Usage
Cyclophosphamide is prescribed for a range of malignant and non-malignant conditions. It’s used to treat various cancers, including lymphomas (Hodgkin’s disease, non-Hodgkin’s lymphoma), leukemias, multiple myeloma, breast cancer, ovarian cancer, neuroblastoma, retinoblastoma, and others. It’s also used for minimal change nephrotic syndrome in children and, off-label, for lupus nephritis, juvenile idiopathic arthritis/vasculitis, and systemic sclerosis.
Cyclophosphamide is classified as an alkylating antineoplastic agent, specifically a nitrogen mustard.
It acts as a prodrug, requiring hepatic activation to form its active metabolites. These metabolites cross-link DNA, preventing cell division and ultimately leading to cell death. This mechanism is particularly effective against rapidly dividing cells, such as cancer cells.
Alternate Names
While “cyclophosphamide” is the generic name, it’s marketed under several brand names, most notably Cytoxan®. There are no widely recognized international or regional variations of the generic name.
How It Works
Pharmacodynamics: Cyclophosphamide’s primary effect is disrupting DNA replication and leading to cell death. It primarily affects rapidly dividing cells like cancer cells, but also impacts other quickly proliferating cells like those in bone marrow, hair follicles, and the gastrointestinal tract.
Pharmacokinetics:
- Absorption: Cyclophosphamide is well-absorbed orally.
- Metabolism: Metabolized in the liver by cytochrome P450 enzymes to active alkylating metabolites, phosphoramide mustard, and acrolein. These metabolites are responsible for both the therapeutic and toxic effects. Significant interpatient variability in its hepatic metabolism exists.
- Elimination: Primarily eliminated through renal excretion, with about 30% excreted as unchanged drug. The half-life is 4-10 hours in adults and 1-6.5 hours in children.
Mode of Action: Cyclophosphamide’s alkylating metabolites cross-link DNA strands, forming covalent bonds between DNA bases. This damage prevents DNA replication and transcription, leading to cell cycle arrest and apoptosis (programmed cell death). It doesn’t bind to specific receptors or modulate neurotransmitters but inhibits DNA function directly.
Elimination Pathways: Renal excretion is the primary pathway. Hepatic metabolism via CYP450 enzymes generates active and inactive metabolites, some of which are also eliminated renally.
Dosage
Dosage is highly individualized and dependent on the specific indication, patient characteristics, and treatment protocol. Always consult relevant protocols and guidelines.
Standard Dosage
Adults:
- Malignant Diseases: IV: 40-50 mg/kg divided over 2-5 days; or 10-15 mg/kg every 7-10 days; or 3-5 mg/kg twice weekly. PO: 1-5 mg/kg/day.
- Nephrotic Syndrome: 2-3 mg/kg/day for up to 12 weeks.
Children:
- Malignant Diseases: IV: 40-50 mg/kg divided over 2-5 days; or 10-15 mg/kg every 7-10 days; or 3-5 mg/kg twice weekly. PO: 1-5 mg/kg/day.
- Nephrotic Syndrome: 2 mg/kg/day for 8-12 weeks (maximum cumulative dose 168 mg/kg).
Special Cases:
- Elderly Patients: Increased monitoring for toxicity due to potential age-related decline in organ function. Dose adjustments may be needed.
- Patients with Renal Impairment: Dose reduction may be necessary, especially with severe impairment (CrCl < 10 mL/min).
- Patients with Hepatic Dysfunction: Reduced conversion to active metabolites may necessitate dose adjustment or closer monitoring.
- Patients with Comorbid Conditions: Individualized assessment and dose adjustment are necessary, especially with cardiac disease or prior mediastinal radiation.
Clinical Use Cases
Cyclophosphamide’s dosage in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergencies is dependent on the underlying condition being treated (e.g., cancer, lupus nephritis). There is no standard cyclophosphamide dosing specific to these settings. The dosing recommendations provided here are general guidelines, and many other regimens exist.
Dosage Adjustments
Dose modification is essential based on hematological toxicity, hepatic or renal impairment, and other patient-specific factors. Regular monitoring of blood counts, liver and kidney function is crucial.
Side Effects
Common Side Effects:
Nausea, vomiting, hair loss, skin rashes, loss of appetite, bladder irritation (dysuria, hematuria), increased risk of infections.
Rare but Serious Side Effects:
Hemorrhagic cystitis, bone marrow suppression, cardiotoxicity (especially at high doses), secondary malignancies, pulmonary toxicity, veno-occlusive disease, infertility, fetal harm.
Long-Term Effects:
Infertility, premature menopause, increased risk of secondary cancers, bladder damage.
Adverse Drug Reactions (ADR):
Severe myelosuppression, hemorrhagic cystitis, cardiotoxicity, anaphylaxis.
Contraindications
- Hypersensitivity to cyclophosphamide
- Urinary outflow obstruction
- Severe bone marrow suppression
Drug Interactions
Cyclophosphamide interacts with numerous medications, including:
- CYP450 interactions: Drugs that induce or inhibit CYP450 enzymes can alter cyclophosphamide metabolism.
- Allopurinol: May enhance bone marrow suppression.
- Anticoagulants: May increase bleeding risk.
- Immunosuppressants: May potentiate immunosuppression.
- Grapefruit juice: Can inhibit CYP3A4 and increase cyclophosphamide levels.
Consult drug databases for a comprehensive list.
Pregnancy and Breastfeeding
Cyclophosphamide is contraindicated during pregnancy (Pregnancy Category D/X) due to its teratogenic effects. It is also present in breast milk and can harm nursing infants. Effective contraception is crucial during and after treatment.
Drug Profile Summary
- Mechanism of Action: Alkylating agent, cross-links DNA, inhibits cell division.
- Side Effects: Nausea, vomiting, hair loss, myelosuppression, hemorrhagic cystitis, cardiotoxicity, infertility.
- Contraindications: Hypersensitivity, urinary outflow obstruction, severe bone marrow suppression.
- Drug Interactions: CYP450 modulators, allopurinol, anticoagulants, immunosuppressants.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Highly variable depending on indication and patient.
- Monitoring Parameters: Complete blood counts, renal and liver function tests, urine analysis.
Popular Combinations
Cyclophosphamide is frequently used in combination chemotherapy regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for non-Hodgkin’s lymphoma. The combinations aim for synergistic antitumor effects.
Precautions
- General Precautions: Monitor blood counts, renal and hepatic function. Ensure adequate hydration to minimize bladder toxicity.
- Specific Populations: Close monitoring and dose adjustment in patients with renal or hepatic impairment, elderly patients, and those with comorbidities. Contraindicated in pregnancy and breastfeeding.
- Lifestyle Considerations: Alcohol may exacerbate some side effects. Smoking can induce certain CYP enzymes and affect cyclophosphamide metabolism.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Cyclophosphamide?
A: Dosage is individualized and varies widely depending on the indication, patient age and weight, and treatment protocol. See detailed dosage guidelines above.
Q2: What are the major side effects of Cyclophosphamide?
A: Common side effects include nausea, vomiting, hair loss, and increased infection risk. Serious side effects include myelosuppression, hemorrhagic cystitis, cardiotoxicity, and infertility.
Q3: How does Cyclophosphamide work against cancer?
A: Cyclophosphamide’s active metabolites damage DNA, preventing cancer cell replication and leading to cell death.
Q4: Can Cyclophosphamide be used during pregnancy?
A: No, cyclophosphamide is contraindicated during pregnancy due to its teratogenic effects.
Q5: How should Cyclophosphamide be administered?
A: It can be given intravenously or orally, following specific protocols for each indication.
Q6: What are the key drug interactions with Cyclophosphamide?
A: Interactions occur with drugs metabolized by CYP450 enzymes, allopurinol, anticoagulants, and immunosuppressants.
Q7: What precautions are needed when prescribing Cyclophosphamide?
A: Close monitoring of blood counts, renal and liver function, and ensuring adequate hydration are crucial. Dose adjustment is often necessary in special populations.
Q8: What are the long-term risks of Cyclophosphamide treatment?
A: Infertility, premature menopause, and increased risk of secondary cancers are potential long-term risks.
Q9: Is there a specific antidote for Cyclophosphamide overdose?
A: No specific antidote exists. Supportive care and management of complications are essential.
Q10: How does renal impairment affect Cyclophosphamide dosing?
A: Reduced renal function can lead to accumulation of drug and metabolites, increasing toxicity. Dose reduction is usually needed.
