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(ka pe SITE a been)

Brand Name: Xeloda®

Capecitabine is the generic name for the trade name drug Xeloda. In some cases, health care professionals may use the trade name Xeloda when referring to the generic drug name capecitabine.

Drug Type:

Capecitabine is an anti-cancer (“antineoplastic” or “cytotoxic”) chemotherapy drug. Capecitabine is classified as an “antimetabolite.” (For more detail, see “How Capecitabine Works” section below).قرص xeloda 500

Note: If a drug has been approved for one use, physicians may elect to use this same drug for other problems if they believe it may be helpful.

The amount of capecitabine that you will receive depends on many factors, including your height and weight, your general health or other health problems, and the type of cancer or condition being treated. Your doctor will determine your dose and schedule.

Important things to remember about the side effects of capecitabine:

The following side effects are common (occurring in greater than 30%) for patients taking capecitabine:

These side effects are less common side effects (occurring in about 10-29%) of patients receiving capecitabine:

Not all side effects are listed above. Some that are rare (occurring in less than 10% of patients) are not listed here. However, you should always inform your health care provider if you experience any unusual symptoms.

Contact your health care provider immediately, day or night, if you should experience any of the following symptoms:

The following symptoms require medical attention, but are not an emergency. Contact your health care provider within 24 hours of noticing any of the following:

Always inform your health care provider if you experience any unusual symptoms.

You will be checked regularly by your doctor while you are taking capecitabine, to monitor side effects and check your response to therapy. Periodic blood work to monitor your complete blood count (CBC) as well as the function of other organs (such as your kidneys and liver) will also be ordered by your doctor.

Cancerous tumors are characterized by cell division, which is no longer controlled as it is in normal tissue. “Normal” cells stop dividing when they come into contact with like cells, a mechanism known as contact inhibition. Cancerous cells lose this ability. Cancer cells no longer have the normal checks and balances in place that control and limit cell division. The process of cell division, whether normal or cancerous cells, is through the cell cycle. The cell cycle goes from the resting phase, through active growing phases, and then to mitosis (division).

The ability of chemotherapy to kill cancer cells depends on its ability to halt cell division. Usually, the drugs work by damaging the RNA or DNA that tells the cell how to copy itself in division. If the cells are unable to divide, they die. The faster the cells are dividing, the more likely it is that chemotherapy will kill the cells, causing the tumor to shrink. They also induce cell suicide (self-death or apoptosis).

Chemotherapy drugs that affect cells only when they are dividing are called cell-cycle specific. Chemotherapy drugs that affect cells when they are at rest are called cell-cycle non-specific. The scheduling of chemotherapy is set based on the type of cells, rate at which they divide, and the time at which a given drug is likely to be effective. This is why chemotherapy is typically given in cycles.

Chemotherapy is most effective at killing cells that are rapidly dividing. Unfortunately, chemotherapy does not know the difference between the cancerous cells and the normal cells. The “normal” cells will grow back and be healthy but in the meantime, side effects occur. The “normal” cells most commonly affected by chemotherapy are the blood cells, the cells in the mouth, stomach and bowel, and the hair follicles; resulting in low blood counts, mouth sores, nausea, diarrhea, and/or hair loss. Different drugs may affect different parts of the body.

Capecitabine belongs to the category of chemotherapy called antimetabolites. Antimetabolites are very similar to normal substances within the cell. When the cells incorporate these substances into the cellular metabolism, they are unable to divide. Antimetabolites are cell-cycle specific. They attack cells at very specific phases in the cycle. Antimetabolites are classified according to the substances with which they interfere.

Note: We strongly encourage you to talk with your health care professional about your specific medical condition and treatments. The information contained in this website is meant to be helpful and educational, but is not a substitute for medical advice.

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InChI=1S/C15H22FN3O6/c1-3-4-5-6-24-15(23)18-12-9(16)7-19(14(22)17-12)13-11(21)10(20)8(2)25-13/h7-8,10-11,13,20-21H,3-6H2,1-2H3,(H,17,18,22,23)/t8-,10-,11-,13-/m1/s1 YKey:GAGWJHPBXLXJQN-UORFTKCHSA-N Y

کپسیتابین (به انگلیسی: Capecitabine)

رده درمانی: ترکیبات درمان سرطان .

اشکال دارویی: قرص

درمان سرطان کولورکتال متاستاتیک (مرحله ۴) و احتمالاً پیشگیری از بروز متاستاز آن در مرحله ۳، درمان سرطان سینه متاستاتیک.
قرص xeloda 500

این ترکیب در واقع یک پیش دارو است و در بدن به ۵-fluorouracil تبدیل می شود که با ایجاد اشتباه در بازسازی DNA سلولهای سرطانی عمل می کند.

عوارض شیمی درمانی مانند ریزش مو و… .
تاری دید و بی اشتهایی و زردی پوست و احساس خستگی و حالت تهوع و اسهال…

Updated

April 10, 2019

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XELODA 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 XELODA-Warfarin drug interaction was demonstrated in a clinical pharmacology trial [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time XELODA was introduced. 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. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Patients receiving concomitant XELODA and oral coumarin-derivative anticoagulants such as warfarin and phenprocoumon should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered coagulation parameters and/or bleeding, including death, have been reported during concomitant use. قرص xeloda 500

XELODA (capecitabine) is a nucleoside metabolic inhibitor with antineoplastic activity indicated for:

Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 2/2019

XELODA tablets should be swallowed whole with water within 30 minutes after a meal. XELODA is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 If XELODA tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures. XELODA dose is calculated according to body surface area.

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)

The recommended dose of XELODA is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles (see Table 1).

Adjuvant treatment in patients with Dukes’ C colon cancer is recommended for a total of 6 months [ie, XELODA 1250 mg/m2 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)].

In Combination With Docetaxel (Metastatic Breast Cancer)

In combination with docetaxel, the recommended dose of XELODA is 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m2 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. Table 1 displays the total daily dose of XELODA by body surface area and the number of tablets to be taken at each dose.

General

XELODA dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of XELODA should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14)]. 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. Doses of XELODA omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.

The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with XELODA [see Drug Interactions (7.1)].

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)

XELODA dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.

In Combination With Docetaxel (Metastatic Breast Cancer)

Dose modifications of XELODA for toxicity should be made according to Table 2 above for XELODA. At the beginning of a treatment cycle, if a treatment delay is indicated for either XELODA or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.

The dose reduction schedule for docetaxel when used in combination with XELODA for the treatment of metastatic breast cancer is shown in Table 3.

Renal Impairment

No adjustment to the starting dose of XELODA 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 XELODA starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m2 to 950 mg/m2 twice 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 XELODA monotherapy and XELODA in combination use with docetaxel.قرص xeloda 500

Cockroft and Gault Equation:

Creatinine clearance for females = 0.85 × male value

Geriatrics

Physicians should exercise caution in monitoring the effects of XELODA in the elderly. Insufficient data are available to provide a dosage recommendation.

XELODA is supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg of capecitabine and each peach-colored tablet contains 500 mg of capecitabine.

XELODA is 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)].

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.

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 Boxed Warning and Drug Interactions (7.1)].

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 [see Dosage and Administration (2.3)]. Standard antidiarrheal treatments (e.g., loperamide) are recommended.

Necrotizing enterocolitis (typhlitis) has been reported.

The cardiotoxicity observed with XELODA includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.

Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by XELODA (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by XELODA.

Withhold or permanently discontinue XELODA based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No XELODA dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.

Dehydration has been observed and may cause acute renal failure which can be fatal. Patients with pre-existing compromised renal function or who are receiving concomitant XELODA with known nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Monitor patients when XELODA is administered to prevent and correct dehydration at the onset. If grade 2 (or higher) dehydration occurs, XELODA treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications should be applied for the precipitating adverse event as necessary [see Dosage and Administration (2.3)].

Patients with moderate renal impairment at baseline require dose reduction [see Dosage and Administration (2.4)]. Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2 [see Dosage and Administration (2.3), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

Based on findings from animal reproduction studies and its mechanism of action, XELODA may cause fetal harm when given to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited available data are not sufficient to inform use of XELODA in pregnant women. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Use in Specific Populations (8.1)]. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of XELODA [see Use in Specific Populations (8.3)].

Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with XELODA [see Adverse Reactions (6.4)]. XELODA should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to XELODA treatment.

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. Persistent or severe hand-and-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints which could impact patient identification. 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 (2.3)].

In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of XELODA 1250 mg/m2 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 3 to 4 elevations in bilirubin occur, administration of XELODA should be immediately interrupted until the hyperbilirubinemia decreases to ≤3.0 × ULN [see recommended dose modifications under Dosage and Administration (2.3)].

In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m2 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.

Patients with baseline neutrophil counts of <1.5 × 109/L and/or thrombocyte counts of <100 × 109/L should not be treated with XELODA. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with XELODA should be interrupted.

Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse reactions. 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 reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions 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.

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 Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Use of XELODA in combination with irinotecan has not been adequately studied.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 4 shows the adverse reactions occurring in ≥5% of patients from one phase 3 trial in patients with Dukes’ C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m2 twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU on days 1-5 every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV.

Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥1% of patients from one phase 3 trial in patients with Dukes’ C colon cancer who received at least one dose of study medication and had at least one safety assessment.

Monotherapy

Table 6 shows the adverse reactions occurring in ≥5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m2 twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to XELODA and 32 (5.4%) randomized to 5-FU/LV.

In Combination with Docetaxel

The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/m2 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/m2 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/m2 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 reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions 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.

Monotherapy

The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m2 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 reactions/intercurrent illness.

Clinically relevant adverse events reported in <5% of patients treated with XELODA either as monotherapy or in combination with docetaxel that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses.

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)

XELODA In Combination With Docetaxel (Metastatic Breast Cancer)

The following adverse reactions have been observed in the postmarketing setting: hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [see Warnings and Precautions (5.5)], cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [see Warnings and Precautions (5.7)], persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints [see Warnings and Precautions (5.7)]

In instances of exposure to crushed XELODA tablets, the following adverse reactions have been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting, and nausea.

Anticoagulants

Altered coagulation parameters and/or bleeding have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon [see Boxed Warning]. 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 [see Clinical Pharmacology (12.3)]. 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.

Phenytoin

The level of phenytoin should be carefully monitored in patients taking XELODA and phenytoin dose may need to be reduced [see Dosage and Administration (2.3)]. 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.

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.

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.

Allopurinol

Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites [see Clinical Pharmacology (12.3)], which may decrease XELODA efficacy. Avoid the use of allopurinol during treatment with XELODA.

Food was shown to reduce both the rate and extent of absorption of capecitabine [see Clinical Pharmacology (12.3)]. In all clinical trials, patients were instructed to administer XELODA within 30 minutes after a meal. It is recommended that XELODA be administered with food [see Dosage and Administration (2)].

Risk Summary

Based on findings in animal reproduction studies and its mechanism of action, XELODA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively [see Data]. Apprise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Oral administration of capecitabine to pregnant mice during the period of organogenesis at a dose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this dose in mice produced 5′-DFUR AUC values that were approximately 0.2 times the AUC 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. Oral administration of capecitabine to pregnant monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality. This dose produced 5′-DFUR AUC values that were approximately 0.6 times the AUC values in patients administered the recommended daily dose.

Risk Summary

There is no information regarding the presence of capecitabine in human milk, or on its effects 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 XELODA and for 2 weeks after the final dose.

Data

Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk.

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating XELODA.

Contraception

Females

XELODA 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 XELODA.

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 XELODA [see Nonclinical Toxicology (13.1)].

Infertility

Based on animal studies, XELODA may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of XELODA in pediatric patients have not been established. No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to XELODA was similar.

The first trial was conducted in 22 pediatric patients (median age 8 years, range 5-17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas. In the dose-finding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m2 to 850 mg/m2 every 12 hours for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m2 every 12 hours. The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation.

The second trial was conducted in 34 additional pediatric patients with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas (median age 7 years, range 3-16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose-finding trial and met the eligibility criteria for this trial. All patients received 650 mg/m2 capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles.

There was no improvement in one-year progression-free survival rate and one-year overall survival rate in pediatric patients with newly diagnosed intrinsic brainstem gliomas who received capecitabine relative to a similar population of pediatric patients who participated in other clinical trials.

The adverse reaction profile of capecitabine was consistent with the known adverse reaction profile in adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence ≥40%) were increased ALT (75%), lymphocytopenia (73%), leukopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).

Physicians should pay particular attention to monitoring the adverse effects of XELODA in the elderly [see Warnings and Precautions (5.10)].

Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with XELODA. The effect of severe hepatic dysfunction on XELODA is not known [see Warnings and Precautions (5.11) and Clinical Pharmacology (12.3)].

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-DFUR, 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)].

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/m2 basis).

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 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.

Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. 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 2′-deoxyuridylate. 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.

Absorption

Following oral administration of 1255 mg/m2 BID to cancer patients, 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 Warnings and Precautions (5), Dosage and Administration (2), and Drug-Food Interaction (7.2)].

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 XELODA 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 Cmax and 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%). XELODA 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 XELODA 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.

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 XELODA at 1250 mg/m2 twice 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/m2 capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax and 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

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 XELODA. 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 were 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 Warnings and Precautions (5.11) and Use in Special Populations (8.6)].

Effect of Renal Insufficiency

Following oral administration of 1250 mg/m2 capecitabine 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 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/m2 bid) 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 Warning and 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 XELODA (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 XELODA.

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 XELODA on the pharmacokinetics of docetaxel (Taxotere®) and the effect of docetaxel on the pharmacokinetics of XELODA was conducted in 26 patients with solid tumors. XELODA was found to have no effect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5′-DFUR.

Adequate studies investigating 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.

In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m2/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.

A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes’ C colon cancer (X-ACT) provided data concerning the use of XELODA for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving XELODA to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with XELODA 1250 mg/m2 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) or IV bolus 5-FU 425 mg/m2 and 20 mg/m2 IV leucovorin on days 1 to 5, given as 4-week cycles for a total of 6 cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes’ stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5×109/L, platelets ≥ 100×109/L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of randomization.

The baseline demographics for XELODA and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.

All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m2 orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline [see Dosage and Administration (2.4)]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for XELODA included dose reductions, cycle delays and treatment interruptions (see Table 11).

The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for XELODA compared to 5-FU/LV was 0.88 (95% C.I. 0.77 – 1.01) (see Table 12 and Figure 1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, XELODA was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for XELODA compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 – 1.01). The 5-year overall survival rates were 71.4% for XELODA and 68.4% for 5-FU/LV (see Figure 2).

Figure 2 Kaplan-Meier Estimates of Overall Survival (All Randomized Population)

General

The recommended dose of XELODA was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m2/day in two divided doses, n=39), intermittent therapy with capecitabine (2510 mg/m2/day in two divided doses, n=34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m2/day in two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting. There was no apparent advantage in response rate to adding leucovorin to XELODA; however, toxicity was increased. XELODA, 1250 mg/m2 twice daily for 14 days followed by a 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied.

Monotherapy

Data from two open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of XELODA in the first-line treatment of patients with metastatic colorectal carcinoma. The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study 1 was conducted in the US, Canada, Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with XELODA at a dose of 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5, every 28 days).

In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed. Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm. Survival was assessed based on a non-inferiority analysis.

The baseline demographics for XELODA and 5-FU/LV patients are shown in Table 13.

The efficacy endpoints for the two phase 3 trials are shown in Table 14 and Table 15.

Figure 3 Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies 1 and 2)

XELODA was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of XELODA and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that XELODA has a clinically meaningful survival effect, statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by XELODA. The estimate of the survival effect of 5-FU/LV was derived from a meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies 1 and 2. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between 5-FU/LV and XELODA, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out. It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study 2 and 10% for Study 1. The pooled result is consistent with a retention of at least 50% of the effect of 5-FU/LV. It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs XELODA difference. These results do not exclude the possibility of true equivalence of XELODA to 5-FU/LV (see Table 14, Table 15, and Figure 3).

XELODA has been evaluated in clinical trials in combination with docetaxel (Taxotere®) and as monotherapy.

In Combination With Docetaxel

The dose of XELODA used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of XELODA (14 days of treatment, followed by a 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m2 administered in 3-week cycles of docetaxel in combination with 1250 mg/m2 twice daily for 14 days of XELODA administered in 3-week cycles. The approved dose of 100 mg/m2 of docetaxel administered in 3-week cycles was the control arm of the phase 3 study.

XELODA in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive XELODA 1250 mg/m2 twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16.

XELODA in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17, Figure 4, and Figure 5.

Figure 4 Kaplan-Meier Estimates for Time to Disease Progression XELODA and Docetaxel vs Docetaxel

Figure 5 Kaplan-Meier Estimates of Survival XELODA and Docetaxel vs Docetaxel

Monotherapy

The antitumor activity of XELODA as a monotherapy 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 dose of 1255 mg/m2 twice daily 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 Table 18. 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.

Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.

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 18). The median time to progression was 90 days and the median survival was 306 days.

150 mg

500 mg

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. KEEP TIGHTLY CLOSED.

XELODA is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 Any unused product should be disposed of in accordance with local requirements, or drug take back programs.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Diarrhea

Inform patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever to stop taking XELODA. Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to manage diarrhea [see Warnings and Precautions (5.2)].

Cardiotoxicity

Advise patients of the risk of cardiotoxicity and to immediately contact their healthcare provider or to go to an emergency room for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [see Warnings and Precautions (5.3)].

Dihydropyrimidine Dehydrogenase Deficiency

Advise patients to notify their healthcare provider if they have a known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity they are at an increased risk of acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by XELODA (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity) [see Warnings and Precautions (5.4)].

Dehydration and Renal Failure

Instruct patients experiencing grade 2 or higher dehydration (IV fluids indicated < 24 hours) to stop taking XELODA immediately and to call their healthcare provider to correct the dehydration. Advise patients to not restart XELODA until rehydrated and any precipitating causes have been corrected or controlled [see Warnings and Precautions (5.5)].

Important Administration Instructions

Advise patients to swallow XELODA tablets whole with water within 30 minutes of a meal. Advise patients and caregivers not to crush or cut XELODA tablets. Advise patients if they cannot swallow XELODA tablets whole, to inform their healthcare provider [see Dosage and Administration (2.1)].

Nausea

Instruct patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater to stop taking XELODA immediately and to contact their healthcare provider for management of nausea [see Adverse Reactions (6.1)].

Vomiting

Instruct patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater to stop taking XELODA immediately and to contact their healthcare provider for management of vomiting [see Adverse Reactions (6.1)].

Hand-and-Foot Syndrome

Instruct 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 to stop taking XELODA immediately and to contact their healthcare provider. Inform patients that initiation of symptomatic treatment is recommended and hand-and-foot syndrome can lead to loss of fingerprints which could impact personal identification [see Adverse Reactions (6.1)].

Stomatitis

Inform patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater to stop taking XELODA immediately and to contact their healthcare provider [see Adverse Reactions (6.1)].

Fever and Neutropenia

Inform patients who develop a fever of 100.5°F or greater or other evidence of potential infection to contact their healthcare provider [see Adverse Reactions (6.1)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with XELODA and for 6 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1 and 8.3)].

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with XELODA and for 3 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise females not to breastfeed during treatment with XELODA and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

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Genentech USA, Inc. A Member of the Roche Group1 DNA WaySouth San Francisco, CA 94080-4990

XELODA® is a registered trademark of Hoffmann-La Roche, Inc.

© 2019 Genentech, Inc. All rights reserved.

Patient InformationXELODA® (zeh-LOE-duh)(capecitabine)tablets

What is the most important information I should know about XELODA?

XELODA can cause serious side effects, including:

See “What are the possible side effects of XELODA?” for more information about side effects.

What is XELODA?

XELODA is a prescription medicine used to treat people with:

It is not known if XELODA is safe and effective in children.

Do not take XELODA if you:

Talk to your healthcare provider before taking XELODA if you are not sure if you have any of the conditions listed above.

Before taking XELODA, tell your healthcare provider about all your medical conditions, including if you:

See “What is the most important information I should know about XELODA?”

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. XELODA may affect the way other medicines work, and other medicines may affect the way XELODA works.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take XELODA?

What are the possible side effects of XELODA?

XELODA may cause serious side effects including:

See “What is the most important information I should know about XELODA?”.

People 80 years of age or older may be more likely to develop severe or serious side effects with XELODA.

The most common side effects of XELODA include:

XELODA may cause fertility problems in females and males. This may affect the ability to have a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of XELODA.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store XELODA?

Keep XELODA and all medicines out of the reach of children.

General information about the safe and effective use of XELODA.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use XELODA for a condition for which it was not prescribed. Do not give XELODA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about XELODA that is written for health professionals.

What are the ingredients in XELODA?

Active ingredient: capecitabine

Inactive ingredients: 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.

For more information, go to http://www.gene.com/patients/medicines/xeloda or call 1-877-436-3683.

Distributed by:

Genentech USA, Inc. A Member of the Roche Group1 DNA WaySouth San Francisco, CA 94080-4990

XELODA® is a registered trademark of Hoffmann-La Roche, Inc.© 2019 Genentech, Inc. All rights reserved.

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

NDC 0004-1100-20

Xeloda® (capecitabine)Tablets

150 mg

Each tablet contains 150 mgcapecitabine.

Rx only

60 tabletsGenentech

10210268

NDC 0004-1101-50

Xeloda® (capecitabine)Tablets

500 mg

Each tablet contains 500 mgcapecitabine.

Rx only

120 tabletsGenentech

10210269

Boxed Warnings,

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Presence in Breast Milk

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Capecitabine is an orally-administered chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers. Capecitabine is a prodrug, that is enzymatically converted to fluorouracil (antimetabolite) in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue.

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.قرص xeloda 500

For the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen. May also be used in combination with docetaxel for the treatment of metastatic breast cancer in patients who have failed to respond to, or recurred or relasped during or following anthracycline-containing chemotherapy. Capecitabine is used alone as an adjuvant therapy following the complete resection of primary tumor in patients with stage III colon cancer when monotherapy with fluroprymidine is preferred. The use or capecitabine in combination regimens for advanced gastric cancer is currently being investigated.

Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity indicated for the treatment of metastatic breast cancer and colon cancer. It is an orally administered systemic prodrug that has little pharmacologic activity until it is converted to fluorouracil by enzymes that are expressed in higher concentrations in many tumors. Fluorouracil it then metabolized both normal and tumor cells to 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP).

Capecitabine is a prodrug that is selectively tumour-activated to its cytotoxic moiety, fluorouracil, by thymidine phosphorylase, an enzyme found in higher concentrations in many tumors compared to normal tissues or plasma. Fluorouracil is further metabolized to two active metabolites, 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), within normal and tumour cells. 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 2′-deaxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, therefore a deficiency of this compound can inhibit cell division. Secondly, 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 through the production of fraudulent RNA.

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

Readily absorbed through the GI tract (~70%)

< 60% (mainly albumin)

Metabolized by thymidine phosphorylase to fluoruracil.

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.

45-60 minutes for capecitabine and its metabolites.

Extended description of the mechanism of action and particular properties of each drug interaction.

A severity rating for each drug interaction, from minor to major.

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The date on which a patent was filed with the relevant government.

There is additional data available for commercial users including Adverse Effects, Contraindications, and Blackbox Warnings. Contact us to learn more about these and other features.

Drug created on June 13, 2005 07:24 / Updated on August 12, 2019 12:28

Public Summary Document for Capecitabine,
tablet, 150 mg and 500 mg, Xeloda® – March 2010

Page last updated: 02 July 2010

PDF printable version for Capecitabine, tablet, 150 mg and 500 mg, Xeloda® (PDF 37
KB)

Product: Capecitabine, tablet, 150 mg and 500 mg,
Xeloda®Sponsor: Roche Products Pty LimitedDate of PBAC Consideration: March 2010

To provide a revised economic analysis of the administration costs
associated with capecitabine treatment compared to 5-fluorouracil
(5-FU) when used in combination with cisplatin for the treatment of
previously untreated advanced oesophago-gastric cancer following
deferral at the July 2009 PBAC meeting.قرص xeloda 500

In July 2009, the PBAC deferred a submission to extend capecitabine’s Authority required
listing to include treatment, in combination with a platinum-based regimen, of a patient
with previously untreated advanced oesophago-gastric cancer with a WHO performance
status of 2 or less, so that issues regarding the cost of the diagnostic related groups
(DRGs) and the magnitude of the cost offsets could be resolved.The main matter of
concern to the PBAC was the use of resources to offset the higher drug cost requested
for capecitabine. The PBAC considered that the administration costs associated with
5-FU had been overestimated so that the higher cost of capecitabine could be offset.The PBAC accepted that 5-FU was the appropriate comparator. The PBAC noted that the
submission presented one randomised open-label triplet chemotherapy trial (REAL-2)
which compared capecitabine plus epirubicin (either with oxaliplatin or cisplatin)
with 5-FU plus epirubicin (either with oxaliplatin or cisplatin) in patients with
oesophago-gastric cancer (OGC). The PBAC also noted that oxaliplatin was not PBS listed
for use in OGC and was much more expensive than cisplatin. Therefore, the PBAC considered
that any future restriction proposed by the sponsor should include use of capecitabine
with cisplatin only rather than platinum-based therapies. The current submission was
in accordance with this advice and requested capecitabine use with a cisplatin-based
regimen only.For further details see the capecitabine Public Summary Document for the July 2009 PBAC meeting. 

Capecitabine was registered by the TGA in February 2009 for first
line treatment of patients with advanced oesophagogastric cancer in
combination with a platinum-based regimen.

Authority required
Treatment, in combination with a cisplatin-based regimen, of a patient with previously
untreated advanced oesophago-gastric cancer with a WHO performance status of 2 or
less.

For PBAC’s view see Recommendation and Reasons.
 

For patients with locally advanced growth or metastases, the main
therapeutic option is chemotherapy. 5-FU has been the backbone of
chemotherapy in advanced oesophago-gastric cancer for over forty
years and is among the most active single agents against metastatic
oesophago-gastric cancer. Combination chemotherapy using two or
three-drug combinations has produced higher response rates and
longer disease-free survival (DFS) compared with 5-FU alone, with
incremental toxicity. Capecitabine would provide an oral
alternative to 5-FU in the above treatment algorithms, which the
submission claimed may be more convenient for patients and less
resource intensive than continuous infusions of 5-FU.

The submission nominated 5-fluorouracil (5-FU) as the main
comparator. This is as previously agreed by the PBAC.

No changes have been made to the trial data presented in the
previous submission: one randomised open-label triplet chemotherapy
trial (REAL-2) comparing capecitabine plus epirubicin (either with
oxaliplatin or cisplatin) with 5-FU plus epirubicin (either with
oxaliplatin or cisplatin) in patients with advanced OGC; and one
randomised open-label doublet chemotherapy trial (ML17032)
comparing capecitabine plus cisplatin with 5-FU plus cisplatin in
patients with advanced gastric cancer. The citations for the REAL-2
and ML17032 trials may be found in the Public Summary Document from
the July 2009 PBAC meeting.

No new efficacy data were presented in the re-submission. A summary
of the primary efficacy analyses of the REAL-2 and ML17032 trials
is presented in the capecitabine Public Summary Document for the
July 2009 PBAC meeting.
A summary of the secondary analyses from the REAL-2 trial of
overall survival (OS) and progression-free survival (PFS) in the
ITT population showed that there was no statistically significant
difference in OS between the epirubicin and cisplatin plus
capecitabine (ECX) and epirubicin and cisplatin plus 5-FU (ECF)
treatment arms [HR = 0.92 (95 % CI: 0.76, 1.11)]. The results were
similar for PFS [HR = 0.98 (95 % CI: 0.82, 1.17)].
The PBAC previously accepted that capecitabine is non-inferior in
terms of comparative effectiveness over 5-FU.
No new toxicity data were presented in the re-submission. A summary
of the safety results from the REAL-2 and ML17032 trials is
presented in the capecitabine Public Summary Document for the July
2009 PBAC meeting.For PBAC’s view, see Recommendations and
Reasons.

The re-submission described capecitabine as non-inferior in terms
of comparative effectiveness and non-inferior in terms of
comparative safety over 5-FU. This was unchanged from the previous
submission and was previously accepted by the PBAC.For PBAC’s view, see Recommendations and Reasons.

The resubmission presented two cost minimisation analyses: one for
triplet therapy based on the REAL-2 study (ECX versus ECF) and one
for doublet therapy based on the ML17032 study (CX versus CF). This
is appropriately changed from the previous submission which
provided a weighted analysis of doublet and triplet therapy. Cost
of drug acquisition was calculated using trial-based mean
cumulative doses, which is one of three approaches presented in the
original submission. This approach is reasonable.
The difference in pharmaceutical acquisition costs between the
capecitabine containing arms and the 5-FU containing arms are
offset by differences in the cost of preparation and drug
administration (includes costs of visits and central venous access
devices (CVAD) placements and removals). The analysis excludes the
cost of adverse events, which is unchanged from the previous
submission and may not be reasonable, and tumour assessment costs,
which is changed from the previous submission and is
appropriate.
Costs were estimated for five treatment settings compared to two in
the previous submission. These were then weighted to arrive at the
final estimate of total costs. The weights applied to distribute
patients across treatment settings are uncertain and may not be
appropriate. The sensitivity analyses presented were limited and
did not address many of the previous concerns of the PBAC regarding
uncertainty surrounding the costs of chemotherapy administration
and CVAD removal. Furthermore, there was no analysis of the impact
of variation in the treatment survey responses other than the
proportion of patients requiring a CVAD through the worse/best case
scenario analysis.
During the evaluation of the Submission, further sensitivity
analyses were conducted, including changes to various cost
estimates and changed treatment setting weights. When all proposed
changes were incorporated, the use of capecitabine in triplet and
doublet chemotherapy regimens remained cost-saving, however the
cost savings are not to the PBS.
The cost savings that accrue as a result of using the intervention
in preference to the comparator are not in terms of PBS items. The
savings are derived through the cost of drug administration, which
are; MBS item numbers, prostheses costs, and the cost of drug
administration in hospitals. Although the intervention is not
cost-saving to the PBS, the intervention is cost saving from a
government health budget perspective.
For PBAC’s view, see Recommendations and
Reasons.

The likely number of patients was <10,000 in Year 1 and the
financial cost per year to the PBS (excluding co-payments) minus
any savings in use of other drugs was estimated to be < $10
million in Year 1.

The PBAC recommended listing of capecitabine for treatment of advanced oesophago-gastric
cancer in combination with cisplatin-based regimen on a cost-minimisation basis with
5-fluorouracil. The equi-effective doses are capecitabine 625 mg/m2 twice daily and 5-fluorouracil 200 mg/m2 per day (triplet therapy) and capecitabine 1000 mg/m2 twice daily for 14 days of each 3 week cycle and 5-fluorouracil 800 mg/m2 continuous infusion day 1 to 5 of each 3 week cycle (doublet therapy).

The PBAC considered that the stage of the disease should be added to the restriction
as this reflects the patient population enrolled in the clinical trials. The PBAC
also considered that doublet therapy should be allowed even though it is not as effective
as triple therapy but would provide clinicians with an alternative treatment option
for patients in whom epirubicin cannot be tolerated or is contraindicated.

No changes had been made to the trial data presented in the previous submission. However,
the PBAC noted the updated results of the REAL-2 study with respect to a secondary
analysis of the trial data, which was not published at the time of the first submission.
The analysis found that there was a significantly higher rate of venous thromboembolic
events (TEs) in the ECX arm compared to the ECF arm when CVAD-related thrombosis was
excluded (9.1 % vs 4.4 %, p=0.038). However, the PBAC considered that the overall
incidence of TEs was more clinically relevant and agreed with the Pre Sub-Committee
Response that CVAD-related thrombosis events should not be excluded. When all thromboembolic
events were examined, the incidence of thromboembolism for ECX compared with ECF was
not significantly different (13.3 % versus 16.9 %, p=0.267).

The re-submission presented two cost minimisation analyses, one for triplet therapy
based on the REAL-2 study (ECX versus ECF) and one for doublet therapy based on the
ML17032 study (CX versus CF). The PBAC considered this to be appropriate. Cost of
drug acquisition was calculated using trial-based mean cumulative doses.

The PBAC noted that the difference in pharmaceutical acquisition costs between the
capecitabine containing arms and the 5-FU containing arms are offset by differences
in the cost of preparation and drug administration (includes costs of visits and CVAD
placements and removals). Changes in the methodology compared to the previous submission
included:

The approach to calculate the cost-offsets was considered appropriate. However, the
following uncertainties were identified. Costs were estimated for five treatment settings
compared to two in the previous submission. These were weighted to arrive at the final
estimate of total costs. The PBAC noted that for triplet therapy, the difference between
ECX and ECF total treatment cost per patient across the settings varies from cost
savings of $2,874 to $7,821, with a weighted differential cost saving of $5,291. For
doublet therapy, the difference between CX and CF total treatment cost per patient
across the settings varies from a cost saving of $537 to $3,764, with a weighted differential
cost saving of $2,142. The PBAC considered that the weights applied to distribute
patients across treatment settings were uncertain and may not be appropriate. However,
the PBAC noted that regardless of the weights used, capecitabine remained cost saving.

The PBAC noted that the patterns of drug administration used in the economic evaluation
are obtained from a small treatment pattern survey and may not reflect practices across
the public and private treatment settings. The distribution of patients across the
five treatment settings is also uncertain due to the methodology used which applied
multiple sources of information and required mapping of ICD-10 codes to MBS codes.

The PBAC considered that the assumption that a new CADD pump is bought for each of
these patients (at a cost of $4950) was not reasonable and overestimated costs, as
the pumps may be re-used and are expected to last 2 to 5 years. The Pre-Sub Committee
Response agreed that costs were overestimated. However, the PBAC noted that even if
the lowest cost estimate of $190 is used as recommended in the Commentary, the intervention
remained cost-saving.

The PBAC noted that the cost of outpatient PICC placement when medical intervention
is required and PICC removal (when on a different day from chemotherapy) was still
based on the NHCDC cost report (non-admitted medical oncology) and thus remained overestimated.
The cost from the NHCDC cost report (general surgery) may have been more appropriate.

The PBAC considered that the use of a single AR-DRG code (R63Z) was not appropriate
for subsequent chemotherapy administration visits which require a few minutes of nursing
time to connect/disconnect an ambulatory 5-FU infusion pump. However, the PBAC noted
that the use of alternative costings still result in cost savings.

The PBAC considered it would be more appropriate to charge only one MBS item for subsequent
visits and MBS item 13918 for the first day of treatment of each cycle. The Pre-Sub
Committee Response noted that if the MBS item 13945 is used to cost the access/flushing
of the CVAD, capecitabine treatment remains cost saving.

The PBAC noted that the cost savings are derived through the cost of drug administration,
which are MBS item numbers, prostheses costs, and the cost of drug administration
in hospitals and that the intervention is not cost-saving to the PBS. However, even
in the worst case scenario the treatment costs of capecitabine were still cost saving
in both treatment groups.

The PBAC considered that further discussion was needed to determine the true cost
of drug administration in the various settings. Further, the price of capecitabine
should be reviewed in 12 months time after consideration by the Department of drug
administration costs in the various settings.

Recommendation
CAPECITABINE, tablets, 150 mg and 500 mg

Extend the current restriction to include:
Authority required

Advanced (Stage III or IV) oesophago-gastric cancer, previously untreated, in combination
with a cisplatin-based regimen, in a patient with a WHO performance status of 2 or
less.

Maximum quantity: 60 (150 mg)
120 (500 mg)
Repeats: 2
 

The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.

The sponsor has no further comment.

© Commonwealth of AustraliaABN: 83 605 426 759

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