 mg/kg/day PO | Regimen-dependent | For initial and maintenance dosing Administer in the morning with aggressive hydration |
| Paediatric nephrotic syndrome (steroid-resistant) | 2 mg/kg PO daily × 8–12 weeks | N/A — limited course | 168 mg/kg cumulative | Treatment >90 days increases male sterility risk Biopsy-proven minimal change disease only |
Cyclophosphamide should be given in the morning with aggressive hydration (at least 2–3 L fluid intake over 24 hours) and frequent voiding to minimise bladder exposure to acrolein. For IV pulses ≥1 g, consider IV mesna (2-mercaptoethane sulfonate sodium) to bind acrolein in the urinary tract and prevent hemorrhagic cystitis. Antiemetic prophylaxis is typically required (5-HT3 antagonist ± dexamethasone). Monitor the white blood cell count 10–14 days post-pulse to assess nadir; target nadir WBC >2,500–3,000/mm³. If WBC drops below this, reduce the next dose by 25%. Peripheral blood counts typically normalise by day 20.
Pharmacology
Mechanism of Action
Cyclophosphamide is an inactive prodrug that requires hepatic bioactivation. The cytochrome P450 system (primarily CYP2B6 and CYP3A4, with contributions from CYP2C9, CYP2C19, and CYP2A6) hydroxylates cyclophosphamide to 4-hydroxycyclophosphamide, which exists in equilibrium with its ring-open tautomer aldophosphamide. Aldophosphamide spontaneously decomposes into two active species: phosphoramide mustard (the principal DNA cross-linking alkylating agent) and acrolein (responsible for urotoxicity). Phosphoramide mustard forms irreversible interstrand and intrastrand DNA cross-links at guanine N-7 positions, leading to cell cycle arrest and apoptosis. The selectivity of cyclophosphamide for tumour cells and activated lymphocytes partly reflects the low aldehyde dehydrogenase (ALDH) activity in these cells; ALDH-rich tissues (bone marrow stem cells, liver, intestinal epithelium) detoxify aldophosphamide to the inactive carboxyphosphamide metabolite, conferring relative protection. At immunosuppressive doses used in autoimmune disease, cyclophosphamide preferentially depletes B lymphocytes and suppresses both cellular and humoral immune responses.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral bioavailability >75% (some studies report 89–96%); near-complete absorption; Tmax ~1–2 h (oral) | Oral and IV doses are clinically interchangeable at standard immunosuppressive doses; oral absorbed rapidly in the morning with hydration |
| Distribution | Vd = 30–50 L; parent drug ~20% protein-bound; active metabolites >60% protein-bound; crosses placenta; present in breast milk | Moderate volume of distribution; low parent binding means dialysis can remove parent drug but not the highly bound active metabolites |
| Metabolism | Prodrug activated by hepatic CYP2B6, 3A4, 2C9, 2C19, 2A6 → 4-OH-CPA ↔ aldophosphamide → phosphoramide mustard + acrolein; ALDH detoxifies to carboxyphosphamide; auto-induction of CYP metabolism with repeated dosing | CYP inducers (rifampin, phenytoin, barbiturates) may increase activation and toxicity; CYP inhibitors may reduce activation and efficacy. Auto-induction causes shortened t½ and faster clearance with repeated doses |
| Elimination | t½ = 3–12 h; primarily excreted as metabolites; 10–20% unchanged in urine; WBC nadir at weeks 1–2, recovery by day ~20; dialysable | Morning administration with forced diuresis reduces acrolein contact time with bladder. Renal impairment (CrCl <25) increases AUC by ~77% — monitor for toxicity. Auto-induction means clearance increases with repeated dosing |
Side Effects
The PI does not provide incidence rates from controlled trials in the standard table format because cyclophosphamide was approved in 1959 under earlier FDA standards. Instead, adverse reactions are reported from clinical experience and postmarketing surveillance. The profile below reflects well-established toxicities from decades of clinical use.
| Adverse Effect | Estimated Incidence | Clinical Note |
|---|---|---|
| Nausea & vomiting | 30–90% (dose-dependent) | Highly emetogenic at oncologic doses; moderate at autoimmune doses; 5-HT3 antagonist prophylaxis recommended |
| Alopecia | Very common | Usually reversible weeks to months after discontinuation; texture may change on regrowth |
| Myelosuppression (leukopenia/neutropenia) | Very common (expected) | Dose-limiting toxicity; nadir at weeks 1–2, recovery by day ~20. Do not administer if ANC ≤1,500 or platelets <50,000 |
| Infections | Common | Secondary to immunosuppression; bacterial, viral, fungal, protozoal including reactivation of latent infections |
| Amenorrhea / oligomenorrhea | Common (dose- and age-dependent) | Risk of premature ovarian failure increases with age >30 and cumulative dose; gonadal preservation counselling essential |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hemorrhagic cystitis | 5–40% (without prophylaxis; lower with mesna/hydration) | Hours to months after exposure | Morning dosing + aggressive hydration + frequent voiding; IV mesna for high-dose pulses; check urine for RBCs regularly; discontinue if severe |
| Gonadal toxicity (infertility) | Dose- and age-dependent; may be irreversible | During and after treatment | Discuss fertility preservation before starting (oocyte/sperm cryopreservation, GnRH agonists). Male: azoospermia risk increases with cumulative dose >7.5 g/m²; treatment >90 days in paediatrics increases sterility risk. Female: higher risk if age >30 |
| Secondary malignancies (bladder cancer, MDS, leukaemia) | Cumulative dose-dependent; bladder cancer risk estimated 5% at 10 years with chronic oral dosing | Years to decades | Minimise cumulative exposure; prefer pulse IV over chronic oral; lifelong haematuria surveillance for chronic oral users |
| Cardiotoxicity (myocarditis, heart failure, arrhythmia) | Rare at standard autoimmune doses; higher risk at oncologic/transplant doses (>150 mg/kg over 4 days) | Days to weeks after high-dose therapy | Cardiac monitoring in patients with risk factors; avoid in decompensated heart failure; risk increased by prior cardiac irradiation |
| Pulmonary toxicity (pneumonitis, fibrosis) | Rare; late-onset (>6 mo) associated with higher mortality | Weeks to years | Monitor for dyspnoea and cough; chest imaging if symptomatic; may develop years after treatment |
| Veno-occlusive liver disease (VOD) | Rare at immunosuppressive doses; risk increased with TBI or busulfan in transplant conditioning | Weeks | Monitor LFTs; can be fatal; greatest risk in myeloablative conditioning |
| Hyponatraemia (SIADH-like syndrome) | Uncommon | Hours to days after high-dose IV | Monitor sodium with high-dose IV; forced hydration can worsen; fluid restrict if symptomatic |
| Severe bone marrow failure | Rare at immunosuppressive doses | Weeks | CBC monitoring essential; G-CSF may be used for neutropenia prophylaxis in high-risk patients |
Acrolein, a toxic by-product of cyclophosphamide metabolism, causes direct urothelial damage. Prevention is essential: (1) administer cyclophosphamide in the morning, (2) ensure ≥2–3 L oral/IV fluid intake over 24 hours, (3) encourage frequent voiding (every 2–3 hours including before bed), (4) for IV pulses ≥1 g, administer IV mesna at 60–80% of the cyclophosphamide dose, divided into bolus at time 0 and repeat doses at 4 and 8 hours post-infusion. Check urinalysis for microscopic haematuria before each cycle. Discontinue cyclophosphamide if gross haematuria develops. The risk of bladder cancer is cumulative and particularly associated with chronic daily oral use.
Drug Interactions
Cyclophosphamide’s interaction profile is driven by its dependence on CYP-mediated hepatic activation. Drugs that induce CYP enzymes may increase formation of active (and toxic) metabolites, while CYP inhibitors may reduce activation and efficacy. Additionally, cyclophosphamide inhibits cholinesterase and interacts with depolarising muscle relaxants.
Monitoring
- CBC with differentialBefore each pulse; day 10–14 for nadir check; then q2–4wk
RoutineMost critical parameter. Do not administer if ANC ≤1,500 or platelets <50,000. WBC nadir weeks 1–2, recovery by day ~20. Adjust next dose if nadir WBC <2,500–3,000. - UrinalysisBefore each dose; periodically during treatment
RoutineCheck for microscopic haematuria (RBCs). If positive, evaluate for hemorrhagic cystitis. Discontinue if gross haematuria. Chronic oral users require lifelong bladder surveillance post-treatment. - Renal functionBaseline, before each pulse
RoutineCrCl <25 increases AUC by ~77%. Adjust dose in renal impairment. Drug is dialysable. - Pregnancy testBefore initiation
RoutineTeratogenic. Effective contraception required: females for up to 1 year post-treatment, males for 4 months post-treatment. - Fertility counsellingBefore first dose
RoutineDiscuss oocyte/sperm cryopreservation. Consider GnRH agonist co-administration in pre-menopausal women. Treatment >90 days (oral) increases male sterility risk. - Hepatic functionBaseline, periodically
Trigger-basedSevere hepatic impairment reduces activation (decreased efficacy). Monitor for VOD (hepatomegaly, ascites, weight gain, bilirubin rise), especially in myeloablative conditioning. - Serum sodiumDuring high-dose IV therapy
Trigger-basedSIADH-like hyponatraemia can occur; paradox of forced hydration worsening water retention. Monitor and restrict fluids if symptomatic.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to cyclophosphamide, its metabolites, or product components. Cross-sensitivity with other alkylating agents can occur. Anaphylaxis including death has been reported.
- Urinary outflow obstruction: Must be excluded or corrected before starting treatment (risk of acrolein accumulation and severe urotoxicity).
Relative Contraindications (Specialist Input Recommended)
- Severe bone marrow depression: Do not administer if ANC ≤1,500/mm³ or platelets <50,000/mm³.
- Active serious infection: Treatment may need to be interrupted or dose reduced.
- Pregnancy: Teratogenic in humans and all animal species tested. Malformations of skeleton, palate, limbs, and eyes reported. Contraception required for females (1 year post-therapy) and males (4 months post-therapy).
Use with Caution
- Active urinary tract infection or haematuria: Increases risk of urotoxicity complications.
- Renal impairment (CrCl 10–50): Increased plasma levels of cyclophosphamide and metabolites; monitor for toxicity.
- Hepatic impairment: Severe hepatic impairment may reduce conversion to active metabolites, decreasing efficacy.
- Pre-existing cardiac disease or prior cardiac irradiation: Cardiotoxicity risk increases.
- Elderly (≥65): Start at lower end of dosing range; greater frequency of decreased organ function.
- Surgery within 10 days: Cyclophosphamide inhibits cholinesterase; alert anaesthesiologist regarding risk of prolonged succinylcholine-induced apnoea.
While cyclophosphamide does not carry a formal boxed warning in the current PI, it has multiple serious safety warnings covering: myelosuppression and fatal infections; hemorrhagic cystitis and bladder cancer; cardiotoxicity (potentially fatal); pulmonary toxicity and fibrosis; secondary malignancies; veno-occlusive liver disease; embryofetal toxicity; and infertility. These risks require careful patient selection, thorough pre-treatment counselling, aggressive supportive care, and close monitoring throughout treatment.
Patient Counselling
Purpose of Therapy
Cyclophosphamide is a powerful medicine that suppresses the overactive immune system in conditions like lupus nephritis or vasculitis, or is used to treat certain cancers. Depending on your condition, it may be given as intravenous infusions (usually once every 2 weeks or monthly for a limited number of doses) or as daily capsules. While effective, it requires careful monitoring and specific protective measures to prevent side effects.
How to Take
For oral dosing, take capsules in the morning with a large glass of water. Do not crush or open capsules. Drink at least 2–3 litres of fluid throughout the day and empty your bladder frequently, including just before bed. For IV infusions, you will receive fluids and sometimes a bladder-protective medication (mesna) during your treatment session. Anti-nausea medication will be provided.
Sources
- Baxter Healthcare Corporation. Cyclophosphamide for injection prescribing information. Revised September 2024. FDA LabelPrimary source for FDA-approved dosing, warnings, contraindications, adverse reactions, and pharmacokinetics.
- Houssiau FA, Vasconcelos C, D’Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46(8):2121-2131. doi:10.1002/art.10461Established that low-dose IV CYC (500 mg q2wk x 6) is as effective as high-dose NIH protocol for LN induction with fewer side effects.
- Houssiau FA, Vasconcelos C, D’Cruz D, et al. The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis. 2010;69(1):61-64. doi:10.1136/ard.2008.10253310-year follow-up confirming sustained non-inferiority of Euro-Lupus low-dose protocol with better safety profile.
- de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial (CYCLOPS). Ann Intern Med. 2009;150(10):670-680. doi:10.7326/0003-4819-150-10-200905190-00004CYCLOPS trial: pulse IV cyclophosphamide non-inferior to daily oral for ANCA vasculitis remission induction with lower cumulative dose and fewer leukopenic episodes.
- Austin HA 3rd, Klippel JH, Balow JE, et al. Therapy of lupus nephritis: controlled trial of prednisone and cytotoxic drugs. N Engl J Med. 1986;314(10):614-619. doi:10.1056/NEJM198603063141004Landmark NIH trial establishing IV cyclophosphamide superiority over prednisone alone for preventing renal failure in LN.
- Sammaritano LR, Askanase A, Bermas BL, et al. 2024 American College of Rheumatology (ACR) guideline for the screening, treatment, and management of lupus nephritis. Arthritis Rheumatol. 2025;77(9):1115-1135. doi:10.1002/art.432122024 ACR LN guideline: recommends Euro-Lupus CYC + belimumab as one of three triple therapy options for Class III/IV LN.
- Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2024;83(1):15-29. doi:10.1136/ard-2023-224762EULAR guideline supporting Euro-Lupus low-dose CYC as an alternative to MMF for LN induction.
- Kidney Disease: Improving Global Outcomes (KDIGO) Lupus Nephritis Work Group. KDIGO 2024 clinical practice guideline for the management of lupus nephritis. Kidney Int. 2024;105(1S):S1-S69. doi:10.1016/j.kint.2023.09.002KDIGO guideline positioning low-dose CYC as an alternative initial therapy option for Class III/IV LN.
- Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009;6(11):638-647. doi:10.1038/nrclinonc.2009.146Comprehensive review of cyclophosphamide metabolism (CYP activation, ALDH detoxification), mechanism of DNA cross-linking, and clinical pharmacology.
- Moore MJ. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet. 1991;20(3):194-208. doi:10.2165/00003088-199120030-00002Definitive PK review: t½ 3–12 h, bioavailability >75%, auto-induction of metabolism, and hepatic/renal impairment effects.
- Teles KA, Medeiros-Souza P, Lima FAC, Araújo BG, Lima RAC. Cyclophosphamide administration routine in autoimmune rheumatic diseases: a review. Rev Bras Reumatol Engl Ed. 2017;57(6):596-604. doi:10.1016/j.rbre.2016.09.008Practical review covering autoimmune dosing protocols (Euro-Lupus, NIH, CYCLOPS), mesna use, hydration strategies, and fertility preservation.