XELODA
Antimetabolite, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
Capecitabine is a prodrug that is selectively tumour-activated to its cytotoxic moiety, fluorouracil, by thymidine phosphorylase. Fluorouracil is further metabolized to two active metabolites, 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), within normal and tumour cells. FdUMP inhibits DNA synthesis by reducing normal thymidine production, while FUTP inhibits RNA and protein synthesis by competing with uridine triphosphate.1 The active moiety of capecitabine, fluorouracil, is cell cycle phase-specific (S- phase).
| Interpatient variability | high interpatient variability 2 | |
| Oral Absorption | Rapidly and almost completely absorbed unchanged from GI tract 3 ; food decreases rate and extent of absorption but the clinical significance is unclear. 1,4 Capecitabine is recommended to be taken with food because its efficacy and safety are based on studies when it was given within 30 min after a meal. 4 | |
| time to peak plasma concentration | capecitabine: 1.5 h; fluorouracil: 2 h | |
| Distribution | cross blood brain barrier? | no information found |
| volume of distribution | no information found | |
| plasma protein binding | capecitabine and metabolites: < 60% | |
| Metabolism | Metabolized in the liver to 5'-deoxy-5-fluorocytidine (5'-DFCR) and then to 5'- deoxy-5-fluororuidine (5'-DFUR) in liver and tumour tissues. 5'-DFUR is activated to fluorouracil mainly at tumour site. Fluorouracil is metabolized to the active metabolites FdUMP and FUTP in normal and tumour cells and to the inactive metabolite a -fluoro- b -alanine (FBAL) by dihydropyrimidine dehydrogenase. Mild to moderate hepatic dysfunction has no clinically significant influence on the pharmacokinetics of capecitabine and its metabolites. 5 | |
| active metabolite(s) | fluorouracil, 5'-DFCR, 5'-DFUR, FdUMP, FUTP | |
| inactive metabolite(s) | FBAL | |
| Excretion | mainly renal excretion | |
| urine | 84% in the first 24 h and 96% over 7 days as capecitabine and metabolites 3 | |
| terminal half life | capecitabine: 0.75 h; fluorouracil: 0.75 h | |
| clearance | no information found | |
| Gender | no clinically significant difference | |
| Elderly | no clinically significant difference on 5'-DFUR and fluorouracil pharmacokinetics | |
| Children | no information found | |
| Ethnicity | similar in black and white patients; no information found with other ethnic groups | |
Adapted from reference 3 unless specified otherwise.
| Primary uses: | Other uses: |
| * Breast cancer 6,7 | Pancreatic cancer 8,9 |
| * Colorectal cancer 10-12 | |
*
Health Canada Therapeutic Products Programme approved indication No pediatric indications.
Contraindicated in patients with known hypersensitivity to capecitabine or fluorouracil1 and in patients with severe renal dysfunction (CrCl < 30 mL/min).13
Dihydropyrimidine dehydrogenase (DPD) deficiency:
DPD is a rate-limiting enzyme in the metabolism of fluorouracil, the active moiety of capecitabine. DPD deficiency is present in about 3% of cancer patients and follows an autosomal recessive inheritance. DPD deficient patients are at a greater risk of severe capecitabine-related
toxicities. Capecitabine should be used with caution in this patient population and may require dose reduction.14,15 Currently, screening for DPD deficiency is not readily available.14 Geriatrics: Patients over 65 (particularly over 80) may be more sensitive to the adverse effects of fluorouracil, specially severe GI toxicity (eg, diarrhea, nausea, vomiting).1,16,17 Dose reduction may be required.18
Carcinogenicity:
No information found.
Mutagenicity:
Not mutagenic in Ames test and in mammalian in vitro mutation tests. Capecitabine is clastogenic in human lymphocytes in vitro but not in other mammalian in vivo chromosome test. Note that fluorouracil is mutagenic in Ames test and clastogenic in mammalian in vivo chromosome test.
1,16
Fertility:
Studies in animals have shown decreased fertility.
1,16
Pregnancy: FDA Pregnancy Category D.16 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
Breastfeeding 1
is not recommended because significant amounts of capecitabine metabolites have been found in breast milk in animal studies.
The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important. When placebo-controlled trials are available, adverse events are included if the incidence is >5% higher in the treatment group.
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| blood/bone marrow | anemia (72-80%, severe 2-4%) |
| lymphopenia (94%, severe 37 * -59 + %) | |
| neutropenia (21-26%, severe 4%) | |
| thrombocytopenia (20-24%, severe 1-4%) | |
| cardiovascular (general) | cardiotoxicity (3%, severe 1%) 19 (see below) |
| edema (5-9%, severe 1%) | |
| coagulation | idiopathic thrombocytopenic purpura (severe 1%) |
| ORGAN SITE | SIDE EFFECT |
| Clinically important side effects are in bold, italics | |
| constitutional symptoms | fatigue (32-41%, severe 3-8%) |
| fever (9-12%, severe 1%) | |
| dermatology/skin | alopecia (6%) |
| rash (24-37%, severe 1%) | |
| hand-foot skin reaction (53-57%, severe 11-17%) | |
| nail changes (7%, severe 0%) | |
| photosensitivity (rare) | |
| radiation recall reaction (rare) | |
| skin discoloration (7%, severe 0%) | |
| gastrointestinal | emetogenic potential: low moderate 20 |
| anorexia (20-23%, severe 1-3%) | |
| constipation (7-15%, severe 1%) | |
| dehydration (4-7%, severe 2-4%) | |
| diarrhea (49-57%, severe 15%) | |
| dyspepsia (8%, severe 0%) | |
| nausea (38 * -53 + %, severe 4%) | |
| stomatitis (25%, severe 2-7%) | |
| vomiting (23 * -37 + %, severe 4%) | |
| hepatic | hyperbilirubinemia (22 + -49 * %, severe 19%) |
| elevated alkaline phosphatase (29%) 10 | |
| elevated AST (26%) 10 | |
| elevated ALT (15%, severe 3%) 10 | |
| metabolic/laboratory | hypocalcemia (severe 2%) 6 |
| neurology | dizziness (5-8%, severe 0%) |
| insomnia (8%, severe 0%) | |
| paresthesia (9-21%, severe 1%) | |
| sensory disturbance (6%, severe 0%) | |
| ocular/visual | eye irritation/conjunctivitis 10 (11%, severe 3%) |
| pain | abdominal pain (17-20%, severe 4%) |
| headache (9%, severe 1%) | |
| myalgia (9%, severe 0%) | |
| pain in limb (6%, severe 1%) | |
| pulmonary | dyspnea (6%, severe 0%) |
Adapted from reference 3 unless specified otherwise. Cardiotoxicity occurs in 3% of patients treated with capecitabine and can be fatal.19,21 The spectrum of cardiotoxicity is similar to that reported with 5-fluorouracil (5-FU) and includes myocardial infarction, angina, dysrhythmias, cardiac arrest, cardiac failure and ECG changes.22 Symptoms often occur within 2-3 days after capecitabine is started. The mechanism of capecitabine-related cardiotoxicity is not known.23 Risk factors include a history of cardiotoxicity associated with 5-FU therapy, and a prior history of coronary artery disease.22,23 Management includes discontinuation of capecitabine.19,21,23
Capecitabine
Hand-foot skin reaction
: Also known as hand-and-foot syndrome and palmar-plantar erythrodysesthesia. The palms of the hands and soles of the feet become dry, furrowed, red, numb, and tingling, with or without associated swelling. The reaction may interfere with daily activities, especially when blistering, moist desquamation (shedding of
scales or small sheets of skin), severe pain, or ulceration occurs.6,17 The exact mechanism of the reaction is unknown, although manual labour or vigorous exercise may exacerbate the condition.17 It usually appears during the early cycles but can also occur in later cycles of capecitabine. Symptoms may manifest at any time within a treatment cycle or in between cycles and usually improve with interruption of capecitabine.6,17 When hand-foot skin reaction of >= grade 2 severity (skin changes with pain but not interfering with function) occurs, capecitabine therapy should be interrupted immediately and resumed at a reduced dose when the toxicity resolves to grade 0-1.24 Limited data are available on the prevention and management of hand-foot skin reaction but the following measures have been suggested:
avoid tight-fitting shoes or repetitive rubbing pressure to hands and feet, such as that produced by strenuous activities
apply lanolin-containing creams (eg, Bag Balm(r), Udderly Smooth(r)) liberally and frequently to affected areas17
vitamin B6 (pyridoxine) 50-150 mg orally daily.25-27
Hyperbilirubinemia: Severe hyperbilirubinemia has been reported, with twice the prevalence in patients with liver metastases.1 Concurrent elevations in alkaline phosphatase and/or transaminases may occur with hyperbilirubinemia.6,10 If hyperbilirubinemia of >= grade 2 severity (serum bilirubin > 1.5 times the normal upper limit) occurs, capecitabine therapy should be interrupted immediately until hyperbilirubinemia resolves; dosage reduction may be needed for subsequent capecitabine doses. The effect of severe hepatic dysfunction on capecitabine is unknown.1,5,16
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
| warfarin | increased anticoagulation | unknown | monitor INR regularly (eg, weekly) 28 during and after capecitabine therapy (eg, up to 1 month after stopping capecitabine therapy); adjust warfarin dose as needed |
| docetaxel 2 | no pharmacokinetic interactions | ||
| magnesium and aluminum hydroxide- containing antacid (eg, Maalox (r) ) | no significant influence on capecitabine pharmacokinetics 29 | Maalox (r) can be taken with capecitabine if an antacid is needed; other antacids should be taken two hours apart from capecitabine 17,29 | |
| paclitaxel 30 | no pharmacokinetic interactions | ||
| phenytoin and fosphenytoin | increased serum phenytoin levels | unknown | monitor serum phenytoin level regularly and monitor patients closely for phenytoin toxicities during concurrent therapy |
Adapted from reference 3 unless specified otherwise.
Tablets: 150 and 500 mg, inactive ingredients include lactose. Store at room temperature.1
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.
Adults:
BCCA usual dose noted in bold, italics Cycle Length
Oral:
3 weeks1,9,24: 1250 mg/m2 (range 313-1250 mg/m2) PO twice a day for 14 consecutive days starting on day 1 (total dose per cycle 35 000 mg/m2 [range 8764- 35 000 mg/m2]). For dose level of 1250 mg/m2, round dose according to dose calculation table below; for other dose levels, round off to the nearest 150 mg. Administer within 30 min following the end of a meal.1 Capecitabine dose calculation according to BSA1:
| dose level 1250 mg/m 2 twice a day | number of tablets per dose | ||
| surface area (m 2 ) | single dose (mg) | 150 mg | 500 mg |
| <= 1.25 | 1500 | 0 | 3 |
| 1.26-1.37 | 1650 | 1 | 3 |
| 1.38-1.51 | 1800 | 2 | 3 |
| 1.52-1.65 | 2000 | 0 | 4 |
| 1.66-1.77 | 2150 | 1 | 4 |
| 1.78-1.91 | 2300 | 2 | 4 |
| 1.92-2.05 | 2500 | 0 | 5 |
| 2.06-2.17 | 2650 | 1 | 5 |
| >= 2.18 | 2800 | 2 | 5 |
| Adverse event | 1st event dose * | 2nd event dose * | 3rd event dose * | 4th event dose * | |
| grade | hand-foot skin reaction | ||||
| 1 | Skin changes (e.g., numbness, dysesthesia, paresthesia, tingling, erythema) with discomfort not disrupting normal activities | 100% | 100% | 100% | 100% |
| 2 | Skin changes (e.g., erythema, swelling) with pain affecting activities of daily living | delay then 100% | delay then 75% | delay then 50% | discontinue |
| 3 | Severe skin changes (e.g., moist desquamation, ulceration, blistering) with pain, causing severe discomfort and inability to work or perform activities of daily living | delay then 75% | discontinue or delay then 50% | discontinue | discontinue |
Dosage in myelosuppression: Dosage in hand-foot skin reaction22: modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression". * as a percentage of the original starting dose Doses omitted for toxicity should not be replaced. Instead, the patient should resume the originally planned treatment. For example, if treatment is interrupted on day 3 of a 14-day course, the patient would still take the last dose of capecitabine on day 14. Once the dose has been reduced, it should not be increased at later time.1 For example, if the original starting dose level of 1250 mg/m2 dose was reduced to 625 mg/m2 during a treatment cycle, then the dose for subsequent cycles should not exceed 625mg/m2.
Dosage in renal failure:
No dose adjustment is required in mild renal dysfunction (CrCl 50-80 mL/min).
Starting dose should be reduced to 75% of recommended dose for moderate renal dysfunction (CrCl 30-50 mL/min). Capecitabine is contraindicated in severe renal dysfunction (CrCl < 30 mL/min).13 Dosage in hepatic failure: No dose adjustment required with mild to moderate hepatic dysfunction due to liver metastases.1,5 Studies have not been done in patients with severe hepatic dysfunction.1
Dosage in dialysis:
no information found
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Frickhofen N, Beck FJ, Jung B, et al. Capecitabine can induce acute coronary syndrome similar to 5-fluorouracil. Ann Oncol 2002; 13(5):797-801.
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Vukelja S, Lombardo F, James W, et al. Pyridoxine for the palmar-plantar erythrodysesthesia syndrome. Annals of Internal Medicine 1989; 111:688-689.
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