Capecitabine - A Game-Changer in Colon Cancer Treatment

Overview

5-Fluorouracil (5-FU) was first launched almost four decades ago and has remained a cornerstone in colorectal cancer (CRC) treatment protocols, either alone or in combination with other medicines. Despite the role of the drug in cancer therapy, its short half-life, the necessity for a central line, and the need for repeated infusions prompted scientists to create an oral formulation.

The Food and Drug Administration (FDA) authorized Capecitabine in June 2005 as an oral prodrug of 5-FU for use as monotherapy in the adjuvant context for managing Duke's stage-C CRC. Capecitabine offers several benefits over conventional 5-FU. It is transformed to 5-FU by three consecutive enzyme processes after absorption across the digestive system. The last enzyme in the cycle, thymidine phosphorylase (TP), is thought to be available at disproportionately high levels in tumor tissue, increasing both the effectiveness and tolerance of the medication through targeted administration.

Dosage And Administration:

• Take Capecitabine along with water within 30 minutes of food.

• Monotherapy involves 1250 milligrams per square meter orally twice daily for two weeks, followed by a one-week pause in three-week cycles.

• Adjuvant therapy for a total of six months is advised (eight cycles). The recommended dose of Capecitabine in conjunction with Docetaxel is 1250 milligrams per square meter twice daily for two weeks, followed by a one-week rest interval, along with Docetaxel at 75 milligrams per square meter as a one-hour intravenous infusion every three weeks.

• In order to enhance patient treatment, the Capecitabine dose may need to be customized as per the requirement of the patient.

• In patients with significant renal impairment, reduce the dosage of Capecitabine by 25 percent.

Dosage Forms And Strengths:

Capecitabine is supplied as a biconvex, oblong film-coated tablet to be taken orally. Each light peach-colored tablet is available at 150 milligrams and 500 milligrams.

Indications And Usage:

Capecitabine is a nucleoside metabolic inhibitor with an antineoplastic activity that is indicated for:

1. Colorectal Cancer:

• Capecitabine is authorized as a single drug for adjuvant treatment for individuals with Dukes'-C colon cancer who have undergone full resection of the primary tumor. When Fluoropyrimidine therapy alone is chosen, Capecitabine is authorized as a first-line treatment for individuals with colorectal cancer that has metastasized.

2. Breast Cancer:

• Capecitabine in combination with Docetaxel is approved for the treatment of individuals with advanced breast cancer who have previously failed Anthracycline-containing chemotherapy.

• Capecitabine monotherapy is also approved for the treatment of individuals who have advanced breast cancer who are resistant to both Paclitaxel and an Anthracycline-containing chemotherapy regimen, or who are resistant to Paclitaxel but do not require additional Anthracycline therapy.

Contraindications

• Severe Renal Impairment: In individuals with severe renal impairment (creatinine clearance less than 30 milliliters per minute), Capecitabine is not recommended.

• Hypersensitivity: Capecitabine is not recommended for individuals who have a history of hypersensitivity to Capecitabine or any of its components. Those with a known hypersensitivity to 5-fluorouracil should not use Capecitabine.

What Are the Warnings and Precautions for the Drug?

1. General Precautions:

• Individuals undergoing Capecitabine medication should be supervised by a physician who is familiar with the administration of cancer chemotherapeutic drugs. The majority of adverse events are reversible and do not require cessation of the drug. However, dosages may need to be altered or lowered.

2. Coagulopathy:

• Patients undergoing concurrent Capecitabine and oral coumarin-derivative anticoagulant treatment should have their anticoagulant response (INR or prothrombin time) thoroughly evaluated and the anticoagulant dosage altered as needed.

3. Diarrhea:

• Capecitabine might cause diarrhea occasionally. Individuals with severe diarrhea should be closely watched and provided fluid and electrolyte replacement when they get dehydrated.

• The median duration until the first onset of grade two to four diarrhea in about 875 individuals with metastatic breast or colorectal cancer who received Capecitabine as monotherapy was 34 days (range from one to 369 days). The average duration of grade three to four diarrhea was five days.

• The National Cancer Institute of Canada (NCIC) defines grade two diarrhea as an increase of four to six bowel movements per day or nocturnal bowel movements, grade three diarrhea as an increase of seven to nine bowel movements per day or incontinence and malabsorption, and grade four diarrhea as an increase of ten bowel movements per day or bloody diarrhea or the requirement for antibiotics.

4. Cardiotoxicity:

• Myocardial infarction or ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic alterations, and cardiomyopathy have all been reported as side effects of Capecitabine. These side effects may be more likely in those who have a history of coronary artery disease

5. Dihydropyrimidine Dehydrogenase Deficiency:

• Patients who have certain homozygous or complex heterozygous mutations in the DPD gene that lead to the complete or closer to complete absence of DPD activity are more likely to experience acute early-onset toxicity and severe, life-threatening, or potentially deadly adverse reactions caused by Capecitabine (for example - mucositis, diarrhea, neutropenia, and neurotoxicity). Individuals with incomplete DPD activity may be more likely to experience severe, life-threatening, or lethal adverse effects with Capecitabine.

• Withdraw or permanently stop Capecitabine in patients with signs of acute early-onset or unusually severe toxicity, which may represent near complete or entire lack of DPD action, based on clinical evaluation of the start, duration, and severity of the observed toxicities.

• No Capecitabine dosage is safe for people who have no DPD activity. In individuals with incomplete DPD activity, as determined by any particular test, there is insufficient information to prescribe a specific dosage.

6. Dehydration and Renal Failure:

• Dehydration has been reported, which can lead to acute renal failure, which is life-threatening. Individuals with pre-existing renal dysfunction or who are receiving Capecitabine concurrently with known nephrotoxic medications are at greater risk. Individuals suffering from anorexia (eating disorders), asthenia (lack of energy), nausea, vomiting, or diarrhea may get dehydrated quickly.

• When Capecitabine is delivered, patients should be monitored to avoid and rectify dehydration. If dehydration of grade two (or greater) appears, Capecitabine medication should be stopped immediately and the dehydration addressed.

• The patient's treatment should not be continued until the patient has been rehydrated and any precipitating reasons have been rectified or managed. Dosage adjustments for the triggering adverse event should be made as needed.

• Individuals with significant renal impairment at the start of treatment require a dosage decrease. Individuals with mild to severe renal impairment at the outset should be closely watched for adverse effects. If a patient has grade two to four adverse effects, it is best to discontinue the medication immediately and then reduce the dose.

7. Pregnancy: When administered to a pregnant woman, Capecitabine may cause fetal damage. When delivered during organogenesis, Capecitabine produced teratogenicity in mice and embryo lethality in monkeys. If this medication is used during pregnancy, or if a patient gets pregnant while taking Capecitabine, the patient should be informed of the potential risk to the fetus.

8. Mucocutaneous and Dermatologic Toxicity: Patients on Capecitabine may experience severe mucocutaneous reactions, some of which are deadly, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). The drug should be stopped completely in individuals who have a severe mucocutaneous response that may be caused by Capecitabine medication. Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous complication caused by chemotherapy.

9. Hyperbilirubinemia: Stop Capecitabine therapy quickly till the hyperbilirubinemia resolves or until the intensity is subsided.

10. Hematologic: Patients with neutrophil counts of 1.5 x 109/liter or thrombocyte levels of 100 x 109/liter should not be treated. If neutropenia or thrombocytopenia of grades three to four develops, discontinue medication until the illness disappears.

11. Geriatric Patients: Individuals above the age of 80 may have a higher frequency of grade three or four adverse events.

12. Hepatic Insufficiency: Individuals with mild to moderate hepatic impairment as a result of metastases of the liver should be closely monitored when using Capecitabine. The effect of severe hepatic impairment on Capecitabine disposition is unknown.

13. Combination with Other Drugs: The use of Capecitabine in association with Irinotecan has not been thoroughly investigated.

For Patients:

What Is Colorectal Cancer?

Colorectal cancer (CRC) is a condition that only affects the colon or rectum and is triggered by the abnormal growth of glandular epithelial cells in the colon. CRC is classified into three types: sporadic, inherited, and colitis-associated. The risk of getting CRC is determined by both environmental and hereditary factors. Moreover, in individuals with long-standing ulcerative colitis or Crohn's disease, the chance of getting CRC increases with age.

Several studies have found that food and lifestyle, family history, and chronic inflammation are all risk factors for CRC. Screening is very important in CRC since it is not only a prevalent condition, but it is also considered to be characterized by a steady progression of the adenoma-carcinoma sequence.

Colorectal adenomas can be surgically removed to avoid CRC, and the sooner CRC is found, the less likely the patient will die. It requires years for CRC to develop. A polyp usually takes ten to 15 years to develop into a dangerous tumor. As a result, frequent screening, detection, and removal of polyps at an early stage are critical; CRC can therefore be avoided.

What Are The Side-effects Of Capecitabine?

• Severe Adverse Effects Occur In Persons Who Lack The Enzyme Dihydropyrimidine Dehydrogenase (DPD): Individuals who have some DPD enzyme may be at a higher risk of major adverse effects from Capecitabine therapy, which can occasionally result in death. If a person has any of the following severe symptoms, contact the healthcare professional immediately. Mouth, tongue, throat, and esophageal sores (mucositis) diarrhea, reduced white blood cell counts Problems with the neurological system.

• Problems In The Heart: Capecitabine can cause cardiac issues such as heart attacks and reduced blood supply to the heart, chest discomfort, irregular heartbeats, changes in the heart's electrical activity detected on an electrocardiogram (ECG), problems with the muscle tissue of the heart, heart failure, and sudden death. If the patient has a history of coronary artery narrowing or blockage (coronary artery disease), the patients are at an increased risk of cardiac issues with Capecitabine. If patients notice any new signs of a cardiac condition while taking Capecitabine, call the healthcare practitioner immediately.

Chest discomfort, lightheadedness, dizziness, or shortness of breath.

• Diarrhea: Diarrhea is usual with Capecitabine and can be severe at times.

• Too Much Fluid Loss (Dehydration) With Kidney Failure: With Capecitabine, nausea and vomiting are prevalent. Patients can easily get dehydrated if they lose their appetite, feel weak, and experience nausea, vomiting, or diarrhea.

• Severe Skin And Mouth Reactions: Capecitabine may induce serious skin responses that might result in death. Inform the healthcare practitioner straight away if a person gets a skin rash, blisters, or peeling skin. If the patient develops a severe skin response, the doctor may advise to discontinue using Capecitabine. If this happens, do not take Capecitabine again. Capecitabine can potentially induce "hand and foot" syndrome. Hand and foot syndrome is frequent in people with Capecitabine and can include numbness and alterations in feeling in the hands and feet, redness, discomfort, and edema. If the patient experiences any of these symptoms and is unable to perform normal activities, stop taking Capecitabine and contact the healthcare provider immediately.

• The most common adverse effects of Capecitabine in conjunction with Docetaxel in persons with metastatic breast cancer include diarrhea, mouth sores and inflammation of the mouth, hand and foot syndrome, hair loss, edema, stomach-area (abdominal) discomfort, nausea, and vomiting.

• The most prevalent adverse effects in persons with metastatic breast cancer who use Capecitabine alone are a reduction in the red blood cell and white blood cell count, vomiting and nausea, diarrhea, tiredness, hand and foot syndrome, inflammation of the skin, and rashes.

Serious adverse reactions to Capecitabine:

• Red itching welts on the skin are possible (hives).

• Redness of the skin, swollen face, lips, tongue, or throat rash.

• Itching.

• Difficulty swallowing or breathing.

What If An Overdose Occurs?

Severe overdose symptoms include nausea, vomiting, diarrhea, gastrointestinal problems and hemorrhage, and depression in the bone marrow. Overdose medical care should comprise the usual supportive medical procedures to address the presenting clinical symptoms. Although no clinical experience with dialysis as a therapy for Capecitabine overdose has been recorded, it may be beneficial in lowering circulating levels of 5'-DFUR, a low-molecular-weight metabolite of the parent molecule.

For Doctors:

What Is Capecitabine?

• Capecitabine is an antineoplastic fluoropyrimidine carbamate. It is a systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) that is converted to 5-fluorouracil when taken orally. Capecitabine's chemical formula is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine with a molecular weight of 359.35. At 20 degrees Celsius, Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL.

• Capecitabine is available in the form of biconvex, oblong film-coated tablets for oral administration. Each light peach pill carries 150 mg of Capecitabine, whereas each peach tablet contains 500 mg of Capecitabine.

Inactive Components:

• Anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate, and purified water.

• Hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides are present in the peach or light peach film coating.

Clinical Pharmacology:

1. Mechanism Of Action: In vivo, enzymes convert Capecitabine to 5-fluorouracil (5-FU). 5-FU is metabolized by both normal and malignant cells to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites harm cells through two distinct methods. Initially, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, create a covalently bonded ternary complex with thymidylate synthase (TS). This binding prevents thymidylate production from 2'-deoxyuridylate. Thymidylate is a required precursor of thymidine triphosphate, which is required for DNA synthesis. Hence a lack of this chemical can hinder cell division. Second, during RNA synthesis, nuclear transcriptional enzymes may include FUTP instead of uridine triphosphate (UTP). This metabolic mistake has the potential to disrupt RNA processing and protein synthesis.

2. Pharmacokinetics:

• Absorption: Capecitabine attained peak blood levels in cancer patients after an oral dose of 1255 mg/m2 twice a day for around 1.5 hours (Tmax), with peak 5-FU levels reaching somewhat later at two hours. Food lowered both the rate and extent of Capecitabine absorption, with mean Cma x and AUC0- decreasing by 60 percent and 35 percent, respectively. Food also lowered the Cmax and AUC0- of 5-FU by 43 and 21 percent, respectively.

• Distribution: Capecitabine and its metabolites have less than 60 percent plasma protein binding and are not dependent on the concentration. Capecitabine was largely (about 35 percent) bound to human albumin. Capecitabine has a modest risk of pharmacokinetic interactions with plasma protein binding.

• Bioactivation And Metabolism: Capecitabine is substantially enzymatically metabolized to 5-FU. A 60 kDa carboxylesterase hydrolyzes most of the molecule in the liver to 5'-deoxy-5-fluoro cytidine (5'-DFCR). An enzyme cytidine deaminase is present in nearly all tissues, including malignancies, and transforms 5'-DFCR to 5'-DFUR. Thymidine phosphorylase (dThdPase) then hydrolyzes 5'- DFUR to produce the active medication 5-FU. Thymidine phosphorylase is found in many tissues throughout the body. This enzyme is expressed in greater amounts in some human carcinomas than in surrounding normal tissues. In patients with colorectal cancer who received XELODA orally seven days before surgery, the median ratio of 5-FU concentration in colorectal tumors to surrounding tissues was 2.9.

• Excretion: Capecitabine and its metabolites are mostly eliminated in the urine; 95.5 percent of the Capecitabine dosage given is recovered in the urine. Fecal excretion is negligible (2.6 percent). FBAL is the most common metabolite excreted in the urine, accounting for 57 percent of the given dosage. About 3 percent of the given dosage is eliminated as unaltered medication in the urine. Both parent Capecitabine and 5-FU had an elimination half-life of around 0.75 hours.

Use In Specific Populations:

• Pregnancy: When given to a pregnant woman, Capecitabine can cause fetal damage. Capecitabine at 198 milligrams per kilogram per day induced abnormalities and embryo mortality in mice throughout organogenesis. There are no sufficient and well-controlled trials of Capecitabine in pregnant women. If this medication is taken during pregnancy, or if a patient gets pregnant while using Capecitabine, the patient should be informed of the potential risk to the fetus. Women should be told to prevent becoming pregnant while using Capecitabine.

• Nursing Mothers: When lactating mice received a single oral Capecitabine dosage excreted large levels of Capecitabine metabolites in their milk. It is unknown whether this medication is excreted in human milk. Since many medications are excreted in human milk and because Capecitabine has the potential for major adverse effects in nursing infants, a choice should be made whether to quit breastfeeding or the drug, taking into consideration the value of the drug to the mother.

• Pediatric Use: The safety and efficacy of Capecitabine in pediatric patients have not been verified.

• Geriatric Use: Practitioners should pay special attention to the side effects of Capecitabine in the elderly.

• Hepatic Insufficiency: When treating individuals with mild to severe hepatic dysfunction caused by liver metastases, use care. It is unknown what effect severe hepatic impairment has on Capecitabine.

• Renal Insufficiency: Individuals with moderate renal impairment (creatinine clearance of 30 to 50 milliliters per min) and severe renal impairment (creatinine clearance of 30 milliliters per min) had greater exposure to Capecitabine, 5-DFUR, and FBAL than those with normal renal function.

Drug Interactions

• Anticoagulants: Anticoagulant patients receiving Capecitabine concurrently with coumarin-derivative anticoagulants like Warfarin and Phenprocoumon have experienced alterations in the coagulation factors or hemorrhage. These incidents happened within a few days to many months of starting Capecitabine medication, and in a few individuals, within one month of terminating Capecitabine. These occurrences happened in both patients with and without metastases of the liver. The mean area under the curve (AUC) of S-warfarin increased significantly in a pharmacological interaction investigation with a single-dose administration of Warfarin administration. The highest observed international normalized ratio (INR) value grew by 91 percent. This interaction is most likely caused by Capecitabine or its metabolites inhibiting cytochrome P450 2C9.

• Phenytoin: Phenytoin levels should be closely checked in Capecitabine patients, and the dose might have to be lowered. According to studies, some individuals using Capecitabine with Phenytoin experienced toxicity due to high levels of Phenytoin. Although formal drug-drug interaction investigations with Phenytoin have not been undertaken, the mechanism of interaction is thought to be Capecitabine or its metabolites inhibiting the CYP2C9 isoenzyme.