HLR 11/17/00
`
`XELODA®
`(capecitabine)
`TABLETS
`
`DESCRIPTION: 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:
`
`O
`
`N
`
`NH
`
`O
`
`H3C
`
`O
`
`N
`
`O
`
`F
`
`HO
`
`OH
`
`Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL
`at 20ºC.
`
`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.
`
`CLINICAL PHARMACOLOGY: Capecitabine is relatively non-cytotoxic in vitro. This drug
`is enzymatically converted to 5-fluorouracil (5-FU) in vivo.
`
`Bioactivation: Capecitabine is readily absorbed from the gastrointestinal tract. In the liver, a 60
`kDa carboxyesterase 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.
`
`C:\WINDOWS\TEMP\FrontPageTempDir\xeloda.doc
`
`FMI v. Caris MPI
`Exhibit 1155
`IPR2019-00170
`
`

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`HLR 11/17/00
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`XELODA® (capecitabine)
`
`Metabolic Pathway of capecitabine to 5-FU
`
`NH-CO-O
`F
`
`N
`
`O
`
`H3C
`
`N
`
`O
`
`H3C
`Carboxylesterase
`HO
`OH
`Capecitabine
`
`NH2
`
`N
`
`O
`
`N
`
`O
`
`F
`
`HO
`OH
`5’-DFCR
`
`Cyd deaminase
`
`F
`
`O
`
`NH
`
`HN
`O
`
`5-FU
`
`dThdPase
`
`O
`
`N
`
`HN
`O
`
`O
`
`F
`
`H3C
`
`HO
`OH
`5’-DFUR
`
`Mechanism of Action: Both normal and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine
`monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell
`injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-
`methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary
`complex. This binding inhibits the formation of thymidylate from uracil. Thymidylate is the
`necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so
`that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional
`enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the
`synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.
`
`Pharmacokinetics in Colorectal Tumors and Adjacent Healthy Tissue: 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.
`
`Human Pharmacokinetics: The pharmacokinetics of XELODA 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
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`HLR 11/17/00
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`XELODA® (capecitabine)
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`than on day 1. The elimination half-life of both parent capecitabine and 5-FU was about ¾ of an
`hour. The inter-patient variability in the Cmax and AUC of 5-FU was greater than 85%.
`
`Absorption, Distribution, Metabolism and Excretion: Capecitabine reached peak blood levels in
`about 1.5 hours (Tmax) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced
`both the rate and extent of absorption of capecitabine with mean Cmax and AUC0-∞ decreased by
`60% and 35%, respectively. The Cmax and AUC0-∞ of 5-FU were also reduced by food by 43%
`and 21%, respectively. Food delayed Tmax of both parent and 5-FU by 1.5 hours (see
`PRECAUTIONS and DOSAGE AND ADMINISTRATION).
`
`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 is extensively metabolized enzymatically to 5-FU. 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.
`
`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.
`
`Special Populations:
`
`Age, Gender and Ethnicity: No formal studies were conducted to examine the effect of age or
`gender or ethnicity on the pharmacokinetics of capecitabine and its metabolites.
`
`Hepatic Insufficiency: XELODA 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/m2 dose of capecitabine. Both AUC0-∞ and
`Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients
`with normal hepatic function (n=14). The AUC0-∞ and Cmax of 5-FU was not affected. In patients
`with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised
`when XELODA is administered. The effect of severe hepatic dysfunction on XELODA is not
`known (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
`
`Drug-Drug Interactions:
`
`Drugs Metabolized by Cytochrome P450 Enzymes: In vitro enzymatic studies with human liver
`microsomes indicated that capecitabine and 5'-DFUR had no inhibitory effects on substrates of
`cytochrome P450 for the major isoenzymes such as 1A2, 2A6, 3A4, 2C9, 2C19, 2D6, and 2E1,
`suggesting a low likelihood of interactions with drugs metabolized by cytochrome P450
`
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`XELODA® (capecitabine)
`
`enzymes.
`
`Antacid: 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 Cmax increased 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.
`
`XELODA has a low potential for pharmacokinetic interactions related to plasma protein binding.
`
`CLINICAL STUDIES: In a phase 1 study with XELODA in patients with solid tumors, the
`maximum tolerated dose as a single agent was 3000 mg/m2 when administered daily for 2 weeks,
`followed by a 1-week rest period. The dose-limiting toxicities were diarrhea and leukopenia.
`
`Breast Carcinoma: The antitumor activity of XELODA was evaluated in an open-label single-
`arm trial conducted in 24 centers in the US and Canada. A total of 162 patients with stage IV
`breast cancer were enrolled. The primary endpoint was tumor response rate in patients with
`measurable disease, with response defined as a ≥50% decrease in sum of the products of the
`perpendicular diameters of bidimensionally measurable disease for at least 1 month. XELODA
`was administered at a daily dose of 2510 mg/m2 for 2 weeks followed by a 1-week rest period
`and given as 3-week cycles. The baseline demographics and clinical characteristics for all
`patients (n=162) and those with measurable disease (n=135) are shown in the table below.
`Resistance was 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 chemotherapy regimen.
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`XELODA® (capecitabine)
`
`Table 1. Baseline Demographics and Clinical Characteristics
`
`Age (median, years)
`Karnofsky PS
`No. Disease Sites
`1-2
`3-4
`>5
`Dominant Site of Disease
`Visceral1
`Soft Tissue
`Bone
`Prior Chemotherapy
`Paclitaxel
`Anthracycline2
`5-FU
`
`Patients with
`Measurable Disease
`(n=135)
`55
`90
`
`43 (32%)
`63 (46%)
`29 (22%)
`
`101 (75%)
`30 (22%)
`4 (3%)
`
`135 (100%)
`122 (90%)
`110 (81%)
`
`Resistance to Paclitaxel
`Resistance to an Anthracycline2
`Resistance to both Paclitaxel and
`an Anthracycline2
`1Lung, pleura, liver, peritoneum
`2Includes 2 patients treated with an anthracenedione
`
`103 (76%)
`55 (41%)
`
`43 (32%)
`
`All Patients
`(n=162)
`56
`90
`
`60 (37%)
`69 (43%)
`34 (21%)
`
`110 (68%)
`35 (22%)
`17 (10%)
`
`162 (100%)
`147 (91%)
`133 (82%)
`
`124 (77%)
`67 (41%)
`
`51(31%)
`
`Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are
`shown in the table below.
`
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`HLR 11/17/00
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`XELODA® (capecitabine)
`
`Table 2. Response Rates in Doubly-Resistant Patients
`
`Resistance to Both Paclitaxel and
`an Anthracycline
`(n=43)
`0
`11
`11
`25.6%
`(13.5, 41.2)
`
`154
`(63 to 233)
`
`CR
`PR1
`CR + PR1
`Response Rate1
`(95% C.I.)
`Duration of Response,1
`Median in days2
`(Range)
`1Includes 2 patients treated with an anthracenedione
`2From date of first response
`
`For the subgroup of 43 patients who were doubly resistant, the median time to progression was
`102 days and the median survival was 255 days. The objective response rate in this population
`was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135
`patients with measurable disease, who were less resistant to chemotherapy (see Table 1). The
`median time to progression was 90 days and the median survival was 306 days.
`
`INDICATIONS AND USAGE: XELODA is 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, eg, patients who have received cumulative doses of 400 mg/m2 of 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.
`
`This indication is based on demonstration of a response rate. No results are available from
`controlled trials that demonstrate a clinical benefit resulting from treatment, such as
`improvement in disease-related symptoms, disease progression, or survival.
`
`CONTRAINDICATIONS: XELODA is contraindicated in patients who have a known
`hypersensitivity to 5-fluorouracil.
`
`XELODA is also contraindicated in patients with severe renal impairment (creatinine clearance
`below 30 mL/min [Cockroft and Gault]).
`
`WARNINGS: Renal Insufficiency: In patients with moderate renal impairment (creatinine
`clearance 30-50 mL/min [Cockroft and Gault]) at baseline, a dose reduction to 75% of the
`XELODA starting dose is recommended. In patients with mild renal impairment (creatinine
`clearance 51-80 mL/min) no adjustment in starting dose is recommended. (see DOSAGE AND
`ADMINISTRATION). Careful monitoring and prompt treatment interruption is recommended if
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`XELODA® (capecitabine)
`
`the patient develops a grade 2, 3, or 4 adverse event with subsequent dose adjustments as
`outlined in the table in DOSAGE AND ADMINISTRATION.
`
`Coagulopathy: 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 one month after stopping XELODA.
`These events occurred in patients with and without liver metastases. Patients taking coumarin-
`derivative anticoagulants concomitantly with XELODA should be monitored regularly for
`alterations in their coagulation parameters (PT or INR) (see PRECAUTIONS: Drug-Drug
`Interactions).
`
`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.
`The median time to first occurrence of grade 2-4 diarrhea was 31 days (range from 1 to 322
`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 grade 3 or 4 diarrhea, subsequent doses of XELODA
`should be decreased (see DOSAGE AND ADMINISTRATION). Standard antidiarrheal
`treatments (eg, loperamide) are recommended.
`
`Necrotizing enterocolitis (typhlitis) has been reported.
`
`Geriatric Patients (gastrointestinal toxicity): Patients ≥80 years old may experience a greater
`incidence of gastrointestinal grade 3 or 4 adverse events (see PRECAUTIONS: Geriatric Use).
`Among the 14 patients 80 years of age and greater treated with capecitabine, three (21.4%), three
`(21.4%) and one (7.1%) patients experienced reversible grade 3 or 4 diarrhea, nausea and
`vomiting, respectively.
`
`Among the 313 patients age 60 to 79 years old, the incidence of gastrointestinal toxicity was
`similar to that in the overall population.
`
`Pregnancy: XELODA may cause fetal harm when given to a pregnant woman. Capecitabine at
`doses of 198 mg/kg/day during organogenesis caused teratogenic 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. Teratogenic 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
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`XELODA® (capecitabine)
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`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.
`
`PRECAUTIONS: 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 DOSAGE AND ADMINISTRATION).
`
`Hand-and-Foot Syndrome: Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or
`chemotherapy induced acral erythema) is characterized by the following: numbness,
`dysesthesia/paresthesia, tingling, painless or painful swelling, erythema, desquamation, blistering
`and severe pain. 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 and 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 DOSAGE AND ADMINISTRATION).
`
`Cardiac: There has been cardiotoxicity associated with fluorinated pyrimidine therapy, including
`myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and
`electrocardiograph changes. These adverse events may be more common in patients with a prior
`history of coronary artery disease.
`
`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 CLINICAL PHARMACOLOGY
`and DOSAGE AND ADMINISTRATION).
`
`Hyperbilirubinemia: Grade 3 or 4 hyperbilirubinemia occurred in 17% (n=97) of 570 patients
`with either metastatic breast or colorectal cancer who received a dose of 2510 mg/m2 daily for 2
`weeks followed by a 1-week rest period. Of 339 patients who had hepatic metastases at baseline
`and 231 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred
`in 21.2% and 10.4%, respectively. Seventy-four (76%) of the 97 patients with grade 3 or 4
`hyperbilirubinemia also had concurrent elevations in alkaline phosphatase and/or hepatic
`transaminases; 6% of these were grade 3 or 4. Only 4 patients (4%) had elevated hepatic
`transaminases without a concurrent elevation in alkaline phosphatase. If drug related grade 2-4
`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 x normal, grade 3 hyperbilirubinemia as 1.5-3 x normal and
`grade 4 hyperbilirubinemia as >3 x normal. (See recommended dose modifications under
`DOSAGE AND ADMINISTRATION.)
`
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`HLR 11/17/00
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`XELODA® (capecitabine)
`
`Hematologic: In 570 patients with either metastatic breast or colorectal cancer who received a
`dose of 2510 mg/m2 administered daily for 2 weeks followed by a 1-week rest period, 4%, 2%,
`and 3% of patients had grade 3 or 4 neutropenia, thrombocytopenia and decreases in hemoglobin,
`respectively.
`
`Carcinogenesis, Mutagenesis and Impairment of Fertility: Long-term studies in animals to
`evaluate the carcinogenic potential of capecitabine 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 DOSAGE AND ADMINISTRATION). 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.
`
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`

`HLR 11/17/00
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`XELODA® (capecitabine)
`
`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 DOSAGE AND
`ADMINISTRATION).
`
`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
`DOSAGE AND ADMINISTRATION).
`
`Drug-Drug Interactions:
`
`Antacid: The effect of an aluminum hydroxide- and magnesium hydroxide-containing antacid
`(Maalox)* on the pharmacokinetics of capecitabine was investigated in 12 cancer patients. There
`was a small increase in plasma concentrations of capecitabine and one metabolite (5’-DFCR);
`there was no effect on the 3 major metabolites (5’-DFUR, 5-FU and FBAL).
`
`Coumarin Anticoagulants: Altered coagulation parameters and/or bleeding have been reported in
`patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as
`warfarin and phenprocoumon. Patients taking coumarin-derivative anticoagulants concomitantly
`with capecitabine should be monitored regularly for alterations in their coagulation parameters
`(PT or INR) (see WARNINGS: Coagulopathy).
`
`Phenytoin: Postmarketing reports indicate that some patients receiving capecitabine and
`phenytoin had toxicity associated with elevated phenytoin levels. The level of phenytoin should
`be carefully monitored in patients taking XELODA and phenytoin dose may need to be reduced
`(see DOSAGE AND ADMINISTRATION: Dose Modification Guidelines).
`
`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 WARNINGS). Women of childbearing
`potential should be advised to avoid becoming pregnant while receiving treatment with
`XELODA.
`
`Nursing Women: It is not known whether the drug is excreted in human milk. Because many
`drugs are excreted in human milk and because of the potential for serious adverse reactions in
`nursing infants, it is recommended that nursing be discontinued when receiving XELODA
`therapy.
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`XELODA® (capecitabine)
`
`Pediatric Use: The safety and effectiveness of XELODA in persons <18 years of age have not
`been established.
`
`Geriatric Use: No separate studies have been conducted to examine the effect of age on the
`pharmacokinetics of capecitabine and its metabolites. Patients ≥80 years old may experience a
`greater incidence of gastrointestinal grade 3 or 4 adverse events (see WARNINGS). Among the
`14 patients 80 years of age and greater treated with capecitabine, 21.4%, 21.4% and 7.1%
`experienced grade 3 or 4 diarrhea, nausea and vomiting, respectively. Among the 313 patients 60
`to 79 years old, the incidence was similar to the overall population.
`
`The elderly may be pharmacodynamically more sensitive to the toxic effects of 5-FU. Physicians
`should pay particular attention to monitoring the adverse effects of XELODA in the elderly.
`
`ADVERSE REACTIONS:
`
`The following table shows the adverse events occurring in ≥5% of patients reported as at least
`remotely related to the administration of XELODA. Rates are rounded to the nearest whole
`number. The data are shown both for the study in stage IV breast cancer and for a group of 570
`patients with breast and colorectal cancer who received a dose of 2510 mg/m2 administered daily
`for 2 weeks followed by a 1-week rest period. The 570 patients were enrolled in 6 clinical trials
`(162 from the breast cancer trial described under CLINICAL STUDIES, 83 other patients with
`breast cancer and 325 patients with colorectal cancer). The mean duration of treatment was 121
`days. A total of 71 patients (13%) discontinued treatment because of adverse events/intercurrent
`illness.
`
`Table 3. Percent Incidence of Adverse Events Considered Remotely, Possibly or Probably
`Related to Treatment in ≥≥≥≥5% of Patients
`
`Adverse Event
`
`Body System/Adverse Event
`GI
`Diarrhea
`Nausea
`Vomiting
`Stomatitis
`Abdominal pain
`Constipation
`Dyspepsia
`Skin and Subcutaneous
`Hand-and-Foot Syndrome
`Dermatitis
`Nail disorder
`
`Phase 2 Trial in Stage IV
`Breast Cancer
`(n=162)
`Total Grade 3 Grade 4
`
`Overall Safety Database
`
`(n=570)
`Total Grade 3 Grade 4
`
`57
`53
`37
`24
`20
`15
`8
`
`57
`37
`7
`
`12
` 4
` 4
`7
`4
`1
`–
`
`11
`1
`–
`
`3
`–
`–
`–
`–
`–
`–
`
`–
`–
`–
`
`50
`44
`26
`23
`17
`9
`6
`
`45
`31
`4
`
`11
` 4
` 3
` 4
`4
`1
`–
`
`13
` 1
`–
`
`2
`–
`–
`–
`–
`–
`–
`
`–
`–
`–
`
`11
`
`

`

`HLR 11/17/00
`
`XELODA® (capecitabine)
`
`Adverse Event
`
`Body System/Adverse Event
`General
`Fatigue
`Pyrexia
`Pain in limb
`Neurological
`Paraesthesia
`Headache
`Dizziness
`Insomnia
`Metabolism
`Anorexia
`Dehydration
`Eye
`Eye irritation
`Musculoskeletal
`Myalgia
`Cardiac
`Edema
`Blood
`Neutropenia
`Thrombocytopenia
`Anemia
`Lymphopenia
`Hepatobiliary
`Hyperbilirubinemia
`– Not observed or applicable.
`
`Phase 2 Trial in Stage IV
`Breast Cancer
`(n=162)
`Total Grade 3 Grade 4
`
`Overall Safety Database
`
`(n=570)
`Total Grade 3 Grade 4
`
`41
`12
`6
`
`21
`9
`8
`8
`
`23
`7
`
`15
`
`9
`
`9
`
`26
`24
`72
`94
`
`22
`
`8
`1
`1
`
`1
`1
`–
`–
`
`3
`4
`
`–
`
`–
`
`1
`
`2
`3
`3
`44
`
`9
`
`–
`–
`–
`
`–
`–
`–
`–
`
`–
`1
`
`–
`
`–
`
`–
`
`2
`1
`1
`15
`
`2
`
`34
`10
` 4
`
`12
`7
`5
`3
`
`20
`5
`
`10
`
`4
`
`6
`
`22
`21
`74
`94
`
`34
`
`5
`–
`–
`
`–
`1
`–
`–
`
`2
`2
`
`–
`
`–
`
`–
`
`3
`1
`2
`36
`
`14
`
`–
`–
`–
`
`–
`–
`–
`–
`
`–
`1
`
`–
`
`–
`
`–
`
`2
`1
`1
`10
`
`3
`
`Shown below by body system are the adverse events in <5% of 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: intestinal obstruction (1.1), rectal bleeding (0.4), GI hemorrhage (0.2),
`esophagitis (0.4), gastritis, colitis, duodenitis, haematemesis, necrotizing enterocolitis
`
`Skin: increased sweating (0.2), photosensitivity (0.2), radiation recall syndrome (0.2)
`
`General: chest pain (0.2)
`
`Neurological: ataxia (0.4), encephalopathy (0.2), depressed level of consciousness (0.2), loss of
`consciousness (0.2)
`
`12
`
`

`

`HLR 11/17/00
`
`XELODA® (capecitabine)
`
`Metabolism: cachexia (0.4), hypertriglyceridemia (0.2)
`
`Respiratory: dyspnea (0.5), epistaxis (0.2), bronchospasm (0.2), respiratory distress (0.2)
`
`Infections: oral candidiasis (0.2), upper respiratory tract infection (0.2), urinary tract infection
`(0.2), bronchitis (0.2), pneumonia (0.2), sepsis (0.4), bronchopneumonia (0.2), gastroenteritis
`(0.2), gastrointestinal candidiasis (0.2), laryngitis (0.2), esophageal candidiasis (0.2)
`
`Musculoskeletal: bone pain (0.2), joint stiffness (0.2)
`
`Cardiac: angina pectoris (0.2), cardiomyopathy
`
`Vascular: hypotension (0.2), hypertension (0.2), venous phlebitis and thrombophlebitis (0.2),
`deep venous thrombosis (0.7), lymphoedema (0.2), pulmonary embolism (0.4), cerebrovascular
`accident (0.2)
`
`Blood: coagulation disorder (0.2), idiopathic thrombocytopenic purpura (0.2), pancytopenia (0.2)
`
`Psychiatric: confusion (0.2)
`
`Renal and Urinary: nocturia (0.2)
`
`Hepatobiliary: hepatic fibrosis (0.2), cholestatic hepatitis (0.2), hepatitis (0.2)
`
`Immune System: drug hypersensitivity (0.2)
`
`OVERDOSAGE: Acute: Based on experience in animals and in humans treated up to doses of
`3514 mg/m2/day, the anticipated manifestations of acute overdose would be 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 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/m2 basis).
`
`DOSAGE AND ADMINISTRATION: The recommended dose of XELODA is 2500 mg/m2
`administered orally daily with food for 2 weeks followed by a 1-week rest period given as 3 week
`cycles. The XELODA daily dose is given orally in two divided doses (approximately 12 hours
`apart) at the end of a meal. XELODA tablets should be swallowed with water. The following
`table displays the total daily dose by body surface area and the number of tablets to be taken at
`each dose.
`
`13
`
`

`

`HLR 11/17/00
`
`XELODA® (capecitabine)
`
`Table 4. XELODA Dose Calculation According to Body Surface Area
`
`Number of tablets to be taken at each
`Dose level 2500 mg/m2/day
`dose (morning and evening)
`Surface Area
`Total Daily*
`150 mg
`500 mg
`(m2)
`Dose (mg)
`0
`3
`(cid:148) 1.24
`3000
`1
`3
`1.25 - 1.36
`3300
`2
`3
`1.37 - 1.51
`3600
`0
`4
`1.52 - 1.64
`4000
`1
`4
`1.65 - 1.76
`4300
`2
`4
`1.77 - 1.91
`4600
`0
`5
`1.92 - 2.04
`5000
`1
`5
`2.05 - 2.17
`5300
`2
`5
`(cid:149) 2.18
`5600
`*Total Daily Dose divided by 2 to allow equal morning and evening doses.
`
`Dose Modification Guidelines: Patients should be carefully monitored for toxicity. Toxicity due
`to XELODA administration may be managed by symptomatic treatment, dose interruptions and
`adjustment of XELODA dose. Once the dose has been reduced it should not be increased at a
`later time.
`
`The phenytoin dose may need to be reduced when phenytoin is concomitantly administered with
`XELODA (see PRECAUTIONS: Drug-Drug Interactions).
`
`Toxicity
`NCIC Grades*
`
`• Grade 1
`• Grade 2
`-1st appearance
`-2nd appearance
`-3rd appearance
`-4th appearance
`• Grade 3
`-1st appearance
`-2nd appearance
`-3rd appearance
`
`Table 5. Recommended Dose Modifications
`
`During a Course of Therapy
`
`Maintain dose level
`
`Dose Adjustment
`for Next Cycle
`(% of starting dose)
`Maintain dose level
`
`Interrupt until resolved to grade 0-1
`Interrupt until resolved to grade 0-1
`Interrupt until resolved to grade 0-1
`Discontinue treatment permanently
`
`Interrupt until resolved to grade 0-1
`Interrupt until resolved to grade 0-1
`Discontinue treatment permanently
`
`100%
`75%
`50%
`
`75%
`50%
`
`14
`
`

`

`HLR 11/17/00
`
`XELODA® (capecitabine)
`
`Toxicity
`NCIC Grades*
`• Grade 4
`-1st appearance
`
`During a Course of Therapy
`
`Dose Adjustment
`for Next Cycle
`(% of starting dose)
`
`Discontinue permanently
`or
`If physician deems it to be in the patient’s
`best interest to continue, interrupt until
`resolved to grade 0-1
`*National Cancer Institute of Canada Common Toxicity Criteria were used except for the Hand-
`and-Foot Syndrome (see PRECAUTIONS).
`
`50%
`
`Dosage modifications are not recommended for grade 1 events. Therapy with XELODA should
`be interrupted upon the occurrence of a grade 2 or 3 adverse experience. Once the adverse event
`has resolved or decreased in intensity to grade 1, then XELODA therapy may be restarted at full
`dose or as adjusted according to the above table. If a grade 4 experience occurs, therapy should
`be discontinued or interrupted until resolved or decreased to grade 1, and therapy should be
`restarted at 50% of the original dose. Doses of capecitabine omitted for toxicity are not replaced
`or restored; instead the patient should resume the