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Xeloda
Overview
What is Xeloda?
XELODA (capecitabine) is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5-fluorouracil.
The chemical name for capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a molecular weight of 359.35. Capecitabine has the following structural formula:
Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20°C.
XELODA is supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 mg capecitabine. The inactive ingredients in XELODA include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.
What does Xeloda look like?
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What are the available doses of Xeloda?
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What should I talk to my health care provider before I take Xeloda?
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How should I use Xeloda?
The recommended dose of XELODA is 1250 mg/m administered orally twice daily (morning and evening; equivalent to 2500 mg/m total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles. XELODA tablets should be swallowed with water within 30 minutes after a meal. In combination with docetaxel, the recommended dose of XELODA is 1250 mg/m twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m as a 1-hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the XELODA plus docetaxel combination. displays the total daily dose by body surface area and the number of tablets to be taken at each dose.
Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months, ie, XELODA 1250 mg/m orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks).
What interacts with Xeloda?
XELODA is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. XELODA is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil. XELODA is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. XELODA is also contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) (see ).
What are the warnings of Xeloda?
Renal Insufficiency
Patients with moderate renal impairment at baseline require dose reduction (see ). Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse events. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in in .
Coagulopathy
See .
Diarrhea
XELODA can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of ≥10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of XELODA should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of XELODA should be decreased (see ). Standard antidiarrheal treatments (eg, loperamide) are recommended.
Necrotizing enterocolitis (typhlitis) has been reported.
Geriatric Patients
Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse events (see ). In 875 patients with either metastatic breast or colorectal cancer who received XELODA monotherapy, 62% of the 21 patients ≥80 years of age treated with XELODA experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with XELODA in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.
Among the 67 patients ≥60 years of age receiving XELODA in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse events, treatment-related serious adverse events, withdrawals due to adverse events, treatment discontinuations due to adverse events and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group.
In 995 patients receiving XELODA as adjuvant therapy for Dukes' C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥65 years of age treated with XELODA experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients ≥65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes' C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for XELODA compared to 5-FU/LV were 1.01 (95% C.I. 0.80 – 1.27) and 1.04 (95% C.I. 0.79 – 1.37), respectively.
Pregnancy
XELODA may cause fetal harm when given to a pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.2 times the corresponding values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5'-DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose. There are no adequate and well-controlled studies in pregnant women using XELODA. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.
What are the precautions of Xeloda?
General
Patients receiving therapy with XELODA should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced (see ).
Combination With Other Drugs
Use of XELODA in combination with irinotecan has not been adequately studied.
Hand-and-Foot Syndrome
Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving XELODA monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If grade 2 or 3 hand-and-foot syndrome occurs, administration of XELODA should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of XELODA should be decreased (see ).
Cardiotoxicity
The cardiotoxicity observed with XELODA includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse events may be more common in patients with a prior history of coronary artery disease.
Dihydropyrimidine Dehydrogenase Deficiency
Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded.
Hepatic Insufficiency
Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when XELODA is administered. The effect of severe hepatic dysfunction on the disposition of XELODA is not known (see and ).
Hyperbilirubinemia
In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of XELODA 1250 mg/m twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 × ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 (>3 × ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.
In the 596 patients treated with XELODA as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of XELODA monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 µm/L at baseline to 13 µm/L during treatment with XELODA. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.
In 251 patients with metastatic breast cancer who received a combination of XELODA and docetaxel, grade 3 (1.5 to 3 × ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 × ULN) hyperbilirubinemia occurred in 2% (n=5).
If drug-related grade 2 to 4 elevations in bilirubin occur, administration of XELODA should be immediately interrupted until the hyperbilirubinemia resolves or decreases in intensity to grade 1. NCIC grade 2 hyperbilirubinemia is defined as 1.5 × normal, grade 3 hyperbilirubinemia as 1.5 to 3 × normal and grade 4 hyperbilirubinemia as >3 × normal. (See recommended dose modifications under .)
Hematologic
In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of XELODA in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Adequate studies investigating the carcinogenic potential of XELODA have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.
Impairment of Fertility
In studies of fertility and general reproductive performance in mice, oral capecitabine doses of 760 mg/kg/day disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.
Information for Patients (see Patient Package Insert)
Patients and patients' caregivers should be informed of the expected adverse effects of XELODA, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary (see ). Patients should be encouraged to recognize the common grade 2 toxicities associated with XELODA treatment.
Diarrhea
Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater should be instructed to stop taking XELODA immediately. Standard antidiarrheal treatments (eg, loperamide) are recommended.
Nausea
Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended.
Vomiting
Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended.
Hand-and-Foot Syndrome
Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients' activities of daily living) or greater should be instructed to stop taking XELODA immediately.
Stomatitis
Patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended (see ).
Fever and Neutropenia
Patients who develop a fever of 100.5°F or greater or other evidence of potential infection should be instructed to call their physician.
Drug-Food Interaction
In all clinical trials, patients were instructed to administer XELODA within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that XELODA be administered with food (see ).
Drug-Drug Interactions
Antacid
The effect of an aluminum hydroxide- and magnesium hydroxide-containing antacid (Maalox) on the pharmacokinetics of XELODA was investigated in 12 cancer patients. There was a small increase in plasma concentrations of XELODA and one metabolite (5'-DFCR); there was no effect on the 3 major metabolites (5'-DFUR, 5-FU and FBAL).
Anticoagulants
Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly (see and ). Altered coagulation parameters and/or bleeding have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These events occurred within several days and up to several months after initiating XELODA therapy and, in a few cases, within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites (see ).
CYP2C9 substrates
Other than warfarin, no formal drug-drug interaction studies between XELODA and other CYP2C9 substrates have been conducted. Care should be exercised when XELODA is coadministered with CYP2C9 substrates.
Phenytoin
The level of phenytoin should be carefully monitored in patients taking XELODA and phenytoin dose may need to be reduced (see ). Postmarketing reports indicate that some patients receiving XELODA and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites (see ).
Leucovorin
The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
Pregnancy
Teratogenic Effects
Category D (see ). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA.
Nursing Women
Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. Because of the potential for serious adverse reactions in nursing infants from capecitabine, it is recommended that nursing be discontinued when receiving XELODA therapy.
Pediatric Use
The safety and effectiveness of XELODA in persons <18 years of age have not been established.
Geriatric Use
Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly (see ).
What are the side effects of Xeloda?
Adjuvant Colon Cancer
Array
Table 11
Array
Table 12
| Adjuvant Treatment for Colon Cancer (N=1969) | ||||
|---|---|---|---|---|
| XELODA(N=995) | 5-FU/LV(N=974) | |||
| Body System/Adverse Event | All Grades | Grade 3/4 | All Grades | Grade 3/4 |
| Gastrointestinal Disorders | ||||
| Diarrhea | 47 | 12 | 65 | 14 |
| Nausea | 34 | 2 | 47 | 2 |
| Stomatitis | 22 | 2 | 60 | 14 |
| Vomiting | 15 | 2 | 21 | 2 |
| Abdominal Pain | 14 | 3 | 16 | 2 |
| Constipation | 9 | - | 11 | <1 |
| Upper Abdominal Pain | 7 | <1 | 7 | <1 |
| Dyspepsia | 6 | <1 | 5 | - |
| Skin and Subcutaneous Tissue Disorders | ||||
| Hand-and-Foot Syndrome | 60 | 17 | 9 | <1 |
| Alopecia | 6 | - | 22 | <1 |
| Rash | 7 | - | 8 | - |
| Erythema | 6 | 1 | 5 | <1 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue | 16 | <1 | 16 | 1 |
| Pyrexia | 7 | <1 | 9 | <1 |
| Asthenia | 10 | <1 | 10 | 1 |
| Lethargy | 10 | <1 | 9 | <1 |
| Nervous System Disorders | ||||
| Dizziness | 6 | <1 | 6 | - |
| Headache | 5 | <1 | 6 | <1 |
| Dysgeusia | 6 | - | 9 | - |
| Metabolism and Nutrition Disorders | ||||
| Anorexia | 9 | <1 | 11 | <1 |
| Eye Disorders | ||||
| Conjunctivitis | 5 | <1 | 6 | <1 |
| Blood and Lymphatic System Disorders | ||||
| Neutropenia | 2 | <1 | 8 | 5 |
| Respiratory Thoracic and Mediastinal Disorders | ||||
| Epistaxis | 2 | - | 5 | - |
| Adverse Event | XELODA(n=995) | IV 5-FU/LV(n=974) | ||
| Grade 3/4 % | Grade 3/4 % | |||
| Increased ALAT (SGPT) | 1.6 | 0.6 | ||
| Increased calcium | 1.1 | 0.7 | ||
| Decreased calcium | 2.3 | 2.2 | ||
| Decreased hemoglobin | 1.0 | 1.2 | ||
| Decreased lymphocytes | 13.0 | 13.0 | ||
| Decreased neutrophils | 2.2 | 26.2 | ||
| Decreased neutrophils/granulocytes | 2.4 | 26.4 | ||
| Decreased platelets | 1.0 | 0.7 | ||
| Increased bilirubin | 20 | 6.3 |
Metastatic Colorectal Cancer
Table 13
| – Not observed | |||||||
| NA = Not Applicable | |||||||
| Adverse Event | XELODA(n=596) | 5-FU/LV(n=593) | |||||
|---|---|---|---|---|---|---|---|
| Total% | Grade 3% | Grade 4% | Total% | Grade 3% | Grade 4% | ||
| 96 | 52 | 9 | 94 | 45 | 9 | ||
| Body System/Adverse Event | |||||||
| Diarrhea | 55 | 13 | 2 | 61 | 10 | 2 | |
| Nausea | 43 | 4 | – | 51 | 3 | <1 | |
| Vomiting | 27 | 4 | <1 | 30 | 4 | <1 | |
| Stomatitis | 25 | 2 | <1 | 62 | 14 | 1 | |
| Abdominal Pain | 35 | 9 | <1 | 31 | 5 | – | |
| Gastrointestinal Motility Disorder | 10 | <1 | – | 7 | <1 | – | |
| Constipation | 14 | 1 | <1 | 17 | 1 | – | |
| Oral Discomfort | 10 | – | – | 10 | – | – | |
| Upper GI Inflammatory Disorders | 8 | <1 | – | 10 | 1 | – | |
| Gastrointestinal Hemorrhage | 6 | 1 | <1 | 3 | 1 | – | |
| Ileus | 6 | 4 | 1 | 5 | 2 | 1 | |
| Hand-and-Foot Syndrome | 54 | 17 | NA | 6 | 1 | NA | |
| Dermatitis | 27 | 1 | – | 26 | 1 | – | |
| Skin Discoloration | 7 | <1 | – | 5 | – | – | |
| Alopecia | 6 | – | – | 21 | <1 | – | |
| Fatigue/Weakness | 42 | 4 | – | 46 | 4 | – | |
| Pyrexia | 18 | 1 | – | 21 | 2 | – | |
| Edema | 15 | 1 | – | 9 | 1 | – | |
| Pain | 12 | 1 | – | 10 | 1 | – | |
| Chest Pain | 6 | 1 | – | 6 | 1 | <1 | |
| Peripheral Sensory Neuropathy | 10 | – | – | 4 | – | – | |
| Headache | 10 | 1 | – | 7 | – | – | |
| Dizziness | 8 | <1 | – | 8 | <1 | – | |
| Insomnia | 7 | – | – | 7 | – | – | |
| Taste Disturbance | 6 | 1 | – | 11 | <1 | 1 | |
| Appetite Decreased | 26 | 3 | <1 | 31 | 2 | <1 | |
| Dehydration | 7 | 2 | <1 | 8 | 3 | 1 | |
| Eye Irritation | 13 | – | – | 10 | <1 | – | |
| Vision Abnormal | 5 | – | – | 2 | – | – | |
| Dyspnea | 14 | 1 | – | 10 | <1 | 1 | |
| Cough | 7 | <1 | 1 | 8 | – | – | |
| Pharyngeal Disorder | 5 | – | – | 5 | – | – | |
| Epistaxis | 3 | <1 | – | 6 | – | – | |
| Sore Throat | 2 | – | – | 6 | – | – | |
| Back Pain | 10 | 2 | – | 9 | <1 | – | |
| Arthralgia | 8 | 1 | – | 6 | 1 | – | |
| Venous Thrombosis | 8 | 3 | <1 | 6 | 2 | – | |
| Mood Alteration | 5 | – | – | 6 | <1 | – | |
| Depression | 5 | – | – | 4 | <1 | – | |
| Viral | 5 | <1 | – | 5 | <1 | – | |
| Anemia | 80 | 2 | <1 | 79 | 1 | <1 | |
| Neutropenia | 13 | 1 | 2 | 46 | 8 | 13 | |
| Hyperbilirubinemia | 48 | 18 | 5 | 17 | 3 | 3 |
Breast Cancer Combination
The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in and . In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/m twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/m on the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m on the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse events. The percentage of patients requiring dose reductions due to adverse events was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse events in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.
| – Not observed | ||||||
| NA = Not Applicable | ||||||
| Adverse Event | XELODA 1250 mg/m/bidWith Docetaxel75 mg/m/3 weeks | Docetaxel100 mg/m/3 weeks | ||||
|---|---|---|---|---|---|---|
| (n=251) | (n=255) | |||||
| Total% | Grade 3% | Grade 4% | Total% | Grade 3% | Grade 4% | |
| Number of Patients With at Least One Adverse Event | 99 | 76.5 | 29.1 | 97 | 57.6 | 31.8 |
| Body System/Adverse Event | ||||||
| GI | ||||||
| Diarrhea | 67 | 14 | <1 | 48 | 5 | <1 |
| Stomatitis | 67 | 17 | <1 | 43 | 5 | – |
| Nausea | 45 | 7 | – | 36 | 2 | – |
| Vomiting | 35 | 4 | 1 | 24 | 2 | – |
| Constipation | 20 | 2 | – | 18 | – | – |
| Abdominal Pain | 30 | <3 | <1 | 24 | 2 | – |
| Dyspepsia | 14 | – | – | 8 | 1 | – |
| Dry Mouth | 6 | <1 | – | 5 | – | – |
| Skin and Subcutaneous | ||||||
| Hand-and-Foot Syndrome | 63 | 24 | NA | 8 | 1 | NA |
| Alopecia | 41 | 6 | – | 42 | 7 | – |
| Nail Disorder | 14 | 2 | – | 15 | – | – |
| Dermatitis | 8 | – | – | 11 | 1 | – |
| Rash Erythematous | 9 | <1 | – | 5 | – | – |
| Nail Discoloration | 6 | – | – | 4 | <1 | – |
| Onycholysis | 5 | 1 | – | 5 | 1 | – |
| Pruritus | 4 | – | – | 5 | – | – |
| General | ||||||
| Pyrexia | 28 | 2 | – | 34 | 2 | – |
| Asthenia | 26 | 4 | <1 | 25 | 6 | – |
| Fatigue | 22 | 4 | – | 27 | 6 | – |
| Weakness | 16 | 2 | – | 11 | 2 | – |
| Pain in Limb | 13 | <1 | – | 13 | 2 | – |
| Lethargy | 7 | – | – | 6 | 2 | – |
| Pain | 7 | <1 | – | 5 | 1 | – |
| Chest Pain (non-cardiac) | 4 | <1 | – | 6 | 2 | – |
| Influenza-like Illness | 5 | – | – | 5 | – | – |
| Neurological | ||||||
| Taste Disturbance | 16 | <1 | – | 14 | <1 | – |
| Headache | 15 | 3 | – | 15 | 2 | – |
| Paresthesia | 12 | <1 | – | 16 | 1 | – |
| Dizziness | 12 | – | – | 8 | <1 | – |
| Insomnia | 8 | – | – | 10 | <1 | – |
| Peripheral Neuropathy | 6 | – | – | 10 | 1 | – |
| Hypoaesthesia | 4 | <1 | – | 8 | <1 | – |
| Metabolism | ||||||
| Anorexia | 13 | 1 | – | 11 | <1 | – |
| Appetite Decreased | 10 | – | – | 5 | – | – |
| Weight Decreased | 7 | – | – | 5 | – | – |
| Dehydration | 10 | 2 | – | 7 | <1 | <1 |
| Eye | ||||||
| Lacrimation Increased | 12 | – | – | 7 | <1 | – |
| Conjunctivitis | 5 | – | – | 4 | – | – |
| Eye Irritation | 5 | – | – | 1 | – | – |
| Musculoskeletal | ||||||
| Arthralgia | 15 | 2 | – | 24 | 3 | – |
| Myalgia | 15 | 2 | – | 25 | 2 | – |
| Back Pain | 12 | <1 | – | 11 | 3 | – |
| Bone Pain | 8 | <1 | – | 10 | 2 | – |
| Cardiac | ||||||
| Edema | 33 | <2 | – | 34 | <3 | 1 |
| Blood | ||||||
| Neutropenic Fever | 16 | 3 | 13 | 21 | 5 | 16 |
| Respiratory | ||||||
| Dyspnea | 14 | 2 | <1 | 16 | 2 | – |
| Cough | 13 | 1 | – | 22 | <1 | – |
| Sore Throat | 12 | 2 | – | 11 | <1 | – |
| Epistaxis | 7 | <1 | – | 6 | – | – |
| Rhinorrhea | 5 | – | – | 3 | – | – |
| Pleural Effusion | 2 | 1 | – | 7 | 4 | – |
| Infection | ||||||
| Oral Candidiasis | 7 | <1 | – | 8 | <1 | – |
| Urinary Tract Infection | 6 | <1 | – | 4 | – | – |
| Upper Respiratory Tract | 4 | – | – | 5 | 1 | – |
| Vascular | ||||||
| Flushing | 5 | – | – | 5 | – | – |
| Lymphoedema | 3 | <1 | – | 5 | 1 | – |
| Psychiatric | ||||||
| Depression | 5 | – | – | 5 | 1 | – |
| Adverse Event | XELODA 1250 mg/m/bidWith Docetaxel75 mg/m/3 weeks | Docetaxel100 mg/m/3 weeks | ||||
| (n=251) | (n=255) | |||||
| Body System/Adverse Event | Total% | Grade 3% | Grade 4% | Total% | Grade 3% | Grade 4% |
| Hematologic | ||||||
| Leukopenia | 91 | 37 | 24 | 88 | 42 | 33 |
| Neutropenia/Granulocytopenia | 86 | 20 | 49 | 87 | 10 | 66 |
| Thrombocytopenia | 41 | 2 | 1 | 23 | 1 | 2 |
| Anemia | 80 | 7 | 3 | 83 | 5 | <1 |
| Lymphocytopenia | 99 | 48 | 41 | 98 | 44 | 40 |
| Hepatobiliary | ||||||
| Hyperbilirubinemia | 20 | 7 | 2 | 6 | 2 | 2 |
Breast Cancer XELODA Monotherapy
The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse events/intercurrent illness.
| – Not observed | ||||
| NA = Not Applicable | ||||
| Adverse Event | Phase 2 Trial in Stage IV Breast Cancer(n=162) | |||
|---|---|---|---|---|
| Body System/Adverse Event | Total% | Grade 3% | Grade 4% | |
| Diarrhea | 57 | 12 | 3 | |
| Nausea | 53 | 4 | – | |
| Vomiting | 37 | 4 | – | |
| Stomatitis | 24 | 7 | – | |
| Abdominal Pain | 20 | 4 | – | |
| Constipation | 15 | 1 | – | |
| Dyspepsia | 8 | – | – | |
| Hand-and-Foot Syndrome | 57 | 11 | NA | |
| Dermatitis | 37 | 1 | – | |
| Nail Disorder | 7 | – | – | |
| Fatigue | 41 | 8 | – | |
| Pyrexia | 12 | 1 | – | |
| Pain in Limb | 6 | 1 | – | |
| Paresthesia | 21 | 1 | – | |
| Headache | 9 | 1 | – | |
| Dizziness | 8 | – | – | |
| Insomnia | 8 | – | – | |
| Anorexia | 23 | 3 | – | |
| Dehydration | 7 | 4 | 1 | |
| Eye Irritation | 15 | – | – | |
| Myalgia | 9 | – | – | |
| Edema | 9 | 1 | – | |
| Neutropenia | 26 | 2 | 2 | |
| Thrombocytopenia | 24 | 3 | 1 | |
| Anemia | 72 | 3 | 1 | |
| Lymphopenia | 94 | 44 | 15 | |
| Hyperbilirubinemia | 22 | 9 | 2 |
XELODA and Docetaxel in Combination
Shown below by body system are the clinically relevant adverse events in <5% of patients in the overall clinical trial safety database of 251 patients (Study Details) reported as related to the administration of XELODA in combination with docetaxel and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 and 4 occurrences of each adverse event.
It is anticipated that the same types of adverse events observed in the XELODA monotherapy studies may be observed in patients treated with the combination of XELODA plus docetaxel.
Gastrointestinal:
Neurological:
Cardiac:
Infection:
Blood and Lymphatic:
Vascular:
Renal:
Hepatobiliary:
Immune System:
XELODA Monotherapy Metastatic Breast and Colorectal Cancer
Shown below by body system are the clinically relevant adverse events in <5% of patients in the overall clinical trial safety database of 875 patients (phase 3 colorectal studies — 596 patients, phase 2 colorectal study — 34 patients, phase 2 breast cancer studies — 245 patients) reported as related to the administration of XELODA and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 or 4 occurrences of each adverse event.
Gastrointestinal:
Skin and Subcutaneous:
General:
Neurological:
Metabolism:
Eye:
Respiratory:
Cardiac:
Infections:
Musculoskeletal:
Blood and Lymphatic:
Vascular:
Psychiatric:
Renal:
Ear:
Hepatobiliary:
Immune System:
Postmarketing:
What should I look out for while using Xeloda?
XELODA is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. XELODA is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil. XELODA is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. XELODA is also contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) (see ).
What might happen if I take too much Xeloda?
The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for XELODA overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-DFUR, a low–molecular-weight metabolite of the parent compound.
Single doses of XELODA were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m basis).
How should I store and handle Xeloda?
Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Protect from light.Dispense in a tight, light-resistant container.Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Protect from light.Dispense in a tight, light-resistant container.XELODA is supplied as biconvex, oblong film-coated tablets, available in bottles as follows:150 mgcolor: light peachengraving: XELODA on one side, 150 on the other500 mgcolor: peachengraving: XELODA on one side, 500 on the other They are supplied by as follows:XELODA is supplied as biconvex, oblong film-coated tablets, available in bottles as follows:150 mgcolor: light peachengraving: XELODA on one side, 150 on the other500 mgcolor: peachengraving: XELODA on one side, 500 on the other They are supplied by as follows:XELODA is supplied as biconvex, oblong film-coated tablets, available in bottles as follows:150 mgcolor: light peachengraving: XELODA on one side, 150 on the other500 mgcolor: peachengraving: XELODA on one side, 500 on the other They are supplied by as follows:XELODA is supplied as biconvex, oblong film-coated tablets, available in bottles as follows:150 mgcolor: light peachengraving: XELODA on one side, 150 on the other500 mgcolor: peachengraving: XELODA on one side, 500 on the other They are supplied by as follows:XELODA is supplied as biconvex, oblong film-coated tablets, available in bottles as follows:150 mgcolor: light peachengraving: XELODA on one side, 150 on the other500 mgcolor: peachengraving: XELODA on one side, 500 on the other They are supplied by as follows:XELODA is supplied as biconvex, oblong film-coated tablets, available in bottles as follows:150 mgcolor: light peachengraving: XELODA on one side, 150 on the other500 mgcolor: peachengraving: XELODA on one side, 500 on the other They are supplied by as follows:
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Capecitabine is readily absorbed from the gastrointestinal tract. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'-deoxy-5-fluorouridine (5'-DFUR). The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5'-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues.
Metabolic Pathway of capecitabine to 5-FU
Non-Clinical Toxicology
XELODA is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. XELODA is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil. XELODA is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency. XELODA is also contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) (see ).Patients receiving therapy with XELODA should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced (see ).
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).