Cycloph

Approved Indications:

Oncology:

• Breast Cancer (early-stage and metastatic)
• Non-Hodgkin’s Lymphoma (NHL)
• Hodgkin’s Lymphoma
• Chronic Lymphocytic Leukemia (CLL)
• Acute Lymphoblastic Leukemia (ALL)
• Multiple Myeloma
• Ovarian Carcinoma
• Neuroblastoma
• Retinoblastoma
• Sarcomas (e.g., Ewing’s sarcoma, osteosarcoma)
• Small Cell Lung Cancer (SCLC) – as part of combination regimens

Immunosuppression/Autoimmune Disorders:

• Severe Rheumatoid Arthritis (refractory cases)
• Systemic Lupus Erythematosus (SLE) – especially lupus nephritis
• Wegener’s Granulomatosis / Granulomatosis with Polyangiitis (GPA)
• Microscopic Polyangiitis (MPA)
• Nephrotic Syndrome (steroid-resistant cases)
• Multiple Sclerosis (MS) – off-label, in refractory progressive disease

Bone Marrow Transplantation:

• High-dose conditioning regimens prior to hematopoietic stem cell transplantation (HSCT)

Routes of Administration: Oral and Intravenous (IV)

Oncologic Dosing (Adults):

• Oral:
  1–5 mg/kg/day in divided doses, depending on protocol
• IV:
  40–50 mg/kg IV as a single dose or
  10–15 mg/kg IV daily for 2–5 days every 3–4 weeks
  or
  500–1,000 mg/m² IV every 3 weeks in combination regimens (e.g., CHOP, CMF)

Non-Oncologic/Immunosuppressive Dosing:

• SLE Nephritis:
  500–1,000 mg/m² IV monthly for 6 months (NIH protocol), then quarterly
• Rheumatoid Arthritis or GPA/MPA:
  500 mg IV every 2 weeks × 3 doses, then every 3 weeks (EULAR protocol)
  or
  1.5–2 mg/kg/day orally for 8–12 weeks, then taper

Pediatrics:

• Dosing is weight- or BSA-based
  (e.g., 2.5–5 mg/kg/day orally for immunosuppression or 750 mg/m² IV every 3 weeks for malignancy)

Elderly:

• Use with caution; start at lower dose due to reduced renal clearance and bone marrow reserve

Renal Impairment:

• CrCl 10–50 mL/min: Reduce dose by 25%
• CrCl <10 mL/min: Reduce dose by 50%
• Hemodialysis: Administer after dialysis; may require supplemental dosing

Hepatic Impairment:

• No standard adjustment; monitor closely in moderate-to-severe hepatic dysfunction

Administration Notes:

• Always administer with adequate hydration and MESNA when used at high doses to prevent hemorrhagic cystitis
• Antiemetics recommended for nausea prevention

Cyclophosphamide is a prodrug that is metabolized in the liver to active metabolites, including phosphoramide mustard and acrolein. These active compounds form DNA crosslinks at the guanine N7 position, preventing DNA replication and RNA transcription, ultimately leading to cell apoptosis. The drug is non-cell cycle-specific, affecting both resting and dividing cells, but is particularly cytotoxic to rapidly dividing cancer or immune cells. Its immunosuppressive action results from lymphocyte depletion, particularly B-cells.

• Absorption (oral): Rapid and complete; bioavailability ~75–90%
• Distribution: Widely distributed; crosses blood-brain barrier and placenta
• Protein Binding: ~20%
• Metabolism: Hepatic via CYP2B6, CYP3A4, and CYP2C9 to active metabolites
• Active Metabolites: Phosphoramide mustard (cytotoxic) and acrolein (urotoxic)
• Elimination: Renal (60–70% within 48 hours, mainly as inactive metabolites)
• Half-life: Parent compound ~3–12 hours; active metabolites ~8–16 hours

• Pregnancy:
  Category D (positive evidence of human fetal risk); may cause fetal malformations, miscarriage, and myelosuppression. Use only if benefits clearly outweigh risks.
• Lactation:
  Contraindicated. Cyclophosphamide is excreted into breast milk and may cause neutropenia, thrombocytopenia, and immune suppression in infants.
• Recommendation:
  Avoid use in pregnancy unless in life-threatening situations. Discontinue breastfeeding during and for at least 7 days after last dose.

• Primary Class: Alkylating Agent (Antineoplastic)
• Subclass: Nitrogen Mustard Derivative; Immunosuppressive Agent

• Known hypersensitivity to cyclophosphamide or any component of the formulation
• Severe bone marrow suppression (e.g., neutrophils <1,500/mm³ or platelets <50,000/mm³)
• Urinary outflow obstruction or active urinary tract infections
• Severe renal or hepatic impairment (if risk outweighs benefit)
• Pregnancy (unless benefit outweighs risk)
• Previous hemorrhagic cystitis induced by cyclophosphamide

• Myelosuppression: Monitor CBC weekly during therapy; dose adjust for neutropenia or thrombocytopenia
• Hemorrhagic cystitis: Risk from acrolein metabolite; use MESNA prophylaxis and ensure hydration
• Secondary malignancies: Increased risk of bladder cancer, acute leukemia, and myelodysplastic syndromes
• Gonadotoxicity/Infertility: Risk of amenorrhea, azoospermia, and premature ovarian failure
• Cardiotoxicity: High-dose regimens can cause arrhythmias, heart failure, or myocarditis
• Pulmonary toxicity: Interstitial pneumonitis or fibrosis may occur
• Immunosuppression: Risk of serious infections (bacterial, viral, fungal); consider PJP prophylaxis
• Hepatotoxicity and SIADH: Reported, though less common
• Monitor: CBC, renal/liver function, urinalysis, pregnancy status, signs of infection

Hematologic:

• Common: Leukopenia, neutropenia, anemia, thrombocytopenia
• Serious: Aplastic anemia, pancytopenia, febrile neutropenia

Gastrointestinal:

• Nausea, vomiting, anorexia, mucositis, diarrhea

Genitourinary:

• Hemorrhagic cystitis (dose-dependent), dysuria, hematuria

Reproductive:

• Amenorrhea, azoospermia, infertility, teratogenicity

Dermatologic:

• Alopecia (reversible), skin pigmentation changes, rash

Neurologic:

• Dizziness, headache; seizures (rare)

Other Serious Effects:

• Cardiomyopathy, SIADH, hepatotoxicity, secondary cancers

Onset & Dose-Dependence:

• Myelosuppression and GI effects typically occur within 5–10 days
• Cystitis and cardiotoxicity more common at high doses (>1 g/m²)

• Increased Toxicity With:
• Anthracyclines (e.g., doxorubicin): Increased cardiotoxicity
• Other myelosuppressants or radiation therapy: Additive bone marrow suppression
• Allopurinol: May increase cyclophosphamide toxicity via hepatic metabolism competition
• CYP inducers (e.g., phenobarbital, rifampin): May increase activation/toxicity
• Decreased Efficacy:
• CYP inhibitors (e.g., fluconazole): May reduce activation of prodrug
• Vaccines: Live vaccines contraindicated due to immunosuppression
• Warfarin: May enhance anticoagulant effect

Enzyme Systems: Primarily CYP2B6, CYP3A4, and CYP2C9

• Updated Lupus Nephritis Guidelines (2023): Continue to support cyclophosphamide as first-line induction therapy in proliferative lupus nephritis, particularly in high-risk populations
• European Vasculitis Society (EUVAS): Recommends cyclophosphamide in remission induction of ANCA-associated vasculitis
• Oncology protocols: Dose optimization based on AUC-guided models under investigation
• Fertility preservation protocols: Strong emphasis on sperm and egg cryopreservation prior to use

Oral Tablets:

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions 15–30°C allowed
• Light & Humidity: Store in dry place, protect from light
• Handling: Use gloves to avoid skin contact

IV Powder for Injection:

• Store at 2°C to 8°C (refrigerate)
• After reconstitution: Stable for 24 hours at room temperature or up to 6 days refrigerated
• Do not freeze after reconstitution

Safety Precautions:

• Treat as a cytotoxic agent: Follow hazardous drug handling guidelines (USP <800>)
• Use in biological safety cabinet when preparing IV doses