Capecitabine + Cyclophosphamide

Usage

• Medical Conditions: Capecitabine + Cyclophosphamide is prescribed as first-line therapy for metastatic breast cancer (MBC), particularly in patients unsuitable for anthracycline or taxane-based therapies or those pretreated with these agents. It is also used to treat advanced and metastatic colorectal cancer and stage III colon cancer.

• Pharmacological Classification: This combination comprises an antimetabolite (Capecitabine) and an alkylating agent (Cyclophosphamide), both classified as antineoplastic or anticancer medications.

• Mechanism of Action: Capecitabine, a prodrug, is metabolized to 5-fluorouracil (5-FU), which disrupts DNA and RNA synthesis, inhibiting cell growth. Cyclophosphamide alkylates DNA, cross-linking DNA strands and preventing cell division. The combined action of these drugs synergistically inhibits cancer cell proliferation.

Alternate Names

• No widely recognized alternate names for the combination exist.

• Brand Name: Comcapsy® (marketed by Intas Pharmaceuticals Ltd, specifically designed as a fixed-dose combination tablet).

How It Works

• Pharmacodynamics: Capecitabine is converted to 5-FU preferentially in tumor tissues due to higher thymidine phosphorylase levels. 5-FU inhibits thymidylate synthase, a key enzyme in DNA synthesis, inducing cell cycle arrest and apoptosis. Cyclophosphamide, after metabolic activation, forms DNA cross-links, preventing DNA replication and transcription, ultimately leading to cell death.

• Pharmacokinetics: Capecitabine is orally administered and well-absorbed. Its conversion to 5-FU occurs in three enzymatic steps, the final step occurring predominantly in tumor cells. Cyclophosphamide is also administered orally. Both drugs are metabolized in the liver. The primary elimination route for Capecitabine and its metabolites is renal excretion, while Cyclophosphamide metabolites are also renally cleared.

• Receptor Binding/Enzyme Inhibition: 5-FU inhibits thymidylate synthase. Cyclophosphamide metabolites bind to DNA, forming interstrand and intrastrand cross-links.

• Elimination Pathways: Primarily renal excretion for both drugs.

Dosage

Standard Dosage

Adults:

• The recommended dose for metastatic breast cancer is Capecitabine 829 mg/m² + Cyclophosphamide 33 mg/m² twice daily on days 1 to 14 of a 21-day cycle. A fixed-dose combination of Capecitabine 1800 mg + Cyclophosphamide 80 mg daily for 14 days of a 21-day cycle has also shown efficacy. Dosage adjustments are often required based on tolerability and individual patient factors.

Children:

• Use in pediatric patients is not well-established. Limited data suggests that Cyclophosphamide dosing for malignant disease in children is 40 to 50 mg/kg intravenously in divided doses over 2 to 5 days, or alternative regimens. Capecitabine use in children is generally avoided. Pediatric dosing should be guided by expert oncologists specializing in pediatric cancers.

Special Cases:

• Elderly Patients: Starting doses may need to be lower, considering age-related changes in organ function and drug clearance. Close monitoring for adverse events is crucial.

• Patients with Renal Impairment: Dosage adjustments are required for patients with renal impairment. Consult renal dosing guidelines and consider alternative fluorouracil-containing regimens for severe renal dysfunction.

• Patients with Hepatic Dysfunction: Dose reduction may be required depending on the severity of liver dysfunction.

• Patients with Comorbid Conditions: Comorbidities like diabetes, cardiovascular disease, and prior heart conditions require cautious consideration and potential dose adjustments. Close monitoring is essential.

Clinical Use Cases

• This drug combination is specifically used in the setting of metastatic breast cancer and certain gastrointestinal cancers. The use of Capecitabine + Cyclophosphamide is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Dosage Adjustments

• Dosage adjustments are individualized based on patient factors including renal or hepatic dysfunction, myelosuppression, other adverse effects, and concomitant medications.

Side Effects

Common Side Effects

• Diarrhea, nausea, vomiting, stomatitis, abdominal pain, constipation, fatigue, hand-foot syndrome, hair loss, skin reactions (rash, erythema), anorexia, conjunctivitis, anemia, neutropenia, thrombocytopenia.

Rare but Serious Side Effects

• Cardiotoxicity (including heart attack, heart failure, arrhythmias), kidney failure, severe myelosuppression, Stevens-Johnson syndrome.

Long-Term Effects

• Secondary malignancies, cardiomyopathy, infertility.

Adverse Drug Reactions (ADR)

• Severe myelosuppression, cardiotoxicity, renal failure, hypersensitivity reactions.

Contraindications

• Pregnancy, breastfeeding, severe renal or hepatic dysfunction, pre-existing severe myelosuppression, hypersensitivity to either drug.

Drug Interactions

• Interactions with anticoagulants (e.g., warfarin), CYP450 enzyme inducers or inhibitors (e.g., phenytoin, ketoconazole), certain antibiotics (e.g., ciprofloxacin), and other chemotherapy agents can occur. Consult drug interaction databases before co-prescribing.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Contraindicated in pregnancy. Can cause fetal harm and birth defects.

• Breastfeeding: Contraindicated during breastfeeding and for 2 weeks after the last dose of Capecitabine.

Drug Profile Summary

• Mechanism of Action: Capecitabine: Inhibits thymidylate synthase; Cyclophosphamide: Alkylates DNA.

• Side Effects: Diarrhea, nausea, vomiting, hand-foot syndrome, myelosuppression, cardiotoxicity.

• Contraindications: Pregnancy, breastfeeding, severe renal/hepatic dysfunction.

• Drug Interactions: Anticoagulants, CYP450 modulators.

• Pregnancy & Breastfeeding: Contraindicated.

• Dosage: Capecitabine 829 mg/m² + Cyclophosphamide 33 mg/m² twice daily, days 1-14 of a 21-day cycle (or fixed-dose equivalent, as per clinical trials and product availability). Adjust dose based on patient-specific factors.

• Monitoring Parameters: Complete blood count (CBC) with differential, renal and liver function tests, cardiac function (ECG).

Popular Combinations

• Capecitabine + Cyclophosphamide is sometimes used in combination with Docetaxel or Oxaliplatin for specific cancer types based on established regimens and clinical trials.

Precautions

• General Precautions: Baseline assessment of organ function, pregnancy testing in women of childbearing potential, contraception counseling. Monitor for myelosuppression, cardiotoxicity, and renal function during therapy.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Capecitabine + Cyclophosphamide in metastatic breast cancer?

A: The recommended starting dose is Capecitabine 829 mg/m² + Cyclophosphamide 33 mg/m² twice daily on days 1-14 of a 21-day cycle. Fixed-dose combinations (e.g., 1800mg/80mg daily) are also available. Individualized dose adjustments based on patient tolerance and clinical response are common.

Q2: What are the major side effects?

A: Common side effects include diarrhea, nausea, vomiting, hand-foot syndrome, myelosuppression (neutropenia, thrombocytopenia, anemia), fatigue, hair loss, and skin reactions. Rare but serious side effects include cardiotoxicity and renal failure.

Q3: Is this combination safe during pregnancy or breastfeeding?

A: No. Capecitabine + Cyclophosphamide is contraindicated during pregnancy and breastfeeding due to potential teratogenic and toxic effects on the fetus/infant.

Q4: What are the key drug interactions to be aware of?

A: Clinically relevant drug interactions can occur with anticoagulants, CYP450 enzyme inducers/inhibitors, and certain antibiotics. Consult a drug interaction resource or clinical pharmacist.

Q5: How should I adjust the dose in patients with renal impairment?

A: Dose adjustments are necessary for patients with renal dysfunction. Consult renal dosing guidelines for Capecitabine and Cyclophosphamide. Alternative fluorouracil-containing regimens may be more appropriate in severe renal impairment.

Q6: How is hand-foot syndrome managed?

A: Management includes dose reduction, topical emollients, pain relief, and patient education regarding preventive measures (e.g., avoiding excessive pressure or friction on hands and feet).

Q7: What monitoring parameters are essential during treatment?

A: Monitor complete blood counts (CBC) with differential, renal function tests, liver function tests, and cardiac function (ECG) periodically. Frequency of monitoring should be individualized.

Q8: What are the absolute contraindications to using this combination?

A: Absolute contraindications include pregnancy, breastfeeding, severe pre-existing myelosuppression, and hypersensitivity to either Capecitabine or Cyclophosphamide.

Q9: Can this drug combination be used in children?

A: The use of Capecitabine and Cyclophosphamide in combination is not routinely recommended for children. If considered, dosing requires specialized pediatric oncology expertise, and should be guided by limited available pediatric data and clinical experience.

Q10: What are the long-term risks associated with this treatment?

A: Potential long-term risks include secondary malignancies, cardiomyopathy, and infertility. Patients require long-term follow-up care.