Capecitabine

Capecitabine is an antineoplastic agent belonging to the pharmacological class of antimetabolites.

The FDA has approved capecitabine for treating breast, colorectal, and gastrointestinal cancers, often used in combination therapy.

Capecitabine undergoes rapid and extensive absorption, influenced by food intake. It exhibits less than 60% plasma protein binding, ensuring widespread distribution. Enzymatic metabolism transforms it into active metabolites, primarily eliminated through urine (96%), with a short elimination half-life of approximately 0.75 hours.

The most common side effects of capecitabine are vomiting, weakness, nausea, abdominal pain, and diarrhea.

Capecitabine is available in the form of oral tablets.

The molecule is available in India, the United States, Canada, the United Kingdom, Australia, Germany, France, Japan, China, Brazil and South Africa.

Capecitabine is an antineoplastic agent belonging to the pharmacological class of antimetabolites.

In vivo, capecitabine is converted by enzymes to 5-fluorouracil (5-FU). 5-FU is metabolized by both normal and malignant cells to 5-fluorouridine triphosphate (FUTP) and 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). These compounds damage cells in two separate ways. To create a covalently bonded ternary complex, first, FdUMP and the folate cofactor N5-10-methylenetetrahydrofolate bind to thymidylate synthase (TS). This binding prevents 2'-deoxyuridylate from becoming thymidylate. Since thymidylate is a prerequisite for thymidine triphosphate, which is required for DNA synthesis, lacking this substance can prevent cells from proliferating. Second, as uridine triphosphate (UTP) is being synthesized into RNA, nuclear transcriptional enzymes may inadvertently incorporate FUTP in mistake. This metabolic error may hamper the processing of RNA and the production of proteins.

The time to reach peak plasma concentration is approximately 1.5 hours after administration.

Capecitabine is available as an oral tablets.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally twice daily, with or without food.

• Cancer of the colon and rectum
• Breast cancer

• Cancer of colon and rectum: Colorectal cancer, originating in the colon or rectum, presents symptoms like blood in the stool, altered bowel movements, weight loss, and fatigue. Capecitabine actively treats and reduces the risk of additional cancerous growths (polyps) and bowel cancer. It functions by inhibiting cancer cell growth, effectively preventing their multiplication. Capecitabine's action includes halting the growth of existing cancer cells and curbing their further development. Recognizing symptoms and promptly administering capecitabine can contribute to effective treatment and a decreased risk of cancer progression in individuals diagnosed with colorectal cancer, enhancing their overall prognosis and well-being. Patients find capecitabine convenient, offering flexibility and improving their quality of life during colon and rectal cancer treatment.
• Breast cancer: In treating breast cancer, capecitabine, whether used alone or in combination with other treatments like chemotherapy, alleviates symptoms such as breast lumps, nipple discharge, or changes in breast texture. Capecitabine actively kills or halts cancer cell growth, preventing their multiplication.

• When fluoropyrimidine therapy is the chosen course of treatment, this medication can be used as a single agent for adjuvant therapy in patients with Dukes' C colon cancer who have complete resection of the primary tumour.
• When fluoropyrimidine therapy alone is not recommended, this form of treatment is indicated as the first line of treatment for metastatic colorectal cancer (CRC).
• Indicated for patients who have metastatic breast cancer and are resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or who are resistant to paclitaxel and do not require additional anthracycline therapy (e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents).
• When anthracycline-containing treatment fails, it is indicated to be used with docetaxel for metastatic breast cancer.

Orally: Patients should take Capecitabine tablets orally with water within 30 minutes after a meal, following prescribed doses strictly. Patients should also be instructed on proper adherence; any missed doses require appropriate action. Regular blood tests may be necessary to monitor treatment response and potential side effects, ensuring an effective and well-tolerated therapeutic approach for conditions like breast and colorectal cancers.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablets: 150mg, 500mg

Capecitabine is available in the form of oral tablets.

Dose Adjustment in Adult Patients:

Colorectal Cancer

Adjuvant treatment for colon cancer: Eight cycles of three weeks each, consisting of 1,250 mg/m2 PO BID for two weeks, followed by a one-week rest period (24 weeks).

First-line monotherapy, administered in 3-week cycles, for metastatic colorectal carcinoma: 1250 mg/m2 BID for two weeks, followed by a one-week rest period.

Breast Cancer

Monotherapy: administered as three-week cycles of 1250 mg/m2 BID for two weeks, followed by a one-week rest period.

Combined with docetaxel 75 mg/m2 IV infusion on Day 1 of a 3-week cycle, the combination dose is 1250 mg/m2 PO BID on Days 1–14.

While taking capecitabine, follow the vital dietary guidelines and precautions. Small, frequent meals help manage any potential gastrointestinal problems. Maintain a balanced, nutrient-rich diet while drinking enough water. Avoid items made from grapefruit because of possible interactions. Minimize alcohol and tobacco consumption, as they may negatively interact with capecitabine. Avoid including things like spicy or high-fibre foods that could exacerbate other symptoms. To minimize issues related to dehydration, maintain general health by eating a well-balanced diet and drinking enough water.

The dietary restriction should be individualized as per patient requirements.

•Hypersensitivity: Anyone previously experienced hypersensitivity to capecitabine or fluorouracil (5-FU)

•Severe renal impairment (CrCl <30 mL/min)

• Monitor anticoagulant response (e.g., INR, PT) closely and adjust doses accordingly, as capecitabine may lead to bleeding and death.
• If severe diarrhoea occurs, promptly interrupt Capecitabine treatment until resolution or grade 1 decrease; recommend standard antidiarrheal treatments.
• Observe cardiotoxicity, including myocardial infarction, angina, dysrhythmias, cardiac arrest, heart failure, sudden death, ECG changes, and cardiomyopathy, particularly in patients with a history of coronary artery disease.
• Patients with low or absent dihydropyrimidine dehydrogenase (DPD) activity: consider withholding or permanently discontinuing capecitabine in cases of acute, unusually severe toxicity.
• Before resuming Capecitabine treatment, correct dehydration to prevent potential acute renal failure.
• Inform women about potential fetal harm associated with Capecitabine use.
• Discontinue therapy if severe mucocutaneous reactions occur, including Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).
• Interrupt therapy for hyperbilirubinemia until resolution or decreased intensity.
• Avoid administering to patients with baseline neutrophil counts <1.5 x 10^9/L or thrombocyte counts <100 x 10^9/L; stop therapy for grade 3-4 neutropenia or thrombocytopenia until resolution.
• Monitor patients with mild-to-moderate hepatic dysfunction carefully due to liver metastases; the effect of severe hepatic dysfunction on Capecitabine disposition is unknown.
• The combination of capecitabine with irinotecan has yet to be sufficiently studied.

It is unsafe to consume capecitabine with alcohol.

It is not recommended for use during breastfeeding.

It is not recommended for use during pregnancy.

The adverse reactions related to capecitabine can be categorized as

•Common Adverse Effects: Diarrhea, nausea, anaemia, lymphopenia, hand and foot syndrome, oedema, fatigue, fever, headache, pain, paresthesia, alopecia, dermatitis, abdominal pain, anorexia, decreased appetite, constipation, stomatitis, vomiting, neutropenia, dyspnea, and eye irritation.

•Less Common Adverse Effects: Dermatitis, pruritus, rash, dizziness, headache, weakness, dehydration, dry mouth, dyspepsia, taste disturbance, and back pain.

•Rare Adverse Effects: Thrombocytopenia, hepatobiliary, hypersensitivity.

Reports on Postmarketing

Hepatic failure, acute renal failure secondary to dehydration with a potentially fatal outcome, lacrimal duct stenosis, cutaneous lupus erythematosus, corneal disorders such as keratitis, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN), toxic leukoencephalopathy,permanent or severe hand-foot syndrome can eventually result in fingerprint loss.

The clinically relevant drug interactions of capecitabine are briefly summarized here.

• May worsen the toxicity and plasma levels of phenytoin.
• Antacids containing magnesium and aluminium may raise the concentration of capecitabine. Allopurinol may lower capecitabine concentrations. Reduced Maximum tolerable dosage when using interferon-α and folinic acid.
• It may cause bleeding when administered with oral coumarin-derived anticoagulants (e.g., warfarin, phenprocoumon) and change coagulation parameters. Brivudine toxicity increased.
• The rate and extent of capecitabine absorption are lowered by food.
• Patients who have issues with their liver, heart, or kidneys, diabetes, glaucoma (higher eye pressure), myelosuppression (lower bone marrow activity), stomatitis, infections, or bleeding disorders may not benefit from capecitabine.

The common side effects of capecitabine include:

• Nausea
• Vomiting
• Weakness
• Increased susceptibility to infection
• Abdominal pain
• Reduced red blood cells
• Loss of appetite
• Hair loss
• Diarrhoea
• Mouth ulcer
• Blisters on fingers/feet

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

Pregnant women may experience fetal injury from drugs according to the mechanism of action and results of animal reproduction studies; however, there is little information available from human studies to determine the risk of pregnancy-related drug use.

Before starting therapy, it is advised Pregnancy testing for females who are capable of becoming pregnant.

Animal studies

Treatment during organogenesis in pregnant animals resulted in teratogenicity and embryo mortality in mice and monkeys, respectively, at 0.2 and 0.6 times the exposure (AUC) in patients.

Contraception

Potentially fertile females: Use reliable birth control during your therapy and for six months following your last dosage.

Males who are sexually active and have female partners should use effective contraception during therapy and for three months following the last dosage.

Infertility

According to research on animals, it may reduce both male and female reproduction.

There isn't enough reliable research on capecitabine in expectant mothers. Patients who take capecitabine while pregnant or who get pregnant while taking the medication should be informed of the possible risks to the developing fetus. It should be recommended to women not to get pregnant while using capecitabine.

• Nursing Mothers

Significant levels of capecitabine metabolites were excreted into the milk of nursing mice that received a single oral dose of the medication. Whether this medication is eliminated in human milk is unknown. Given that many medicines are excreted in human milk and that capecitabine can cause significant adverse reactions in nursing infants, a choice should be made on whether to stop breastfeeding or to stop taking the medication, taking the mother's need for the medication into consideration.

• Pediatric Use

As per the FDA, the safety and efficacy of pediatric patients have not been established.

• Geriatric Use

Studies have shown the safety and effectiveness of capecitabine in the elderly population. Although medication metabolism may be altered by age, there were no appreciable variations in the outcomes of older and younger patients. Depending on the specific patient, dosage adjustments can be required to ensure therapeutic results.

Dose Adjustment in Kidney Impairment Patients:

Mild (CrCl 51-80 mL/min): There is no need to reduce the dosage.

Moderate (CrCl 30–50 mL/min): Lower the dosage to 75% of the first dose, or 950 mg/m2 BID instead of 1250 mg/m2.

Severe (CrCl less than 30 mL/min): Not recommended

Dose Adjustment in Hepatic Impairment Patients:

Caution should be used while administering capecitabine to patients who have liver metastases and mild to moderate hepatic impairment. There is no information on the extent to which liver dysfunction affects capecitabine.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of capecitabine.

Signs and Symptoms

Overconsumption of Capecitabine could lead to nausea, vomiting, diarrhoea, gastrointestinal irritation and bleeding, and bone marrow depression.

Management

There is no specific antidote; management involves supportive care and symptom-specific interventions. Close monitoring of blood counts, vital signs, and liver function is crucial. Hematopoietic growth factors may be considered, and if severe toxicity occurs, dose reduction or treatment discontinuation may be necessary. Hemodialysis may be considered for severe cases, although its effectiveness is limited.

Continuous observation and appropriate, timely medical interventions to address specific symptoms or complications are recommended.

Pharmacodynamics:

Capecitabine prevents the synthesis of DNA, which kills malignant cells. It is a systemic prodrug taken orally with minimal pharmacologic efficacy until it is transformed into 5-fluorouracil (5-FU) by enzymes that are expressed at higher levels in various tumour types. Capecitabine was created to address the drawbacks of 5-FU and simulate its infusional pharmacokinetics without the added complexity and problems of central venous access and infusion pumps. Specifically, because the gastrointestinal tract contains the enzymes that transform 5-FU into active metabolites, 5-FU infusion can harm the gastrointestinal system and lose effectiveness. Due to its ability to pass through the intestinal mucosa intact, capecitabine can be preferentially converted by enzymes inside tumour cells to deliver 5-FU to specific tumour tissues.

The pharmacological activity of 5-FU is achieved by inhibiting and interfering with three primary targets: thymidylate synthase, DNA, and RNA. This ultimately results in the disruption of protein synthesis and apoptosis. According to population-based exposure-effect analyses, AUC of 5-FU showed a positive correlation with grade 3–4 hyperbilirubinemia.

Pharmacokinetics:

• Absorption: The body rapidly and extensively absorbs capecitabine, a process affected by the presence of food, which reduces both the rate and extent of absorption. The time required to reach peak plasma concentration is approximately 1.5 hours.

• Distribution: Capecitabine exhibits a plasma protein binding of less than 60%, with around 35% binding to albumin. This characteristic contributes to its distribution throughout the body.

• Metabolism: Enzymatic processes metabolize capecitabine into fluorouracil, a precursor subsequently metabolized into active forms, including 5-fluoroxyuridine monophosphate (F-UMP) and F-dUMP. These metabolites play a crucial role in the drug's pharmacological activity.

• Excretion: The primary route of elimination for capecitabine is through urine, accounting for 96% of excretion. Within the urine, approximately 57% appears as α-fluoro-β-alanine, while less than 3% is excreted as an unchanged drug. A minor portion is eliminated through faeces, constituting less than 3%. The elimination half-life is approximately 0.75 hours, reflecting the drug's relatively short duration of action within the body.

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