Capecitabine Tablet IP 500mg Capegard

[Drug Name]

Generic Name: Capecitabine Tablets

English Name: Capecitabine Tablets

[Composition] The active ingredient of this product is capecitabine.

[Specification] 10 tablets per small box; one large box contains 10 small boxes. Direct shipping from India is available, with a minimum order quantity of one large box.

[Indications]

1. Adjuvant Chemotherapy for Colon Cancer: Capecitabine is indicated as monotherapy for the adjuvant treatment of patients with Dukes’ C stage colon cancer who have undergone curative resection of the primary tumor and are suitable for single-agent fluoropyrimidine therapy. The disease-free survival (DFS) achieved with this treatment is non-inferior to that of the combination regimen of 5-fluorouracil and leucovorin (5-FU/LV). Neither capecitabine monotherapy nor capecitabine in combination chemotherapy regimens has been shown to prolong overall survival (OS); however, trial data indicate that within combination chemotherapy regimens, capecitabine may improve disease-free survival compared to 5-FU/LV. Physicians may refer to the above study results when prescribing capecitabine monotherapy for the adjuvant treatment of Dukes’ C stage colon cancer.

2. Colorectal Cancer: Capecitabine monotherapy or capecitabine in combination with oxaliplatin (XELOX) is indicated for the first-line treatment of metastatic colorectal cancer.

3. Combination Chemotherapy for Breast Cancer: Capecitabine is indicated in combination with docetaxel for the treatment of metastatic breast cancer that has failed to respond to anthracycline-containing chemotherapy regimens.

4. Monotherapy for Breast Cancer: Capecitabine is also indicated as monotherapy for the treatment of patients with metastatic breast cancer who are resistant to both paclitaxel and anthracycline-containing chemotherapy regimens, or who are resistant to paclitaxel and for whom further anthracycline therapy is contraindicated (e.g., patients who have already received a cumulative dose of 400 mg/m² of doxorubicin or doxorubicin analogs). Drug resistance is defined as continued disease progression during treatment (with or without an initial response), or disease recurrence within 6 months after completing adjuvant chemotherapy containing an anthracycline.

5. Gastric Cancer: Capecitabine is indicated for the first-line treatment of unresectable advanced or metastatic gastric cancer.

[Dosage and Administration] Recommended Dose: 2.5 g/m² daily, administered for 2 weeks, followed by a 1-week rest period. The total daily dose should be divided into two equal doses, taken orally with water half an hour after meals—one in the morning and one in the evening. Treatment should be discontinued if the patient's condition continues to deteriorate or if intolerable toxicity develops. Dose Adjustment During Treatment: Toxicity induced by this product may sometimes require symptomatic management or dose adjustment (temporary interruption of treatment or dose reduction). Once the dose has been reduced, it should not be increased subsequently. The following are recommended dose adjustments for toxicity (based on the Common Toxicity Criteria established by the National Cancer Institute of Canada): Grade 1: Maintain current dose. Grade 2: First occurrence: Discontinue treatment until toxicity resolves to Grade 0–1; resume treatment in the next cycle at 100% of the maintenance dose. Second occurrence: Discontinue treatment until toxicity resolves to Grade 0–1; resume treatment in the next cycle at 75% of the recommended dose. Third occurrence: Discontinue treatment until toxicity resolves to Grade 0–1; resume treatment in the next cycle at 50% of the recommended dose. Fourth occurrence: Permanently discontinue treatment. Grade 3: First occurrence: Discontinue treatment until toxicity resolves to Grade 0–1; resume treatment in the next cycle at 75% of the recommended dose. Second occurrence: Discontinue treatment until toxicity resolves to Grade 0–1; resume treatment in the next cycle at 50% of the recommended dose. Third occurrence: Permanently discontinue use. Grade 4: Permanently discontinue treatment. If treatment is to be resumed following an interruption, the potential benefit to the patient should be carefully weighed; treatment should be resumed at 50% of the recommended dose once toxicity symptoms have resolved to Grade 0–1. Dose Adjustments for Special Populations: Hepatic Impairment: Pharmacokinetic studies of this product conducted in patients with mild to moderate hepatic impairment due to liver metastases indicate that no dose adjustment is required for this patient population. Renal Insufficiency: Pharmacokinetic studies of this product have not yet been conducted in patients with renal insufficiency (defined as elevated serum creatinine). Pediatrics: Efficacy and safety studies of this product have not yet been conducted in children. Geriatrics: No dosage adjustment is required. However, elderly patients (aged 65 and older) are more susceptible to capecitabine-related toxicities than younger patients; therefore, they should be closely monitored. (Refer to the package insert for details.)

[Adverse Reactions] Adverse reactions associated with this product may include the following:

1. Gastrointestinal System: The most common adverse reactions are reversible gastrointestinal disturbances, such as diarrhea, nausea, vomiting, abdominal pain, stomatitis, etc. Severe (Grade 3–4) adverse reactions are relatively uncommon.

2. Skin: Hand-foot syndrome occurs in nearly half of the patients treated with this product; manifestations include numbness, hypoesthesia, paresthesia, tingling sensations, absence of pain sensation or presence of pain, skin swelling or erythema, desquamation, blistering, or severe pain. Dermatitis and alopecia are relatively common, but severe cases are rare.

3. Systemic Adverse Reactions: Fatigue is common, though severe cases are extremely rare. Other common adverse reactions include mucositis, fever, asthenia, and lethargy; however, none of these are severe.

4. Nervous System: Headache, paresthesia, dysgeusia (taste disturbance), dizziness, and insomnia are relatively common, but severe cases are rare.

5. Cardiovascular System: Edema of the lower extremities is mild and uncommon. No other cardiovascular adverse effects have been observed.

6. Hematologic System: Neutropenia is uncommon, and anemia is extremely rare; neither is severe.

7. Other: Anorexia and dehydration are common, but severe cases are extremely rare.

[Precautions] Dose-limiting toxicities include: diarrhea, abdominal pain, nausea, gastritis, and hand-foot syndrome. Nearly half of the patients treated with this product experience diarrhea. Patients with severe diarrhea accompanied by dehydration should be closely monitored and receive fluid replacement therapy. Diarrhea occurring 4 to 6 times daily, or nocturnal diarrhea, is classified as Grade 2; diarrhea occurring 7 to 9 times daily, or accompanied by fecal incontinence or malabsorption, is classified as Grade 3; and diarrhea occurring 10 or more times daily, or accompanied by gross bloody stools or a requirement for intravenous fluid replacement, is classified as Grade 4. If Grade 2, 3, or 4 diarrhea occurs, use of this product should be discontinued until the diarrhea resolves or decreases to Grade 1, at which point treatment may be resumed. Upon resuming treatment following Grade 3 or 4 diarrhea, the dosage of this product should be reduced. Nearly half of the patients treated with this product develop Hand-Foot Syndrome; however, most cases are Grade 1 or 2, while Grade 3 syndrome is uncommon. Most adverse reactions are reversible; while they may necessitate temporary interruption of treatment or dosage reduction, long-term discontinuation of therapy is generally not required.

[Contraindications] This product is contraindicated in patients who have experienced severe adverse reactions to the drug, those with a history of hypersensitivity to fluoropyrimidines (metabolites of capecitabine), and pregnant women.

[Use in Pregnant and Lactating Women] Clinical studies regarding the use of this product in pregnant women have not been conducted; however, it must be assumed that if this product is administered to such patients, it may cause fetal harm. Animal studies have demonstrated that capecitabine can cause fetal death or malformations. These findings suggest that capecitabine derivatives may possess similar effects; therefore, this product must not be used in pregnant women. If this product is used during pregnancy, or if a patient becomes pregnant while taking this product, she must be apprised of the potential risks of fetal harm or teratogenicity associated with the drug. Women of childbearing potential must utilize effective contraceptive measures while undergoing treatment with this product. Although it is currently unknown whether this product is excreted in human milk, many drugs are excreted in breast milk and carry the potential risk of causing serious adverse reactions in nursing infants; therefore, women taking this product are advised to discontinue breastfeeding.

[Pediatric Use] Studies evaluating the efficacy and safety of this product in pediatric patients have not been conducted.

[Geriatric Use] No dosage adjustment is required. However, elderly patients (aged 65 and older) are more susceptible to the toxic effects of capecitabine than younger patients; therefore, they should be closely monitored.

[Drug Interactions]

Combination Therapy: When administered in combination with a wide range of other medications—such as antihistamines, non-steroidal anti-inflammatory drugs (NSAIDs), morphine, paracetamol, aspirin, antiemetics, and H2 receptor antagonists—this product has not been observed to cause clinically significant adverse effects. Protein Binding: Capecitabine exhibits a low rate of binding to serum proteins (64%); consequently, the potential for displacement interactions with other drugs that bind tightly to proteins cannot be predicted at this time. Interactions with Cytochrome P450 Enzymes: *In vitro* studies have revealed no inhibitory effects of capecitabine on human hepatic microsomal P450 enzymes.

[Overdosage]

During clinical trials of this product, no adverse reactions attributable to drug overdose were observed. However, based on animal studies (specifically, aggressive treatment in monkeys at a dose of 25.679 g/m²/day) and treatment in humans at the maximum tolerated dose (3.514 g/m²/day), the manifestations of drug overdose include nausea, vomiting, diarrhea, gastrointestinal irritation, gastrointestinal hemorrhage, and bone marrow suppression. Management of overdose should include dehydration therapy using diuretics and, if necessary, dialysis.

[Pharmacology and Toxicology]

1. Pharmacological Actions:

Both normal cells and tumor cells are capable of metabolizing 5-FU into 5-fluoro-2′-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites induce cellular injury through two distinct mechanisms. First, FdUMP—in conjunction with the folate cofactor N5,10-methylenetetrahydrofolate—binds to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the conversion of 2′-deoxyuridine monophosphate into thymidine monophosphate. Thymidine nucleotides are essential precursors for thymidine triphosphate; since the latter is indispensable for DNA synthesis, a deficiency of this compound can inhibit cell division. Furthermore, during the process of RNA synthesis, nuclear transcriptase may erroneously incorporate FUTP at sites normally occupied by uridine triphosphate (UTP). This metabolic error interferes with RNA processing and protein synthesis.

2. Toxicology Studies:

Currently, there are insufficient studies to evaluate the carcinogenic potential of capecitabine. Capecitabine did not induce mutations in vitro in either bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). In vitro, capecitabine demonstrated clastogenic activity in human peripheral blood lymphocytes; however, it showed no clastogenic activity in vivo in mouse bone marrow (micronucleus test). Fluorouracil has been shown to induce mutations in bacteria and yeast, and to cause chromosomal abnormalities in in vivo micronucleus tests in mice.

In studies evaluating fertility and general reproductive performance in mice, oral administration of capecitabine at a dose of 760 mg/kg/day disrupted the estrous cycle and resulted in reduced fertility. In pregnant mice, no viable embryos were observed at this dose. The disruption of the estrous cycle was reversible. In this study, the same dose induced degenerative changes in male mice, including a reduction in the number of spermatocytes and spermatids. Separate pharmacokinetic studies indicate that the dose corresponding to the observed AUC value of 5′-DFUR in mice is approximately 0.7 times the recommended daily dose for patients.

[Pharmacokinetics] Pharmacokinetic studies of capecitabine, conducted across a dosage range of 502 to 3514 mg/m²/day, demonstrated that the pharmacokinetic parameters for capecitabine, 5′-deoxy-5-fluorocytidine, and 5′-deoxy-5-fluorouridine remained consistent on both Day 1 and Day 14 of administration. By Day 14, the plasma concentration of 5-fluorouracil was 30% higher than on Day 1; however, by Day 22, its concentration showed no further increase. At therapeutic doses—with the exception of 5-fluorouracil—the pharmacokinetic parameters of capecitabine and its metabolites are dose-proportional. Absorption: Following oral administration, capecitabine is rapidly and completely absorbed by the body, crossing the intestinal mucosa as an intact molecule; it is subsequently and completely converted into 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine. Taking capecitabine with food affects its rate of absorption, but has only a minimal effect on the Area Under the Curve (AUC) of 5'-deoxy-5-fluorouridine and its downstream metabolite, 5-fluorouracil. Distribution: *In vitro* studies using human serum indicate that the protein-binding rates (primarily to albumin) for capecitabine, 5'-deoxy-5-fluorocytidine, and 5'-deoxy-5-fluorouridine are 54%, 10%, and 62%, respectively. Metabolism: Capecitabine is primarily metabolized within the liver and tumor tissues. It is first converted into 5'-deoxy-5-fluorocytidine via carboxylesterase, and subsequently into 5'-deoxy-5-fluorouridine via cytidine deaminase. Within tumor cells, under the action of the tumor-associated angiogenic factor thymidine phosphorylase, it is converted into 5-fluorouracil, thereby minimizing the damage inflicted by 5-fluorouracil upon normal tissues. At the recommended dosage, the mean serum AUC values for capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil are 7.40 mg·h/mL, 5.21 mg·h/mL, 21.7 mg·h/mL, and 1.63 mg·h/mL, respectively. The serum AUC of 5-fluorouracil is approximately 10-fold lower than that observed following intravenous administration (at a dose of 600 mg/m²). No cytotoxicities distinct from those of 5-fluorouracil have been observed. Two hours after administration, the plasma concentrations of capecitabine, 5'-deoxy-5-fluorocytidine, and 5'-deoxy-5-fluorouridine reach their peak levels. Subsequently, these levels decline exponentially with a half-life ranging from 0.7 to 1.14 hours. Three hours after administration, alpha-fluoro-beta-alanine—a degradation product of 5-fluorouracil—reaches its peak concentration, with a half-life of 3 to 4 hours. Elimination: The metabolites of capecitabine are primarily eliminated via the kidneys; 71% of the administered dose is recovered in the urine, with alpha-fluoro-beta-alanine constituting the major metabolite (52%).

[Storage] Keep tightly closed; store at temperatures below 25°C.

[Shelf Life] 24 months

Product Specifications

Product Name: Capecitabine Tablets (Capecitabine Tablet IP 500mg) — Capegard — 10 Tablets/Box

Common Name: Capecitabine Tablets

Composition: Capecitabine

Dosage Form: Tablets

Specification: 500 mg/tablet; 10 tablets/box

Manufacturer: Cipla Ltd. (India)

Indications: 1. Adjuvant Chemotherapy for Colon Cancer: Capecitabine is indicated as monotherapy for the adjuvant treatment of patients with Dukes’ C stage colon cancer who have undergone curative surgery for the primary tumor and are suitable candidates for single-agent fluoropyrimidine therapy.

2. Colorectal Cancer: Capecitabine, either as monotherapy or in combination with oxaliplatin (XELOX), is indicated as first-line treatment for metastatic colorectal cancer.

3. Combination Chemotherapy for Breast Cancer: Capecitabine, in combination with docetaxel, is indicated for the treatment of metastatic breast cancer in patients whose disease has progressed following anthracycline-containing chemotherapy regimens.

4. Monotherapy for Breast Cancer: Capecitabine is also indicated as monotherapy for the treatment of metastatic breast cancer in patients whose disease is resistant to both paclitaxel and anthracycline-containing chemotherapy regimens, or in patients who are resistant to paclitaxel and for whom further anthracycline therapy is contraindicated. 5. Gastric Cancer: Capecitabine is indicated for the first-line treatment of unresectable advanced or metastatic gastric cancer.

Dosage and Administration: Recommended Dose: 2.5 g/m² daily, administered for 2 weeks, followed by a 1-week rest period. The total daily dose should be divided into two equal doses, taken orally with water approximately 30 minutes after meals (one in the morning and one in the evening). Treatment should be discontinued if the disease continues to progress or if intolerable toxicity develops. Dosage Adjustment During Treatment: Toxicities induced by this product may sometimes require symptomatic management or dosage adjustment (temporary interruption of treatment or dose reduction). Once the dose has been reduced, it should not be increased subsequently. The following are recommended dosage adjustments for toxicity (based on the Common Toxicity Criteria established by the National Cancer Institute of Canada): Grade 1: Maintain dose. Grade 2: First occurrence: Discontinue treatment until toxicity resolves to Grade 0–1; resume treatment in the next cycle at 100% of the maintenance dose. Second occurrence: Discontinue treatment until toxicity resolves to Grade 0–1; resume treatment in the next cycle at 75% of the recommended dose. Third occurrence: Discontinue treatment until toxicity resolves to Grade 0–1; resume treatment in the next cycle at 50% of the recommended dose. Fourth occurrence: Permanently discontinue treatment. Grade 3: First occurrence: Discontinue treatment until toxicity resolves to Grade 0–1; resume treatment in the next cycle at 75% of the recommended dose. Second occurrence: Discontinue treatment until toxicity resolves to Grade 0–1; resume treatment in the next cycle at 5...