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mechanism of action is Nucleic Acid Synthesis Inhibitors [MoA]

Capecitabine 150mg

(Capecitabine)

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Capecitabine 150mg Prescribing Information

Capecitabine Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important capecitabine-Warfarin drug interaction was demonstrated in a clinical pharmacology trial

[see

5.2 Diarrhea

Capecitabine 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 capecitabine 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 capecitabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1.

[see Dosage and Administration (2.3)]

. Standard antidiarrheal treatments (eg, loperamide) are recommended.

Necrotizing enterocolitis (typhlitis) has been reported.

and Drug Interactions (7.1)]

. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Post marketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time capecitabine was introduced. These events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within 1 month after stopping capecitabine. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Capecitabine tablets are a nucleoside metabolic inhibitor with antineoplastic activity indicated for:

• Adjuvant Colon Cancer

1.1 Colorectal Cancer

Capecitabine tablets are indicated as a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine tablets are non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent capecitabine tablets in the adjuvant treatment of Dukes' C colon cancer.
Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with capecitabine tablets monotherapy. Use of capecitabine tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.

– Patients with Dukes' C colon cancer

• Metastatic Colorectal Cancer

1.1 Colorectal Cancer

Capecitabine tablets are indicated as a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine tablets are non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent capecitabine tablets in the adjuvant treatment of Dukes' C colon cancer.
Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with capecitabine tablets monotherapy. Use of capecitabine tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.

– First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred

• Metastatic Breast Cancer

1.2 Breast Cancer

Capecitabine tablets in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
Capecitabine tablets monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m²of doxorubicin or doxorubicin equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.

– In combination with docetaxel after failure of prior anthracycline containing therapy

– As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen

Lactation:
Advise women not to breast feeding.
8.2 Lactation
Risk Summary
There is no information regarding the presence of capecitabine in human milk, or on its effect on milk production or the breast-fed infant. Capecitabine metabolites were present in the milk of lactating mice
[see Data].
Because of the potential for serious adverse reactions from capecitabine exposure in breast-fed infants, advise women not to breastfeed during treatment with capecitabine and for 2 weeks after the final dose.
Data
Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolise into the milk
Females and males of reproductive potential: Verify pregnancy status of females prior to initiation of Capecitabine tablets. Advise males with female partners of reproductive potential to use effective contraception.
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Pregnancy testing is recommended for females of reproductive potential prior to initiating capecitabine.
Contraception
Females
Capecitabine can cause fetal harm when administered to a pregnant woman
[see Use in Specific Populations (8.1)]
. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the final dose of capecitabine.
Males
Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the last dose of capecitabine
[see Nonclinical Toxicology (13.1)]
Infertility
Based on animal studies, capecitabine may impair fertility in females and males of reproductive potential
[see Nonclinical Toxicology (13.1)]
Geriatric:
Greater incidence of adverse reactions. Monitoring required.
8.5 Geriatric Use
Physicians should pay particular attention to monitoring the adverse effects of capecitabine in the elderly [
see Warnings and Precautions
].
Hepatic Impairment: Monitoring is recommended in patients with mild to moderate hepatic impairment.
8.6 Hepatic Insufficiency
Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with capecitabine. The effect of severe hepatic dysfunction on capecitabine is not known
[see Warnings and Precautions (5.11 )and Clinical Pharmacology (12.3)].
Renal Impairment:
Reduce capecitabine starting dose in patients with moderate renal impairment (
2.4 Adjustment of Starting Dose in Special Populations
Renal Impairment
No adjustment to the starting dose of capecitabine tablets is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the capecitabine starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m²to 950 mg/m²twice daily) is recommended
[see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]
. Subsequent dose adjustment is recommended as outlined in
Table 2
and
Table 3
(depending on the regimen) if a patient develops a grade 2 to 4 adverse event
[see Warnings and Precautions (5.5)]
. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both capecitabine tablets monotherapy and capecitabine tablets in combination use with docetaxel.
Cockroft and Gault Equation:
(140 - age [yrs]) (body wt [kg])
Creatinine clearance for males = —————————————
(72) (serum creatinine [mg/dL])
Creatinine clearance for females = 0.85 x male value
Geriatrics
Physicians should exercise caution in monitoring the effects of capecitabine tablets in the elderly. Insufficient data are available to provide a dosage recommendation.
,
8.7 Renal Insufficiency
Patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for capecitabine, 5-FDUR, and FBAL than in those with normal renal function
[see Contraindications (4.2), Warnings and Precautions (5.5), Dosage and Administration (2.4), and Clinical Pharmacology (12.3)]
.
,
12.3 Pharmacokinetics
Absorption
Following oral administration of 1255 mg/m²BID to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (T_max) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean C_maxand AUC_0-∞decreased by 60% and 35%, respectively. The C_maxand AUC_0-∞of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed T_maxof both parent and 5-FU by 1.5 hours
[see Warnings and Precautions (5), Dosage and Administration (2), and Drug-Food Interaction (7.2)]
.
The pharmacokinetics of capecitabine and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m²/day. Over this range, the pharmacokinetics of capecitabine and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the C_maxand AUC of 5-FU was greater than 85%.
Distribution
Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%). Capecitabine tablet has a low potential for pharmacokinetic interactions related to plasma protein binding.
Bioactivation and Metabolism
Capecitabine is extensively metabolized enzymatically to 5-FU. 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'-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. Following oral administration of capecitabine 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.
Metabolic Pathway of capecitabine to 5-FU3
The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido- propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine.
In vitro
enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.
Excretion
Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-FU was about 0.75 hour.
Effect of Age, Gender, and Race on the Pharmacokinetics of Capecitabine
A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered capecitabine at 1250 mg/m²twice a day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL
[see Warnings and Precautions (5.11)and Dosage and Administration (2.4)]
.
Following oral administration of 825 mg/m²capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower C_maxand 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower C_maxand 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU).
Effect of Hepatic Insufficiency
Capecitabine has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1255 mg/m²dose of capecitabine. Both AUC_0-∞and C_maxof capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC_0-∞and C_maxof 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when capecitabine is administered. The effect of severe hepatic dysfunction on capecitabine is not known
[see Warnings and Precautions (5.11)and Use in Special Populations (8.6)].
Effect of Renal Insufficiency
Following oral administration of 1250 mg/m²capecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day 1 compared to normal renal function patients (creatinine clearance >80 mL/min). Systemic exposure to 5'-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients
[see Dosage and Administration (2.4), Contraindications (4.2), Warnings and Precautions (5.5), and Use in Special Populations (8.7)]
.
Effect of Capecitabine on the Pharmacokinetics of Warfarin
In four patients with cancer, chronic administration of capecitabine (1250 mg/m²bid) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91%
[see Boxed Warningand Drug Interactions (7.1)].
Effect of Antacids on the Pharmacokinetics of Capecitabine
When Maalox^®(20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after capecitabine (1250 mg/m², n=12 cancer patients), AUC and C_maxincreased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5'-DFCR. No effect was observed on the other three major metabolites (5'-DFUR, 5-FU, FBAL) of capecitabine.
Effect of Allopurinol on Capecitabine
Published literature reported that concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites, FdUMP and FUTP; however, the clinical significance was not fully characterized.
Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa
A Phase 1 study evaluated the effect of capecitabine on the pharmacokinetics of docetaxel (Taxotere^®) and the effect of docetaxel on the pharmacokinetics of capecitabine was conducted in 26 patients with solid tumors. Capecitabine was found to have no effect on the pharmacokinetics of docetaxel (C_maxand AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5'-DFUR.

Severe Renal Impairment
4.1 Severe Renal Impairment
Capecitabine tablets are contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault])
[see Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]
.
Hypersensitivity
4.2 Hypersensitivity
Capecitabine tablets are contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. Capecitabine tablets are contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.

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