سلاپسیتابین
Capecitabine (Xeloda)
سلاپسیتابین

نام ژنریک

Capecitabine

شکل دارویی

اشكال دارويي:


Tablet: 150, 500mg

موارد مصرف

موارد و مقدار مصرف


سرطان پستان متاستاتيك مقاوم به پكليتاكسل و يك رژيم حاوي آنتراسايكلين يا سرطان پستان مقاوم به پكليتاكسل كه براي آن درمان بيشتر با آنتراسايكلين انديكاسيون ندارد؛ همراه دوستاكسل در درمان سرطان پستان متاستاتيك، پس از شكست يا پيش از رژيم حاوي آنترا سايكلين؛ درمان خط اول براي سرطان کولورکتال متاستاتيک زماني که مونوتراپي با فلوئوروپ يريميدين ارجح باشد، سرطان كولون در مرحله Dukes C پس از برداشتن تومور اوليه ، زماني كه مونوتراپي با فلوئوروپيريميدين ارجح باشد.


برزگسالان: مقدار mg/m2 2500 روزانه از راه خوراكي در دو روز منقسم (با فاصله حدود 12 ساعت) در پايان وعده غذايي، به مدت دو هفته مصرف مي‌شود، به دنبال آن يك هفته دارو تجويز نمي‌شود و پس از اين مدت، سيكل‌هاي 3 هفته‌اي تكرار مي‌شود. در بيماران مبتلا به سرطان كولون با مرحله Dukes C درمان كمكي ( adjuvant) به مدت 6 ماه توصيه مي‌شود.


تعديل دوز:


دوز شروع دارو در بيماران داراي كليرانس كراتينين ml/min 40-30 بايد به %75 دوز توصيه شده معمول كاهش يابد. همچنين تعديل دوز ممكن است بر اساس شاخص‌هاي سميت ارائه شده توسط انستيتوي ملي كانسر كانادا (NCIC) ضروري باشد:


NCIC grade 2 : در اولين بروز، علائم سميت، درمان بايد قطع شود تا علائم به grade 0-1 برسد ، سپس درمان با %100 دوز شروع در سيكل بعدي آغاز مي‌شود. در دومين بروز، درمان قطع شده تا به grade 0-1 برسد و درمان با %75 دوز در سيكل بعدي آغاز مي‌شود. در سومين بروز ، درمان تا رسيدن به grade 0-1 قطع شده و سپس %50 دوز در سيكل بعدي تجويز مي‌شود. در صورت چهارمين بروز ، درمان براي هميشه قطع مي‌شود.


NCIC grade 3 : در اولين بروز، درمان تا رسيدن به grade 0-1 قطع و در سيكل بعد %75 دوز شروع مي‌شود. در دومين بروز ، درمان تا رسيدن به grade 0-1 قطع و در سيكل بعد ، %50 دوز شروع مي‌شود. در سومين بروز، درمان براي هميشه قطع مي‌شود.


NCIC grade 4 : در اولين بروز، درمان يا براي هميشه و يا تا رسيدن به grade 0-1 قطع شده و در سيكل بعدي %50 دوز شروع استفاده مي‌شود.


شاخص‌هاي سميت مربوط به شدت اسهال، تهوع، استفراغ، استوماتيت و سندرم hand-foot مي‌باشد. براي تعريف‌هاي اختصاصي سميت ، به بروشور دارو مراجعه شود.


مكانيسم اثر


اثر ضد سرطان- كپسيتابين به داروي فعال 5- فلوئورواوراسيل (5-FU) تبديل مي‌شود. 5-FU در سلول‌هاي طبيعي و سرطاني به متابوليت‌هايي تبديل مي‌شود كه با دو مكانيسم مختلف باعث آسيب سلولي مي‌شوند: تداخل در سنتز DNA براي مهار تقسيم سلولي و تداخل در فرآيند‌هاي سنتز پروتئين از RNA.

موارد منع مصرف

تداخل دارويي


آنتاسيد‌ها ممكن است سرعت جذب كپسيتابين را افزايش دهند.


لوكوورين (فولينيك اسيد) ممكن است سطح 5-FU و سميت ناشي از آن را افزايش دهد. كپسيتابين ممكن است سطح فنيتوئين را افزايش دهد. دوز فنيتوئين را کاهش دهيد. كپسيتابين ممكن است اثر وارفارين و خطر خونريزي و حتي مرگ را افزايش دهد. از مصرف همزمان اين دو دارو خودداري نموده و يا مرتباً PT و INR را كنترل نماييد.

موارد قابل توجه

-

تداخل دارویی

عوارض جانبي


اعصاب مركزي: گيجي، خستگي، سر درد، بي‌خوابي، پارستزي، تب.


قلبي- عروقي: ادم.


چشم: تحريك چشم.


دستگاه گوارش: درد شكمي، بي‌اشتهايي، يبوست، اسهال، سوء هاضمه، انسداد روده، تهوع، استوماتيت، استفراغ.


خوني: آنمي، لنفوپني، نوتروپني، ترومبوسيتوپني.


كبدي: هايپربيلي‌روبينمي.


متابوليك: دهيدراسيون.


عضلاني- اسكلتي: درد اندام، درد عضلاني.


پوست: درماتيت، سندرم hand-foot، اختلال ناخن.

مکانیزم اثر

عوارض جانبي


اعصاب مركزي: گيجي، خستگي، سر درد، بي‌خوابي، پارستزي، تب.


قلبي- عروقي: ادم.


چشم: تحريك چشم.


دستگاه گوارش: درد شكمي، بي‌اشتهايي، يبوست، اسهال، سوء هاضمه، انسداد روده، تهوع، استوماتيت، استفراغ.


خوني: آنمي، لنفوپني، نوتروپني، ترومبوسيتوپني.


كبدي: هايپربيلي‌روبينمي.


متابوليك: دهيدراسيون.


عضلاني- اسكلتي: درد اندام، درد عضلاني.


پوست: درماتيت، سندرم hand-foot، اختلال ناخن.

فارماكوكینتیك

موارد منع مصرف و احتياط


منع مصرف: حساسيت به 5-FU، نارسايي كليوي شديد ، اسهال شديد ممكن است بروز نمايد ، بيمار را از نظر تعادل الكتروليت‌ها و هيدراسيون مناسب پايش كنيد.


موارد احتياط: افراد سالمند، سابقه بيماري عروق كرونر، اختلال خفيف تا متوسط كبدي ناشي از متاستاز، هايپربيلي‌روبينمي، اختلال كليوي.

سایر اطلاعات

طبقه‌بندي فارماكولوژيك: كاربامات فلوئوروپيريميدين.


طبقه‌بندي درماني: ضد سرطان.


طبقه‌بندي مصرف در بارداري: رده ‍D


ملاحظات اختصاصي


1- در صورت بروز سندرم hand-foot، ممكن است نياز به قطع يا كاهش دوز دارو باشد.


(علائم سندرم : كرختي، پارستزي، تورم دردناك يا بدون درد، قرمزي، پوسته ريزي، تاول و درد شديد در دست‌ها يا پا‌ها، هايپربيلي‌روبينمي و تهوع شديد).


2- تغيير شاخص‌هاي انعقادي و خونريزي ممكن است طي چند روز تا چند ماه از شروع دارو و به ندرت طي 1 ماه از قطع دارو، اتفاق افتد.


3- در مورد مصرف اسيد‌ فوليك يا وارفارين بايد از بيمار سؤال شود.


4- تست‌هاي عملكرد كبدي در طول درمان بايد پايش شود. بروز هايپر‌بيلي‌روبينمي ممكن است قطع دارو را ضروري نمايد.


5- بيمار بايد از نظر بروز اسهال پايش شود. در صورت بروز اين عارضه، دارو بايد سريعاً قطع شود تا زماني كه اسهال بر طرف شده يا از شدت آن كاسته شود.


نكات قابل توصيه به بيمار


1- عوارض احتمالي به ويژه تهوع، استفراغ، اسهال و علائم سندرم hand-foot بايد به اطلاع بيمار برسد.


2- در صورت بروز هر يك از اين عوارض، دارو بايد سريعاً قطع شده و به پزشك مراجعه شود:


اسهال (بيش از 4 بار دفع روزانه يا اسهال شبانه)، استفراغ (2 تا 5 بار در 24 ساعت)، تهوع، كاهش اشتها، استوماتيت (قرمزي، تورم، درد و زخم در حفره دهان)، سندرم hand-foot، دماي 38 درجه سانتي‌گراد يا بيشتر يا ساير شواهد عفونت.


3- اكثر عوارض جانبي ، 2 تا 3 روز پس از قطع دارو بهبود مي‌يابد.


4- دارو بايد طي 30 دقيقه از مصرف صبحانه و شام، با آب مصرف شود.


مصرف در سالمندان: در افراد بالاي 80 سال ممكن است عوارض گوارشي بيشتري بروز كند.


مصرف در كودكان: اثر بخشي و بي‌خطري اين دارو در كودكان تأييد نشده است.


مصرف در شيردهي: در دوران مصرف اين دارو از شيردهي بايد اجتناب شود.


مصرف در بارداري: به دليل اثرات تراتوژنيك، زنان مصرف كننده نبايد در طول مصرف اين دارو باردار شوند.


اثر بر آزمايشهاي تشخيصي


ممكن است باعث افزايش سطح بيلي‌روبين شود. ممكن است باعث كاهش سطح Hgb و هماتوكريت و شمارش WBC، پلاكت و نوتروفيل شود.


مسموميت و درمان


تظاهرات باليني: تهوع، استفراغ، اسهال، تحريك گوارشي، خونريزي گوارشي و سركوب مغز استخوان.


درمان: درمان حمايتي و علامتي است. دياليز ممكن است كمك كننده باشد.

Capecitabine (Xeloda)

XELODA®
(capecitabine) Tablets

WARNING

XELODA (capecitabine) -WARFARIN INTERACTION

XELODA (capecitabine) Warfarin Interaction: Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important XELODA (capecitabine) -Warfarin drug interaction was demonstrated in a clinical pharmacology trial [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA (capecitabine) 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 (capecitabine) was introduced. These events occurred within several days and up to several months after initiating XELODA (capecitabine) therapy and, in a few cases, within 1 month after stopping XELODA (capecitabine) . These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

DRUG 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:

XELODA® (capecitabine) Structural Formula Illustration

Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20°C.

XELODA (capecitabine) 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 (capecitabine) include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.

What are the possible side effects of capecitabine (Xeloda)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • severe diarrhea (more than 4 times per day, or during the night);
  • vomiting (more than once in 24 hours);
  • nausea, loss of appetite, eating much less than usual;
  • weakness, feeling light-headed, hot or dry skin;
  • pain, tenderness, redness, swelling, blistering, or peeling skin on your hands or feet;
  • fever,...

Read All Potential Side Effects and See Pictures of Xeloda »

What are the precautions when taking capecitabine (Xeloda)?

Before taking capecitabine, tell your doctor or pharmacist if you are allergic to it; or to 5-fluorouracil; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe kidney disease, a certain enzyme deficiency (dihydropyrimidine dehydrogenase deficiency).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood disorders (e.g., bone marrow suppression), heart problems (e.g., coronary artery disease, heart failure), kidney problems, liver...

Read All Potential Precautions of Xeloda »

Last reviewed on RxList: 4/6/2011
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Colorectal Cancer

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

Breast Cancer

  • XELODA (capecitabine) in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
  • XELODA (capecitabine) monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/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.

DOSAGE AND ADMINISTRATION

XELODA (capecitabine) tablets should be swallowed whole with water within 30 minutes after a meal. XELODA (capecitabine) dose is calculated according to body surface area.

Standard Starting Dose

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

The recommended dose of XELODA (capecitabine) 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 (capecitabine) 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)].

Table 1 : XELODA (capecitabine) Dose Calculation According to Body Surface Area

Dose Level 1250 mg/m² Twice a Day Number of Tablets to be Taken at Each Dose (Morning and Evening)
Surface Area (m²) Total Daily Dose* (mg) 150 mg 500 mg
≤ 1.25 3000 0 3
1.26-1.37 3300 1 3
1.38-1.51 3600 2 3
1.52-1.65 4000 0 4
1.66-1.77 4300 1 4
1.78-1.91 4600 2 4
1.92-2.05 5000 0 5
2.06-2.17 5300 1 5
≥ 2.18 5600 2 5
*Total Daily Dose divided by 2 to allow equal morning and evening doses

In Combination With Docetaxel (Metastatic Breast Cancer)

In combination with docetaxel, the recommended dose of XELODA (capecitabine) 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 (capecitabine) plus docetaxel combination. Table 1 displays the total daily dose of XELODA (capecitabine) by body surface area and the number of tablets to be taken at each dose.

Dose Management Guidelines

General

XELODA (capecitabine) dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of XELODA (capecitabine) should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies]. Toxicity due to XELODA (capecitabine) administration may be managed by symptomatic treatment, dose interruptions and adjustment of XELODA (capecitabine) dose. Once the dose has been reduced, it should not be increased at a later time. Doses of XELODA (capecitabine) 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].

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

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

Table 2 : Recommended Dose Modifications of XELODA (capecitabine)

Toxicity NCIC Grades* During a Course of Therapy Dose Adjustment for Next Treatment (% of starting dose)
Grade 1 Maintain dose level Maintain dose level
Grade 2
  -1st appearance Interrupt until resolved to grade 0-1 100%
  -2nd appearance 75%
  -3rd appearance 50%
  -4th appearance Discontinue treatment permanently -
Grade 3
  -1st appearance Interrupt until resolved to grade 0-1 75%
  -2nd appearance 50%
  -3rd appearance Discontinue treatment permanently -
Grade 4
  -1st appearance Discontinue permanently OR If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1 50%
*National Cancer Institute of Canada Common Toxicity Criteria were used except for the hand-and-foot syndrome [see WARNINGS AND PRECAUTIONS].

In Combination With Docetaxel (Metastatic Breast Cancer)

Dose modifications of XELODA (capecitabine) for toxicity should be made according to Table 2 above for XELODA (capecitabine) . At the beginning of a treatment cycle, if a treatment delay is indicated for either XELODA (capecitabine) 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 (capecitabine) for the treatment of metastatic breast cancer is shown in Table 3.

Table 3 : Docetaxel Dose Reduction Schedule in Combination with XELODA (capecitabine)

Toxicity NCIC Grades* Grade 2 Grade 3 Grade 4
1st appearance Delay treatment until resolved to grade 0-1; Resume treatment with original dose of 75 mg/m2 docetaxel Delay treatment until resolved to grade 0-1; Resume treatment at 55 mg/m2 of docetaxel. Discontinue treatment with docetaxel
2nd appearance Delay treatment until resolved to grade 0-1; Resume treatment at 55 mg/m2 of docetaxel. Discontinue treatment with docetaxel -
3rd appearance Discontinue treatment with docetaxel - -
*National Cancer Institute of Canada Common Toxicity Criteria were used except for hand-and-foot syndrome [see WARNINGS AND PRECAUTIONS].

Adjustment of Starting Dose in Special Populations

Renal Impairment

No adjustment to the starting dose of XELODA (capecitabine) 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 (capecitabine) 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 and CLINICAL PHARMACOLOGY]. 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]. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both XELODA (capecitabine) monotherapy and XELODA (capecitabine) in combination use with docetaxel.

Cockroft and Gault Equation:

Creatinine clearance for males = (140 - age [yrs]) (body wt [kg])/ (72) (serum creatinine [mg/dL])

Creatinine clearance for females = 0.85 x male value

Geriatrics

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

HOW SUPPLIED

Dosage Forms And Strengths

XELODA (capecitabine) 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.

Storage And Handling

150 mg

Color: Light peach
Engraving: XELODA (capecitabine) on one side and 150 on the other 150 mg tablets are packaged in bottles of 60 (NDC 0004-1100-20).

500 mg

Color: Peach
Engraving: XELODA (capecitabine) on one side and 500 on the other 500 mg tablets are packaged in bottles of 120 (NDC 0004-1101-50).

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.

Care should be exercised in the handling of XELODA (capecitabine) . XELODA (capecitabine) tablets should not be cut or crushed. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of tablets. If powder from broken XELODA (capecitabine) tablets contacts the skin, wash the skin immediately and thoroughly with soap and water. If XELODA (capecitabine) contacts the mucous membranes, flush thoroughly with water.

Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.1-4

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs: Am J Health-Syst Pharm. 2006;63:1172-1193.

4. Polovich M., White JM, Kelleher LO (eds). Chemotherapy and biotherapy guidelines and recommendations for practice (2nd ed.) 2005. Pittsburgh, PA: Oncology Nursing Society.

Distributed by: Genentech USA, Inc. A Member of the Roche Group, 1 DNA Way, south San Francisco, CA 94080-4990.

Last reviewed on RxList: 4/6/2011
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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.

Adjuvant Colon Cancer

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 (capecitabine) 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 (capecitabine) 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.

Table 4 : Percent Incidence of Adverse Reactions Reported in ≥ 5% of Patients Treated With XELODA (capecitabine) or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)

Body System/ Adverse Event Adjuvant Treatment for Colon Cancer (N=1969)
XELODA (N=995) 5-FU/LV (N=974)
All Grades Grade 3/4 All Grades Grade 3/4
Gastrointestinal Disorders
  Diarrhea 47 12 65 14
  Nausea 34 2 47 2
  Stomatitis 22 2 60 14
  Vomiting 15 2 21 2
  Abdominal Pain 14 3 16 2
  Constipation 9 - 11 < 1
  Upper Abdominal Pain 7 < 1 7 < 1
  Dyspepsia 6 < 1 5 -
Skin and Subcutaneous Tissue Disorders
  Hand-and-Foot 60 17 9 < 1
  Syndrome        
  Alopecia 6 - 22 < 1
  Rash 7 - 8 -
  Erythema 6 1 5 < 1
General Disorders and Administration Site Conditions
  Fatigue 16 < 1 16 1
  Pyrexia 7 < 1 9 < 1
  Asthenia 10 < 1 10 1
  Lethargy 10 < 1 9 < 1
Nervous System Disorders
  Dizziness 6 < 1 6 -
  Headache 5 < 1 6 < 1
  Dysgeusia 6 - 9 -
Metabolism and Nutrition Disorders
  Anorexia 9 < 1 11 < 1
  Eye Disorders        
  Conjunctivitis 5 < 1 6 < 1
Blood and Lymphatic System Disorders
  Neutropenia 2 < 1 8 5
Respiratory Thoracic and Mediastinal Disorders
  Epistaxis 2 - 5 -

Table 5 : Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of Patients Receiving XELODA (capecitabine) Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)

Adverse Event XELODA (n=995) Grade 3/4 % IV 5-FU/LV (n=974) Grade 3/4 %
Increased ALAT (SGPT) 1.6 0.6
Increased calcium 1.1 0.7
Decreased calcium 2.3 2.2
Decreased hemoglobin 1.0 1.2
Decreased lymphocytes 13.0 13.0
Decreased neutrophils* 2.2 26.2
Decreased neutrophils/granulocytes 2.4 26.4
Decreased platelets 1.0 0.7
Increased bilirubin** 20 6.3
*The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the XELODA (capecitabine) arm and 4.9% in the IV 5-FU/LV arm.
**It should be noted that grading was according to NCIC CTC Version 1 (May, 1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 × upper limit of normal (ULN) range, and grade 4 a value of > 3.0 × ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of > 3.0 to 10.0 × ULN, and grade 4 values > 10.0 × ULN.

Metastatic Colorectal Cancer

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 (capecitabine) 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 (capecitabine) and 32 (5.4%) randomized to 5-FU/LV.

Table 6 : Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥ 5% of Patients

Adverse Event XELODA (n=596) 5-FU/LV (n=593)
Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 %
Number of Patients With > One Adverse Event 96 52 9 94 45 9
Body System/Adverse Event
GI
  Diarrhea 55 13 2 61 10 2
  Nausea 43 4 51 3 < 1
  Vomiting 27 4 < 1 30 4 < 1
  Stomatitis 25 2 < 1 62 14 1
  Abdominal Pain 35 9 < 1 31 5
  Gastrointestinal Motility Disorder 10 < 1 7 < 1
  Constipation 14 1 < 1 17 1
  Oral Discomfort 10 10
  Upper GI Inflammatory Disorders 8 < 1 10 1
  Gastrointestinal Hemorrhage 6 1 < 1 3 1
  Ileus 6 4 1 5 2 1
Skin and Subcutaneous
  Hand-and-Foot Syndrome 54 17 NA 6 1 NA
  Dermatitis 27 1 26 1
  Skin Discoloration 7 < 1 5
  Alopecia 6 21 < 1
General
  Fatigue/Weakness 42 4 46 4
  Pyrexia 18 1 21 2
  Edema 15 1 9 1
  Pain 12 1 10 1
  Chest Pain 6 1 6 1 < 1
Neurological
  Peripheral Sensory Neuropathy 10 4
  Headache 10 1 7
  Dizziness* 8 < 1 8 < 1
  Insomnia 7 7
  Taste Disturbance 6 1 11 < 1 1
Metabolism
  Appetite Decreased 26 3 < 1 31 2 < 1
  Dehydration 7 2 < 1 8 3 1
Eye
  Eye Irritation 13 10 < 1
  Vision Abnormal 5 2
Respiratory
  Dyspnea 14 1 10 < 1 1
  Cough 7 < 1 1 8
  Pharyngeal Disorder 5 5
  Epistaxis 3 < 1 6
  Sore Throat 2 6
Musculoskeletal
  Back Pain 10 2 9 < 1
  Arthralgia 8 1 6 1
Vascular
  Venous Thrombosis 8 3 < 1 6 2
Psychiatric
  Mood Alteration 5 6 < 1
  Depression 5 4 < 1
Infections
  Viral 5 < 1 5 < 1
Blood and Lymphatic
  Anemia 80 2 < 1 79 1 < 1
  Neutropenia 13 1 2 46 8 13
Hepatobiliary
  Hyperbilirubinemia 48 18 5 17 3 3
– Not observed
* Excluding vertigo
NA = Not Applicable

Breast Cancer

In Combination with Docetaxel

The following data are shown for the combination study with XELODA (capecitabine) and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the XELODA (capecitabine) and docetaxel combination arm the treatment was XELODA (capecitabine) 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.

Table 7 : Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in ≥ 5% of Patients Participating in the XELODA (capecitabine) and Docetaxel Combination vs Docetaxel Monotherapy Study

Adverse Event XELODA 1250 mg/m²/bid With Docetaxel 75 mg/m²/ 3 weeks (n=251) Docetaxel 100mg/m²/ 3weeks (n=255)
Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 %
Number of Patients With at Least One Adverse Event 99 76.5 29.1 97 57.6 31.8
Body System/Adverse Event
GI
  Diarrhea 67 14 < 1 48 5 < 1
  Stomatitis 67 17 < 1 43 5
  Nausea 45 7 36 2
  Vomiting 35 4 1 24 2
  Constipation 20 2 18
  Abdominal Pain 30 < 3 < 1 24 2
  Dyspepsia 14 8 1
  Dry Mouth 6 < 1 5
Skin and Subcutaneous
  Hand-and-Foot Syndrome 63 24 NA 8 1 NA
  Alopecia 41 6 42 7
  Nail Disorder 14 2 15
  Dermatitis 8 11 1
  Rash Erythematous 9 < 1 5
  Nail Discoloration 6 4 < 1
  Onycholysis 5 1 5 1
  Pruritus 4 5
General
  Pyrexia 28 2 34 2
  Asthenia 26 4 < 1 25 6
  Fatigue 22 4 27 6
  Weakness 16 2 11 2
  Pain in Limb 13 < 1 13 2
  Lethargy  7 6 2
  Pain 7 < 1 5 1
  Chest Pain (non-cardiac) 4 < 1 6 2
  Influenza-like Illness 5 5
Neurological
  Taste Disturbance 16 < 1 14 < 1
  Headache 15 3 15 2
  Paresthesia 12 < 1 16 1
  Dizziness 12 8 < 1
  Insomnia 8 10 < 1
  Peripheral Neuropathy 6 10 1
  Hypoaesthesia 4 < 1 8 < 1
Metabolism
  Anorexia 13 1 11 < 1
  Appetite Decreased 10 5
  Weight Decreased 7 5
  Dehydration 10 2 7 < 1 < 1
Eye
  Lacrimation Increased 12 7 < 1
  Conjunctivitis 5 4
  Eye Irritation 5 1
Musculoskeletal
  Arthralgia 15 2 24 3
  Myalgia 15 2 25 2
  Back Pain 12 < 1 11 3
  Bone Pain 8 < 1 10 2
Cardiac
  Edema 33 < 2 34 < 3 1
Blood
  Neutropenic Fever 16 3 13 21 5 16
Respiratory
  Dyspnea 14 2 < 1 16 2
  Cough 13 1 22 < 1
  Sore Throat 12 2 11 < 1
  Epistaxis 7 < 1 6
  Rhinorrhea 5 3
  Pleural Effusion 2 1 7 4
Infection
  Oral Candidiasis 7 < 1 8 < 1
  Urinary Tract Infection 6 < 1 4
  Upper Respiratory Tract 4 5 1
Vascular
  Flushing 5 5
  Lymphoedema 3 < 1 5 1
Psychiatric
  Depression 5 5 1
– Not observed
NA = Not Applicable

Table 8 : Percent of Patients With Laboratory Abnormalities Participating in the XELODA (capecitabine) and Docetaxel Combination vs Docetaxel Monotherapy Study

Adverse Event XELODA (capecitabine) 1250 mg/m²/bid With Docetaxel 75 mg/m²/ 3 weeks
(n=251)
Docetaxel 100 mg/m²/ 3weeks
(n=255)
Body System/Adverse Event Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 %
Hematologic
Leukopenia 91 37 24 88 42 33
Neutropenia/Granulocytopenia 86 20 49 87 10 66
Thrombocytopenia 41 2 1 23 1 2
Anemia 80 7 3 83 5 < 1
Lymphocytopenia 99 48 41 98 44 40
Hepatobiliary
Hyperbilirubinemia 20 7 2 6 2 2

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.

Table 9 : Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in ≥ 5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer

Adverse Event Phase 2 Trial in Stage IV Breast Cancer (n=162)
Body System/Adverse Event Total % Grade 3 % Grade 4 %
GI
  Diarrhea 57 12 3
  Nausea 53 4
  Vomiting 37 4
  Stomatitis 24 7
  Abdominal Pain 20 4
  Constipation 15 1
  Dyspepsia 8
Skin and Subcutaneous
  Hand-and-Foot Syndrome 57 11 NA
  Dermatitis 37 1
  Nail Disorder 7
General
  Fatigue 41 8
  Pyrexia 12 1
  Pain in Limb 6 1
Neurological
  Paresthesia 21 1
  Headache 9 1
  Dizziness 8
  Insomnia 8
Metabolism
  Anorexia 23 3
  Dehydration 7 4 1
Eye
  Eye Irritation 15
Musculoskeletal
  Myalgia 9
Cardiac
  Edema 9 1
Blood
  Neutropenia 26 2 2
  Thrombocytopenia 24 3 1
  Anemia 72 3 1
  Lymphopenia 94 44 15
Hepatobiliary
  Hyperbilirubinemia 22 9 2
– Not observed
NA = Not Applicable

Clinically Relevant Adverse Events in < 5% of Patients

Clinically relevant adverse events reported in < 5% of patients treated with XELODA (capecitabine) either as monotherapy or in combination with docetaxol 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)

Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%)

Skin & Subcutan.: nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%), skin ulceration, pruritus, radiation recall syndrome (0.2%)

General: chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%), hemorrhage, edema, sedation

Neurological: insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balance

Metabolism: increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemia

Eye: conjunctivitis

Respiratory: cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspnea

Cardiac: tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1%), pericardial effusion

Infections: laryngitis (1.0%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), keratoconjunctivitis, sepsis (0.3%), fungal infections (including candidiasis) (0.2%)

Musculoskeletal: myalgia, bone pain (0.1%), arthritis (0.1%), muscle weakness

Blood & Lymphatic: leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%), idiopathic thrombocytopenia purpura (1.0%), pancytopenia (0.1%)

Vascular: hypotension (0.2%), hypertension (0.1%), lymphoedema (0.1%), pulmonary embolism (0.2%), cerebrovascular accident (0.1%)

Psychiatric: depression, confusion (0.1%)

Renal: renal impairment (0.6%)

Ear: vertigo

Hepatobiliary: hepatic fibrosis (0.1%), hepatitis (0.1%), cholestatic hepatitis (0.1%), abnormal liver function tests

Immune System: drug hypersensitivity (0.1%)

Postmarketing: hepatic failure, lacrimal duct stenosis

XELODA (capecitabine) In Combination With Docetaxel (Metastatic Breast Cancer)

Gastrointestinal: ileus (0.4%), necrotizing enterocolitis (0.4%), esophageal ulcer (0.4%), hemorrhagic diarrhea (0.8%)

Neurological: ataxia (0.4%), syncope (1.2%), taste loss (0.8%), polyneuropathy (0.4%), migraine (0.4%)

Cardiac: supraventricular tachycardia (0.4%)

Infection: neutropenic sepsis (2.4%), sepsis (0.4%), bronchopneumonia (0.4%)

Blood & Lymphatic: agranulocytosis (0.4%), prothrombin decreased (0.4%)

Vascular: hypotension (1.2%), venous phlebitis and thrombophlebitis (0.4%), postural hypotension (0.8%)

Renal: renal failure (0.4%)

Hepatobiliary: jaundice (0.4%), abnormal liver function tests (0.4%), hepatic failure (0.4%), hepatic coma (0.4%), hepatotoxicity (0.4%)

Immune System: hypersensitivity (1.2%)

Read the Xeloda (capecitabine) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Drug-Drug Interactions

Anticoagulants

Altered coagulation parameters and/or bleeding have been reported in patients taking XELODA (capecitabine) 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 (capecitabine) therapy and, in a few cases, within 1 month after stopping XELODA (capecitabine) . 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]. 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 (capecitabine) and phenytoin dose may need to be reduced [see DOSAGE AND ADMINISTRATION]. Postmarketing reports indicate that some patients receiving XELODA (capecitabine) 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 (capecitabine) and other CYP2C9 substrates have been conducted. Care should be exercised when XELODA (capecitabine) is coadministered with CYP2C9 substrates.

Drug-Food Interaction

Food was shown to reduce both the rate and extent of absorption of capecitabine [see CLINICAL PHARMACOLOGY]. In all clinical trials, patients were instructed to administer XELODA (capecitabine) within 30 minutes after a meal. It is recommended that XELODA be administered with food [see DOSAGE AND ADMINISTRATION].

Last reviewed on RxList: 4/6/2011
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

General

Patients receiving therapy with XELODA (capecitabine) should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced [see DOSAGE AND ADMINISTRATION].

Diarrhea

XELODA (capecitabine) can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received XELODA (capecitabine) monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of ≥ 10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of XELODA (capecitabine) should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of XELODA should be decreased [see DOSAGE AND ADMINISTRATION]. Standard antidiarrheal treatments (eg, loperamide) are recommended.

Necrotizing enterocolitis (typhlitis) has been reported.

Coagulopathy

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].

Cardiotoxicity

The cardiotoxicity observed with XELODA (capecitabine) 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.

Dihydropyrimidine Dehydrogenase Deficiency

Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded.

Renal Insufficiency

Patients with moderate renal impairment at baseline require dose reduction [see DOSAGE AND ADMINISTRATION]. 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, Use In Specific Populations, and CLINICAL PHARMACOLOGY].

Pregnancy

XELODA (capecitabine) may cause fetal harm when given to a pregnant woman. Capecitabine caused embryolethality and teratogenicity in mice and embryolethality in monkeys when administered during organogenesis. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving XELODA (capecitabine) , the patient should be apprised of the potential hazard to the fetus [see Use In Specific Populations].

Hand-and-Foot Syndrome

Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving XELODA (capecitabine) monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If grade 2 or 3 hand-and-foot syndrome occurs, administration of XELODA (capecitabine) 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].

Hyperbilirubinemia

In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of XELODA (capecitabine) 1250 mg/m² twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 ( > 3 x 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 (capecitabine) 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 (capecitabine) 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 (capecitabine) . 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 (capecitabine) and docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 ( > 3 x ULN) hyperbilirubinemia occurred in 2% (n=5).

If drug-related grade 3 to 4 elevations in bilirubin occur, administration of XELODA (capecitabine) should be immediately interrupted until the hyperbilirubinemia decreases to ≤ 3.0 X ULN [see recommended dose modifications under DOSAGE AND ADMINISTRATION].

Hematologic

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 (capecitabine) 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 x 109/L and/or thrombocyte counts of < 100 x 109/L should not be treated with XELODA (capecitabine) . If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with XELODA (capecitabine) should be interrupted.

Geriatric Patients

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 (capecitabine) monotherapy, 62% of the 21 patients ≥ 80 years of age treated with XELODA (capecitabine) 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 (capecitabine) 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 (capecitabine) 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 (capecitabine) 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 (capecitabine) 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 (capecitabine) 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.

Hepatic Insufficiency

Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when XELODA (capecitabine) is administered. The effect of severe hepatic dysfunction on the disposition of XELODA (capecitabine) is not known [see Use in Specific Populations and CLINICAL PHARMACOLOGY].

Combination With Other Drugs

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

Patient Counseling Information

Information for Patients (see Patient Package Insert)

Patients and patients' caregivers should be informed of the expected adverse effects of XELODA (capecitabine) , 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]. As described below, patients taking XELODA (capecitabine) should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Patients should be encouraged to recognize the common grade 2 toxicities associated with XELODA (capecitabine) 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 (capecitabine) 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 (capecitabine) 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 (capecitabine) 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 (capecitabine) immediately.

Stomatitis

Patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking XELODA (capecitabine) 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Adequate studies investigating the carcinogenic potential of XELODA have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.

Impairment of Fertility

In studies of fertility and general reproductive performance in 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.

Use In Specific Populations

Pregnancy: Category D

XELODA (capecitabine) can cause fetal harm when administered to a pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.2 times the corresponding values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5'-DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose.

There are no adequate and well controlled studies of XELODA (capecitabine) in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving XELODA (capecitabine) , the patient should be apprised of the potential hazard to the fetus. Women should be advised to avoid becoming pregnant while receiving treatment with XELODA (capecitabine) [see WARNINGS AND PRECAUTIONS].

Nursing Mothers

Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. It is not known whether this 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 from capecitabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of XELODA (capecitabine) in persons < 18 years of age have not been established.

Geriatric Use

Physicians should pay particular attention to monitoring the adverse effects of XELODA (capecitabine) in the elderly [see WARNINGS AND PRECAUTIONS].

Hepatic Insufficiency

Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with XELODA (capecitabine) . The effect of severe hepatic dysfunction on XELODA (capecitabine) is not known [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Renal Insufficiency

Patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance < 30 mL/min) renal impairment showed higher exposure for capecitabine, 5-FDUR, and FBAL than in those with normal renal function [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 4/6/2011
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

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 (capecitabine) 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 (capecitabine) 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).

CONTRAINDICATIONS

Dihydropyrimidine Dehydrogenase (DPD) Deficiency

XELODA (capecitabine) is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.

Severe Renal Impairment

XELODA (capecitabine) is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

Hypersensitivity

XELODA (capecitabine) is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. XELODA (capecitabine) is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.

Last reviewed on RxList: 4/6/2011
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

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, N5-10methylenetetrahydrofolate, 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.

Pharmacokinetics

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, DOSAGE AND ADMINISTRATION, and Drug-Food Interaction].

The pharmacokinetics of XELODA (capecitabine) and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m²/day. Over this range, the pharmacokinetics of XELODA (capecitabine) and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5FU, 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 (capecitabine) 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 (capecitabine) 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.

Metabolic Pathway of capecitabine to 5-FU

Metabolic Pathway of capecitabine to 5-FU - Illustration

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-βalanine (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 (capecitabine) 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 and DOSAGE AND ADMINISTRATION].

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 (capecitabine) has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1255 mg/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 (capecitabine) is administered. The effect of severe hepatic dysfunction on XELODA is not known [see WARNINGS AND PRECAUTIONS and Use in Special Populations].

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 < 30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day 1 compared to normal renal function patients (creatinine clearance > 80 mL/min). Systemic exposure to 5'-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Use In Special Populations].

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].

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 (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 XELODA.

Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa

A Phase 1 study evaluated the effect of XELODA (capecitabine) on the pharmacokinetics of docetaxel (Taxotere®) and the effect of docetaxel on the pharmacokinetics of XELODA (capecitabine) was conducted in 26 patients with solid tumors. XELODA (capecitabine) 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.

Clinical Studies

Adjuvant Colon Cancer

A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes' C colon cancer (X-ACT) provided data concerning the use of XELODA (capecitabine) 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 (capecitabine) to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with XELODA (capecitabine) 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 ≥ 1.5x109/L, platelets ≥ 100x109/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 (capecitabine) and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.

Table 10 : Baseline Demographics

  XELODA
(n=1004)
5-FU/LV
(n=983)
Age (median, years) 62 63
Range (25-80) (22-82)
Gender
  Male (n, %) 542 (54) 532 (54)
  Female (n, %) 461 (46) 451 (46)
ECOG PS
  0 (n, %) 849 (85) 830 (85)
  1 (n, %) 152 (15) 147 (15)
Staging – Primary Tumor
  PT1 (n, %) 12 (1) 6 (0.6)
  PT2 (n, %) 90 (9) 92 (9)
  PT3 (n, %) 763 (76) 746 (76)
  PT4 (n, %) 138 (14) 139 (14)
  Other (n, %) 1 (0.1) 0 (0)
Staging – Lymph Node
  pN1 (n, %) 695 (69) 694 (71)
  pN2 (n, %) 305 (30) 288 (29)
  Other (n, %) 4 (0.4) 1 (0.1)

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]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for XELODA (capecitabine) included dose reductions, cycle delays and treatment interruptions (see Table 11).

Table 11 Summary of Dose Modifications in X-ACT Study

  XELODA
N = 995
5-FU/LV
N = 974
Median relative dose intensity (%) 93 92
Patients completing full course of treatment (%) 83 87
Patients with treatment interruption (%) 15 5
Patients with cycle delay (%) 46 29
Patients with dose reduction (%) 42 44
Patients with treatment interruption, cycle delay, or dose reduction (%) 57 52

The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for XELODA (capecitabine) 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 (capecitabine) 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 5FU/LV effect on DFS. The hazard ratio for XELODA (capecitabine) 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 (capecitabine) and 68.4% for 5FU/LV (see Figure 2).

Table 12 : Efficacy of XELODA (capecitabine) vs 5-FU/LV in Adjuvant Treatment of Colon Cancera

All Randomized Population XELODA
(n=1004)
5-FU/LV
(n=983)
Median follow-up (months) 83 83
5-year Disease-free Survival Rates(%)b 59.1 54.6
Hazard Ratio (XELODA/5-FU/LV) (95% C.I. for Hazard Ratio) 0.88 (0.77-1.01)
p-valuec p=0.068
a Approximately 93.4% had 5-year DFS information
b Based on Kaplan-Meier estimates
c Test of superiority of Xeloda (capecitabine) vs 5-FU/LV (Wald chi-square test)

Figure 1 : Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population)a

Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population) - Illustration

a XELODA (capecitabine) has been demonstrated to be non-inferior to 5-FU/LV.

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

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

Metastatic Colorectal Cancer

General

The recommended dose of XELODA (capecitabine) 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 (capecitabine) ; however, toxicity was increased. XELODA (capecitabine) , 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 (capecitabine) 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 (capecitabine) 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 (capecitabine) and 5-FU/LV patients are shown in Table 13.

Table 13 : Baseline Demographics of Controlled Colorectal Trials

  Study 1 Study 2
XELODA
(n=302)
5-FU/LV
(n=303)
XELODA
(n=301)
5-FU/LV
(n=301)
Age (median, years) 64 63 64 64
Range (23-86) (24-87) (29-84) (36-86)
Gender        
  Male (%) 181 (60) 197 (65) 172 (57) 173 (57)
  Female (%) 121 (40) 106 (35) 129 (43) 128 (43)
Karnofsky PS (median) 90 90 90 90
Range (70-100) (70-100) (70-100) (70-100)
Colon (%) 222 (74) 232 (77) 199 (66) 196 (65)
Rectum (%) 79 (26) 70 (23) 101 (34) 105 (35)
Prior radiation therapy (%) 52 (17) 62 (21) 42 (14) 42 (14)
Prior adjuvant 5-FU (%) 84 (28) 110 (36) 56 (19) 41 (14)

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

Table 14 : Efficacy of XELODA (capecitabine) vs 5-FU/LV in Colorectal Cancer (Study 1)

  XELODA
(n=302)
5-FU/LV
(n=303)
Overall Response Rate
(%, 95% C.I.) 21 (16-26) 11 (8-15)
(p-value) 0.0014
Time to Progression
(Median, days, 95% C.I.) 128 (120-136) 131 (105-153)
Hazard Ratio (XELODA/5-FU/LV) 95% C.I. for Hazard Ratio 0.99 (0.84-1.17)
Survival
(Median, days, 95% C.I.) 380 (321-434) 407 (366-446)
Hazard Ratio (XELODA/5-FU/LV) 95% C.I. for Hazard Ratio 1.00 (0.84-1.18)

Table 15 : Efficacy of XELODA (capecitabine) vs 5-FU/LV in Colorectal Cancer (Study 2)

  XELODA
(n=301)
5-FU/LV
(n=301)
Overall Response Rate
(%, 95% C.I.) 21 (16-26) 14 (10-18)
(p-value) 0.027
Time to Progression
(Median, days, 95% C.I.) 137 (128-165) 131 (102-156)
Hazard Ratio (XELODA/5-FU/LV) 95% C.I. for Hazard Ratio 0.97 (0.82-1.14)
Survival    
(Median, days, 95% C.I.) 404 (367-452) 369 (338-430)
Hazard Ratio (XELODA/5-FU/LV) 95% C.I. for Hazard Ratio 0.92 (0.78-1.09)

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

Kaplan-Meier Curve for Overall Survival of Pooled Data - Illustration

XELODA (capecitabine) was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of XELODA (capecitabine) and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that XELODA (capecitabine) 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 (capecitabine) . 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 (capecitabine) , 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 5FU/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 (capecitabine) difference. These results do not exclude the possibility of true equivalence of XELODA (capecitabine) to 5-FU/LV (see Table 14, Table 15, and Figure 3).

Breast Cancer

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

In Combination With Docetaxel

The dose of XELODA (capecitabine) 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 (capecitabine) (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 3week cycles of docetaxel in combination with 1250 mg/m² twice daily for 14 days of XELODA (capecitabine) 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 (capecitabine) 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 (capecitabine) 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.

Table 16 : Baseline Demographics and Clinical Characteristics XELODA (capecitabine) and Docetaxel Combination vs Docetaxel in Breast Cancer Trial

  XELODA + Docetaxel
(n=255)
Docetaxel
(n=256)
Age (median, years) 52 51
Karnofsky PS (median) 90 90
Site of Disease
  Lymph nodes 121 (47%) 125 (49%)
  Liver 116 (45%) 122 (48%)
  Bone 107 (42%) 119 (46%)
  Lung 95 (37%) 99 (39%)
  Skin 73 (29%) 73 (29%)
Prior Chemotherapy
  Anthracycline1 255 (100%) 256 (100%)
  5-FU 196 (77%) 189 (74%)
  Paclitaxel 25 (10%) 22 (9%)
Resistance to an Anthracycline
  No resistance 19 (7%) 19 (7%)
  Progression on anthracycline therapy 65 (26%) 73 (29%)
  Stable disease after 4 cycles of anthracycline therapy 41 (16%) 40 (16%)
  Relapsed within 2 years of completion of anthracycline-adjuvant therapy 78 (31%) 74 (29%)
  Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose 51 (20%) 50 (20%)
No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease
  0 89 (35%) 80 (31%)
  1 123 (48%) 135 (53%)
  2 43 (17%) 39 (15%)
  3 0 (0%) 2 (1%)
1 Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione

XELODA (capecitabine) 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.

Table 17 : Efficacy of XELODA (capecitabine) and Docetaxel Combination vs Docetaxel Monotherapy

Efficacy Parameter Combination Therapy Monotherapy p-value Hazard Ratio
Time to Disease Progression
  Median Days 186 128 0.0001 0.643
  95% C.I. (165-198) (105-136)    
Overall Survival
  Median Days 442 352 0.0126 0.775
  95% C.I. (375-497) (298-387)    
Response Rate1 32% 22% 0.009 NA2
1 The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm.
2 NA = Not Applicable

Figure 4 : Kaplan-Meier Estimates for Time to Disease Progression XELODA (capecitabine) and Docetaxel vs Docetaxel

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

Figure 5 : Kaplan-Meier Estimates of Survival XELODA (capecitabine) and Docetaxel vs Docetaxel

Kaplan-Meier Estimates of Survival XELODA and Docetaxel vs Docetaxel - Illustration

Monotherapy

The antitumor activity of XELODA (capecitabine) 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 (capecitabine) was administered at a dose of 1255 mg/m² twice daily for 2 weeks followed by a 1week 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.

Table 18 : Baseline Demographics and Clinical Characteristics Single-Arm Breast Cancer Trial

  Patients With Measurable Disease
(n=135)
All Patients
(n=162)
Age (median, years) 55 56
Karnofsky PS 90 90
No. Disease Sites
  1-2 43 (32%) 60 (37%)
  3-4 63 (46%) 69 (43%)
   > 5 29 (22%) 34 (21%)
Dominant Site of Disease
  Visceral1 101 (75%) 110 (68%)
  Soft Tissue 30 (22%) 35 (22%)
  Bone 4 (3%) 17 (10%)
Prior Chemotherapy
  Paclitaxel 135 (100%) 162 (100%)
  Anthracycline2 122 (90%) 147 (91%)
  5-FU 110 (81%) 133 (82%)
  Resistance to Paclitaxel 103 (76%) 124 (77%)
  Resistance to an Anthracycline2 55 (41%) 67 (41%)
  Resistance to both Paclitaxel and an Anthracycline2 43 (32%) 51 (31%)
1 Lung, pleura, liver, peritoneum
2 Includes 2 patients treated with an anthracenedione

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

Table 19 : Response Rates in Doubly-Resistant Patients Single-Arm Breast Cancer Trial

  Resistance to Both Paclitaxel and an Anthracycline
(n=43)
CR 0
PR1 11
CR + PR1 11
Response Rate1 (95% C.I.) 25.6% (13.5, 41.2)
Duration of Response,1 Median in days2 (Range) 154 (63-233)
1 Includes 2 patients treated with an anthracenedione
2 From 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 18). The median time to progression was 90 days and the median survival was 306 days.

Last reviewed on RxList: 4/6/2011
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Read this leaflet before you start taking XELODA® (capecitabine) [zeh-LOE-duh] and each time you refill your prescription in case the information has changed. This leaflet contains important information about XELODA (capecitabine) . However, this information does not take the place of talking with your doctor. This information cannot cover all possible risks and benefits of XELODA (capecitabine) . Your doctor should always be your first choice for discussing your medical condition and this medicine.

What is XELODA (capecitabine) ?

XELODA (capecitabine) is a medicine you take by mouth (orally). XELODA (capecitabine) is changed in the body to 5-fluorouracil (5-FU). In some patients with colon, rectum or breast cancer, 5-FU stops cancer cells from growing and decreases the size of the tumor.

XELODA (capecitabine) is used to treat:

  • cancer of the colon after surgery
  • cancer of the colon or rectum (colorectal cancer) that has spread to other parts of the body (metastatic colorectal cancer). You should know that in studies, other medicines showed improved survival when they were taken together with 5-FU and leucovorin. In studies, XELODA (capecitabine) was no worse than 5-FU and leucovorin taken together but did not improve survival compared to these two medicines.
  • breast cancer that has spread to other parts of the body (metastatic breast cancer) together with another medicine called docetaxel (TAXOTERE ®)
  • breast cancer that has spread to other parts of the body and has not improved after treatment with other medicines such as paclitaxel (TAXOL ®) and anthracycline-containing medicine such as Adriamycin™ and doxorubicin

What is the most important information about XELODA (capecitabine) ?

XELODA (capecitabine) may increase the effect of other medicines used to thin your blood such as warfarin (COUMADIN®). It is very important that your doctor knows if you are taking a blood thinner such as warfarin because XELODA (capecitabine) may increase the effect of this medicine and could lead to serious side effects. If you are taking blood thinners and XELODA (capecitabine) , your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.

Who should not take XELODA (capecitabine) ?

1. DO NOT TAKE XELODA (capecitabine) IF YOU

  • are nursing a baby. Tell your doctor if you are nursing. XELODA (capecitabine) may pass to the baby in your milk and harm the baby.
  • are allergic to 5-fluorouracil
  • are allergic to capecitabine or to any of the ingredients in XELODA (capecitabine)
  • have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)

2. TELL YOUR DOCTOR IF YOU

  • take a blood thinner such as warfarin (COUMADIN). This is very important because XELODA (capecitabine) may increase the effect of the blood thinner. If you are taking blood thinners and XELODA (capecitabine) , your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.
  • take phenytoin (DILANTIN®). Your doctor needs to test the levels of phenytoin in your blood more often or change your dose of phenytoin.
  • are pregnant or think you may be pregnant. XELODA (capecitabine) may harm your unborn child.
  • have kidney problems. Your doctor may prescribe a different medicine or lower the XELODA (capecitabine) dose.
  • have liver problems. You may need to be checked for liver problems while you take XELODA (capecitabine) .
  • have heart problems because you could have more side effects related to your heart.
  • take the vitamin folic acid. It may affect how XELODA (capecitabine) works.

How should I take XELODA (capecitabine) ?

Take XELODA (capecitabine) exactly as your doctor tells you to. Your doctor will prescribe a dose and treatment plan that is right for you. Your doctor may want you to take both 150 mg and 500 mg tablets together for each dose. If so, you must be able to identify the tablets. Taking the wrong tablets could cause an overdose (too much medicine) or underdose (too little medicine). The 150 mg tablets are light peach in color with 150 on one side. The 500 mg tablets are peach in color with 500 on one side. Your doctor may change the amount of medicine you take during your treatment. Your doctor may prescribe XELODA (capecitabine) Tablets with docetaxel (TAXOTERE) injection.

  • XELODA (capecitabine) is taken in 2 daily doses, a morning dose and an evening dose
  • Take XELODA (capecitabine) tablets within 30 minutes after the end of a meal (breakfast and dinner)
  • Swallow XELODA (capecitabine) tablets whole with water
  • If you miss a dose of XELODA (capecitabine) , do not take the missed dose at all and do not double the next dose. Instead, continue your regular dosing schedule and check with your doctor.
  • XELODA (capecitabine) is usually taken for 14 days followed by a 7-day rest period (no drug), for a 21-day cycle. Your doctor will tell you how many cycles of treatment you will need.
  • If you take too much XELODA (capecitabine) , contact your doctor or local poison control center or emergency room right away.

What should I avoid while taking XELODA (capecitabine) ?

  • Women should not become pregnant while taking XELODA (capecitabine) . XELODA (capecitabine) may harm your unborn child. Use effective birth control while taking XELODA (capecitabine) . Tell your doctor if you become pregnant.
  • Do not breast-feed. XELODA (capecitabine) may pass through your milk and harm your baby.
  • Men should use birth control while taking XELODA (capecitabine)

What are the most common side effects of XELODA (capecitabine) ?

The most common side effects of XELODA (capecitabine) are:

  • diarrhea, nausea, vomiting, sores in the mouth and throat (stomatitis), stomach area pain (abdominal pain), upset stomach, constipation, loss of appetite, and too much water loss from the body (dehydration). These side effects are more common in patients age 80 and older.
  • hand-and-foot syndrome (palms of the hands or soles of the feet tingle, become numb, painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, and hair loss
  • tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, and muscle pain), trouble sleeping, and taste problems

These side effects may differ when taking XELODA (capecitabine) with docetaxel (TAXOTERE). Please consult your doctor for possible side effects that may be caused by taking XELODA (capecitabine) with docetaxel (TAXOTERE).

If you are concerned about these or any other side effects while taking XELODA (capecitabine) , talk to your doctor.

Stop taking XELODA (capecitabine) immediately and contact your doctor right away if you have the side effects listed below, or other side effects that concern you. Your doctor can then adjust XELODA (capecitabine) to a dose that is right for you or stop your XELODA (capecitabine) treatment for a while. This should help to reduce the side effects and stop them from getting worse.

  • Diarrhea: if you have an additional 4 bowel movements each day beyond what is normal or any diarrhea at night
  • Vomiting: if you vomit more than once in a 24-hour time period
  • Nausea: if you lose your appetite, and the amount of food you eat each day is much less than usual
  • Stomatitis: if you have pain, redness, swelling or sores in your mouth
  • Hand-and-Foot Syndrome: if you have pain, swelling or redness of your hands or feet that prevents normal activity
  • Fever or Infection: if you have a temperature of 100.5°F or greater, or other signs of infection

Your doctor may tell you to lower the dose or to stop XELODA (capecitabine) treatment for a while. If caught early, most of these side effects usually improve after you stop taking XELODA (capecitabine) . If they do not improve within 2 to 3 days, call your doctor again. After your side effects have improved, your doctor will tell you whether to start taking XELODA (capecitabine) again and what dose to take. Adjusting the dose of XELODA (capecitabine) to be right for each patient is an important part of treatment.

How should I store and use XELODA (capecitabine) ?

  • Never share XELODA (capecitabine) with anyone
  • Store XELODA (capecitabine) at normal room temperature (about 65° to 85°F)
  • Keep XELODA (capecitabine) and all other medicines out of the reach of children
  • If you take too much XELODA (capecitabine) by mistake, contact your doctor or local poison control center or emergency room right away

General advice about prescription medicines:

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use XELODA (capecitabine) for a condition for which it was not prescribed. Do not give XELODA (capecitabine) to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about XELODA (capecitabine) . If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about XELODA (capecitabine) that is written for health professionals.

Last reviewed on RxList: 4/6/2011
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

Read this leaflet before you start taking XELODA® (capecitabine) [zeh-LOE-duh] and each time you refill your prescription in case the information has changed. This leaflet contains important information about XELODA (capecitabine) . However, this information does not take the place of talking with your doctor. This information cannot cover all possible risks and benefits of XELODA (capecitabine) . Your doctor should always be your first choice for discussing your medical condition and this medicine.

What is XELODA (capecitabine) ?

XELODA (capecitabine) is a medicine you take by mouth (orally). XELODA (capecitabine) is changed in the body to 5-fluorouracil (5-FU). In some patients with colon, rectum or breast cancer, 5-FU stops cancer cells from growing and decreases the size of the tumor.

XELODA (capecitabine) is used to treat:

  • cancer of the colon after surgery
  • cancer of the colon or rectum (colorectal cancer) that has spread to other parts of the body (metastatic colorectal cancer). You should know that in studies, other medicines showed improved survival when they were taken together with 5-FU and leucovorin. In studies, XELODA (capecitabine) was no worse than 5-FU and leucovorin taken together but did not improve survival compared to these two medicines.
  • breast cancer that has spread to other parts of the body (metastatic breast cancer) together with another medicine called docetaxel (TAXOTERE ®)
  • breast cancer that has spread to other parts of the body and has not improved after treatment with other medicines such as paclitaxel (TAXOL ®) and anthracycline-containing medicine such as Adriamycin™ and doxorubicin

What is the most important information about XELODA (capecitabine) ?

XELODA (capecitabine) may increase the effect of other medicines used to thin your blood such as warfarin (COUMADIN®). It is very important that your doctor knows if you are taking a blood thinner such as warfarin because XELODA (capecitabine) may increase the effect of this medicine and could lead to serious side effects. If you are taking blood thinners and XELODA (capecitabine) , your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.

Who should not take XELODA (capecitabine) ?

1. DO NOT TAKE XELODA (capecitabine) IF YOU

  • are nursing a baby. Tell your doctor if you are nursing. XELODA (capecitabine) may pass to the baby in your milk and harm the baby.
  • are allergic to 5-fluorouracil
  • are allergic to capecitabine or to any of the ingredients in XELODA (capecitabine)
  • have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)

2. TELL YOUR DOCTOR IF YOU

  • take a blood thinner such as warfarin (COUMADIN). This is very important because XELODA (capecitabine) may increase the effect of the blood thinner. If you are taking blood thinners and XELODA (capecitabine) , your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.
  • take phenytoin (DILANTIN®). Your doctor needs to test the levels of phenytoin in your blood more often or change your dose of phenytoin.
  • are pregnant or think you may be pregnant. XELODA (capecitabine) may harm your unborn child.
  • have kidney problems. Your doctor may prescribe a different medicine or lower the XELODA (capecitabine) dose.
  • have liver problems. You may need to be checked for liver problems while you take XELODA (capecitabine) .
  • have heart problems because you could have more side effects related to your heart.
  • take the vitamin folic acid. It may affect how XELODA (capecitabine) works.

How should I take XELODA (capecitabine) ?

Take XELODA (capecitabine) exactly as your doctor tells you to. Your doctor will prescribe a dose and treatment plan that is right for you. Your doctor may want you to take both 150 mg and 500 mg tablets together for each dose. If so, you must be able to identify the tablets. Taking the wrong tablets could cause an overdose (too much medicine) or underdose (too little medicine). The 150 mg tablets are light peach in color with 150 on one side. The 500 mg tablets are peach in color with 500 on one side. Your doctor may change the amount of medicine you take during your treatment. Your doctor may prescribe XELODA (capecitabine) Tablets with docetaxel (TAXOTERE) injection.

  • XELODA (capecitabine) is taken in 2 daily doses, a morning dose and an evening dose
  • Take XELODA (capecitabine) tablets within 30 minutes after the end of a meal (breakfast and dinner)
  • Swallow XELODA (capecitabine) tablets whole with water
  • If you miss a dose of XELODA (capecitabine) , do not take the missed dose at all and do not double the next dose. Instead, continue your regular dosing schedule and check with your doctor.
  • XELODA (capecitabine) is usually taken for 14 days followed by a 7-day rest period (no drug), for a 21-day cycle. Your doctor will tell you how many cycles of treatment you will need.
  • If you take too much XELODA (capecitabine) , contact your doctor or local poison control center or emergency room right away.

What should I avoid while taking XELODA (capecitabine) ?

  • Women should not become pregnant while taking XELODA (capecitabine) . XELODA (capecitabine) may harm your unborn child. Use effective birth control while taking XELODA (capecitabine) . Tell your doctor if you become pregnant.
  • Do not breast-feed. XELODA (capecitabine) may pass through your milk and harm your baby.
  • Men should use birth control while taking XELODA (capecitabine)

What are the most common side effects of XELODA (capecitabine) ?

The most common side effects of XELODA (capecitabine) are:

  • diarrhea, nausea, vomiting, sores in the mouth and throat (stomatitis), stomach area pain (abdominal pain), upset stomach, constipation, loss of appetite, and too much water loss from the body (dehydration). These side effects are more common in patients age 80 and older.
  • hand-and-foot syndrome (palms of the hands or soles of the feet tingle, become numb, painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, and hair loss
  • tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, and muscle pain), trouble sleeping, and taste problems

These side effects may differ when taking XELODA (capecitabine) with docetaxel (TAXOTERE). Please consult your doctor for possible side effects that may be caused by taking XELODA (capecitabine) with docetaxel (TAXOTERE).

If you are concerned about these or any other side effects while taking XELODA (capecitabine) , talk to your doctor.

Stop taking XELODA (capecitabine) immediately and contact your doctor right away if you have the side effects listed below, or other side effects that concern you. Your doctor can then adjust XELODA (capecitabine) to a dose that is right for you or stop your XELODA (capecitabine) treatment for a while. This should help to reduce the side effects and stop them from getting worse.

  • Diarrhea: if you have an additional 4 bowel movements each day beyond what is normal or any diarrhea at night
  • Vomiting: if you vomit more than once in a 24-hour time period
  • Nausea: if you lose your appetite, and the amount of food you eat each day is much less than usual
  • Stomatitis: if you have pain, redness, swelling or sores in your mouth
  • Hand-and-Foot Syndrome: if you have pain, swelling or redness of your hands or feet that prevents normal activity
  • Fever or Infection: if you have a temperature of 100.5°F or greater, or other signs of infection

Your doctor may tell you to lower the dose or to stop XELODA (capecitabine) treatment for a while. If caught early, most of these side effects usually improve after you stop taking XELODA (capecitabine) . If they do not improve within 2 to 3 days, call your doctor again. After your side effects have improved, your doctor will tell you whether to start taking XELODA (capecitabine) again and what dose to take. Adjusting the dose of XELODA (capecitabine) to be right for each patient is an important part of treatment.

How should I store and use XELODA (capecitabine) ?

  • Never share XELODA (capecitabine) with anyone
  • Store XELODA (capecitabine) at normal room temperature (about 65° to 85°F)
  • Keep XELODA (capecitabine) and all other medicines out of the reach of children
  • If you take too much XELODA (capecitabine) by mistake, contact your doctor or local poison control center or emergency room right away

General advice about prescription medicines:

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use XELODA (capecitabine) for a condition for which it was not prescribed. Do not give XELODA (capecitabine) to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about XELODA (capecitabine) . If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about XELODA (capecitabine) that is written for health professionals.

Last reviewed on RxList: 4/6/2011
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Xeloda Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

CAPECITABINE - ORAL

(cap-eh-SIT-uh-bean)

COMMON BRAND NAME(S): Xeloda

WARNING: Capecitabine may interact with "blood thinners" (anticoagulants such as warfarin or phenprocoumon) and cause serious, rarely fatal bleeding. In some cases, this bleeding has occurred up to one month after stopping capecitabine as well as during treatment.

If you are using an anticoagulant, your laboratory tests (INR/PT) will be closely monitored. Report any signs of bleeding or bruising (such as black stools) to your doctor immediately.

USES: Capecitabine is used alone or with other treatments/medications to treat certain types of cancer (e.g., of the breast, colon, rectum). It works by slowing or stopping cancer cell growth and by decreasing tumor size.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start taking capecitabine and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.

Take this medication by mouth, usually twice daily in the morning and evening or as directed by your doctor. It is best to take this with a full glass of water (8 ounces or 240 milliliters) within 30 minutes after the end of a meal. Capecitabine is usually taken every day for 2 weeks, then stopped for 1 week. This course of treatment may be repeated as directed by your doctor.

If you take any antacid products that contain aluminum or magnesium, take capecitabine 2 hours before or after taking any antacids because these products may change the way your body absorbs capecitabine.

The dosage is based on your medical condition, body size, and response to therapy. You may be taking a combination of different tablet sizes. Pay close attention to your dose and tablet sizes to avoid over- or under-dosing.

Do not increase your dose or take this medication more often than directed without your doctor's approval. Your condition will not improve any faster, and the risk of serious side effects may increase.

Since this drug can be absorbed through the skin, women who are pregnant or who may become pregnant should not handle this medication.

Disclaimer

Xeloda Consumer (continued)

SIDE EFFECTS: Nausea, vomiting, loss of appetite, constipation, tiredness, weakness, back/joint/muscle pain, headache, dizziness, trouble sleeping, skin darkening, or dry/itchy skin may occur. Nausea and vomiting can be severe. Changes in diet and lifestyle, such as eating several small meals or limiting activity, may lessen some of these effects. If any of these effects continue or worsen, notify your doctor.

Temporary hair loss may occur. Normal hair growth should return after treatment has ended. Temporary nail changes may occur, which may rarely include fungal infections in the nail beds.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Diarrhea is a common side effect of this medication. It may become very severe (possibly fatal). To decrease this side effect, your doctor may prescribe medication (e.g., loperamide) to control your symptoms, replace lost fluids by vein, or stop treatment with capecitabine. Drink plenty of fluids to prevent serious problems due to a loss of too much body water (dehydration). If you experience signs of severe diarrhea (e.g., 4 or more stools per day, diarrhea at night, bloody stools), or if you experience signs of dehydration (e.g., dizziness, decreased amount of urine), stop taking this drug and tell your doctor immediately.

Stop taking capecitabine and tell your doctor immediately if you have any of these serious side effects: severe nausea/vomiting (vomiting 2 or more times per day, inability to eat or keep food/fluids in your stomach), painful redness/swelling/sores in mouth or throat.

If any of the above symptoms occur, your doctor may lower your dose when you start taking capecitabine again or may stop treatment with this drug.

Treatment with capecitabine may sometimes cause your hands/feet to develop a skin reaction called hand-foot syndrome (palmar-plantar erythrodysesthesia). You can prevent or reduce these problems by protecting your hands and feet from a great deal of heat or pressure. Avoid unnecessary exposure to heat (e.g., hot dishwater, long hot baths). Avoid pressure on elbows, knees, and soles of feet (e.g., leaning on elbows, kneeling, long walks). Wear loose clothing. Depending on how severe your hand-foot syndrome is, your doctor may prescribe a medication to reduce the symptoms or decrease/delay your next dose of capecitabine. If you experience pain/swelling/redness, blisters, or numbness of the hands/feet that affects your usual activities, stop taking this medication and tell your doctor immediately.

This medication can lower your ability to fight an infection. Stop taking this medication and call your doctor promptly if you develop any signs of an infection such as high fever, chills, or persistent sore throat.

Tell your doctor immediately if you have any of these unlikely but serious side effects: abdominal/stomach pain, unusual bruising or bleeding, extreme tiredness, mental/mood changes (e.g., depression), swelling of the ankles/feet, vision changes, shortness of breath, change in the amount of urine, dark urine, yellowing of the eyes/skin, fast/irregular heartbeat.

Seek immediate medical attention if any of these rare but very serious side effects occur: chest pain, fainting, jaw/left arm pain.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other side effects not listed above, contact your doctor or pharmacist.

In the US -

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

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Xeloda (capecitabine) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking capecitabine, tell your doctor or pharmacist if you are allergic to it; or to 5-fluorouracil; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe kidney disease, a certain enzyme deficiency (dihydropyrimidine dehydrogenase deficiency).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood disorders (e.g., bone marrow suppression), heart problems (e.g., coronary artery disease, heart failure), kidney problems, liver problems.

Wash your hands well to prevent the spread of infections.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use an effective sunscreen and wear protective clothing when outdoors. This will also help protect you from problems related to heat (hand/foot syndrome). See Side Effects section for more information.

To lower the chance of getting cut, bruised or injured, use caution with sharp objects like safety razors and nail cutters, and avoid activities such as contact sports. Use a soft-bristle toothbrush to lower the risk of bleeding gums.

Caution is advised when this drug is used in the elderly because they may be more sensitive to the side effects of this medication, especially nausea, vomiting, and diarrhea.

This drug is not recommended for use during pregnancy. It may harm an unborn baby. Consult your doctor for more details and to discuss reliable forms of birth control. It is recommended that men and women use two effective forms of birth control (e.g., condoms and birth control pills) while taking this medication.

It is not known if this drug passes into breast milk. Because of possible harm to the nursing infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

Disclaimer

Xeloda Consumer (continued)

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially: folic acid (including multivitamins with folic acid), leucovorin, metronidazole, tinidazole.

This drug can change the removal of other drugs from your body by affecting certain liver enzymes. These affected drugs include: "blood thinners" (e.g., warfarin), fosphenytoin, phenytoin.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting capecitabine.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., bilirubin levels, complete blood counts, kidney and liver function tests) should be performed regularly to monitor your progress and check for side effects.

MISSED DOSE: If you miss a dose, do not take the missed dose and do not double the next dose. Continue your regular dosing schedule and check with your doctor.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) in a tightly closed container away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised May 2010. Copyright(c) 2010 First Databank, Inc.

Xeloda Patient Information Including Side Effects

Brand Names: Xeloda

Generic Name: capecitabine (Pronunciation: KAP e SYE ta been)

What is capecitabine (Xeloda)?

Capecitabine is a cancer medication that interferes with the growth of cancer cells and slows their spread in the body

Capecitabine is used to treat breast cancer and colon or rectum cancer that has spread to other parts of the body.

Capecitabine may also be used for other purposes not listed in this medication guide.

Xeloda 150 mg

oval, pink, imprinted with XELODA, 150

Xeloda 500 mg

oval, pink, imprinted with XELODA, 500

What are the possible side effects of capecitabine (Xeloda)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • severe diarrhea (more than 4 times per day, or during the night);
  • vomiting (more than once in 24 hours);
  • nausea, loss of appetite, eating much less than usual;
  • weakness, feeling light-headed, hot or dry skin;
  • pain, tenderness, redness, swelling, blistering, or peeling skin on your hands or feet;
  • fever, chills, body aches, flu symptoms;
  • swelling, white patches, or sores in your mouth or throat;
  • jaundice (yellowing of the skin or eyes);
  • chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;
  • sudden numbness, weakness, headache, confusion, or problems with vision, speech, or balance; or
  • slow heart rate, weak pulse, fainting, slow breathing (breathing may stop).

Less serious side effects may include:

  • stomach pain or upset, constipation;
  • tired feeling;
  • temporary hair loss;
  • mild skin rash;
  • headache, dizziness;
  • altered sense of taste;
  • back pain, joint or muscle pain;
  • eye irritation.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Xeloda (capecitabine) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about capecitabine (Xeloda)?

You should not take this medication if you are allergic to capecitabine or fluorouracil (Adrucil), or if you have severe kidney disease or a metabolic disorder called DPD (dihydropyrimidine dehydrogenase) deficiency.

Before you take capecitabine, tell your doctor if you have liver or kidney disease, a history of coronary artery disease, or if you are also taking folic acid (contained in many vitamin and mineral supplements), leucovorin (Wellcovorin), phenytoin (Dilantin), or a blood thinner (warfarin, Coumadin).

While taking capecitabine, you will need blood tests at your doctor's office on a regular basis. Do not miss any appointments. You must remain under the care of a doctor while you are taking capecitabine.

Call your doctor at once if you have a serious side effect such as severe vomiting or diarrhea, fever or flu symptoms, pain or redness of your hands or feet, jaundice (yellowing of the skin or eyes), chest pain, sudden numbness or weakness, or fainting.

Side Effects Centers

Xeloda Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking capecitabine (Xeloda)?

You should not take this medication if you are allergic to capecitabine or fluorouracil (Adrucil), or if you have:

  • severe kidney disease; or
  • a metabolic disorder called DPD (dihydropyrimidine dehydrogenase) deficiency.

If you have any of these other conditions, you may need a dose adjustment or special tests to safely use capecitabine:

  • kidney disease;
  • liver disease;
  • a history of coronary artery disease; or
  • if you are also taking folic acid (contained in many vitamin and mineral supplements), leucovorin (Wellcovorin), phenytoin (Dilantin), or a blood thinner (warfarin, Coumadin).

FDA pregnancy category D. Do not use capecitabine if you are pregnant. It could harm the unborn baby.

Use birth control to prevent pregnancy while you are taking capecitabine, whether you are a man or a woman. Tell your doctor if a pregnancy occurs during treatment.

It is not known whether capecitabine passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are taking capecitabine.

People over 80 years old may be more likely to have certain side effects from this medication.

How should I take capecitabine (Xeloda)?

Take this medication exactly as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Capecitabine is usually given in a treatment cycle of 2 weeks on and 1 week off. This 3-week cycle is repeated up to 8 times (24 weeks). Your capecitabine dosage may be different. Follow your doctor's instructions.

During the weeks when you take capecitabine, take the medication once in the morning and once in the evening, unless your doctor tells you otherwise. You may also be given other medications as part of a combination cancer treatment.

Capecitabine should be taken with food or within 30 minutes after eating a meal.

Take this medication with a full glass (8 ounces) of water.

To be sure this medication is not causing harmful effects, your blood may need to be tested on a regular basis. Your kidney and liver function may also need to be tested. Do not miss any follow-up visits. You must remain under the care of a doctor while you are taking capecitabine.

Store capecitabine at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

Side Effects Centers

Xeloda Patient Information including If I Miss a Dose

What happens if I miss a dose (Xeloda)?

Take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Xeloda)?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include fever, nausea, vomiting, diarrhea, blood in your stools, coughing up blood.

What should I avoid while taking capecitabine (Xeloda)?

Avoid using antacids without your doctor's advice. Use only the specific type of antacid your doctor recommends.

What other drugs will affect capecitabine (Xeloda)?

Tell your doctor about all other medications you use, especially:

  • bosentan (Tracleer);
  • fluoxetine (Prozac);
  • fosphenytoin (Cerebyx);
  • montelukast (Singulair) or zafirlukast (Accolate);
  • rifampin (Rifater, Rifadin, Rifamate);
  • selegiline (Eldepryl, Emsam, Zelapar);
  • voriconazole (Vfend);
  • cancer medication such as paclitaxel (Taxol) or tamoxifen (Soltamox);
  • heart or blood pressure medications such as amiodarone (Cordarone, Pacerone), carvedilol (Coreg), losartan (Hyzaar, Cozaar), or torsemide (Demadex);
  • type 2 diabetes medications such as glimepiride (Amaryl), glipizide (Glucotrol), nateglinide (Starlix), pioglitazone (Actos, Actoplus Met), repaglinide (Prandin), rosiglitazone (Avandia, Avandamet), or tolbutamide (Orinase); or
  • sulfa drugs (Bactrim, Gantanol, Gantrisin, Septra, SMX-TMP, and others).

This list is not complete and there may be other drugs that can interact with capecitabine. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about capecitabine.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 2.08. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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Side Effects Centers

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