Xeloda

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Xeloda is a prescription medication used to treat breast cancer and cancer of the colon or rectum. Xeloda belongs to a group of drugs called antimetabolites which work by interfering with DNA production, stopping cells from multiplying.

This medication comes in tablet form and is usually taken twice daily, within 30 minutes after the end of a meal.

Swallow Xeloda tablets whole. Do not cut or crush tablets.

Common side effects include diarrhea, nausea, vomiting, and mouth sores.

Xeloda is part of the drug class:

• Pyrimidine analogues

Tell your doctor if you are pregnant or think you may be pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. Xeloda may harm your unborn child. Use effective birth control while taking Xeloda.

Take Xeloda exactly as prescribed by your doctor. Follow the directions on your prescription label carefully. Your doctor will determine the best dose for you.

Standard Starting Dose

• The recommended dose of Xeloda is 1250 mg/m² given by mouth twice daily for 2 weeks. This is followed by by a 1-week rest period.
• In those with Dukes' C colon cancer is recommended for a total of 6 months.

In Combination With Docetaxel (Metastatic Breast Cancer)

• The recommended dose of Xeloda is 1250 mg/m2 twice daily for 2 weeks. This is followed by a 1-week rest period.
• You will be carefully monitored for toxicity.
• Doses of Xeloda should be adjusted as necessary to accommodate tolerance to treatment.

Potential inhibition of CYP2C9.1

Does not inhibit CYP isoenzymes 1A2, 2A6, 3A4, 2C9, 2C19, 2D6, or 2E1 in vitro.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased warfarin metabolism) probably through inhibition of CYP2C9.1 35 (See Specific Drugs under Interactions.)

No formal drug interaction studies between capecitabine and CYP2C9 substrates other than warfarin have been performed.1 35

Specific Drugs

• Importance of informing clinician of any known deficiency in DPD activity.48

• Importance of discontinuing the drug and contacting clinician if stool output increases by 4–6 stools or more daily or if nocturnal stools or severe bloody diarrhea with severe abdominal pain and fever occurs.48

• Importance of discontinuing the drug and contacting clinician if grade 2 or greater dehydration occurs.48

• Importance of discontinuing the drug and contacting clinician if 2–5 or more episodes of vomiting occur in a 24-hour period.48

• Importance of discontinuing the drug and contacting clinician if nausea resulting in a substantial decrease in food intake occurs.48

• Importance of discontinuing the drug and contacting clinician if pain, redness, swelling, or sores in mouth occur.1

• Importance of discontinuing the drug and contacting clinician if pain and swelling or redness of hands or feet that prevents normal activity occur.1

• Importance of notifying clinician if fever (≥100.5°F) or other signs of infection occur.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and to advise pregnant women of risk to the fetus.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Medicines used to treat cancer are very strong and can have many side effects. Before using this medicine, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment.

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

This medicine should come with a patient information leaflet. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Take this medicine with food or within 30 minutes after you eat.

Swallow the tablet whole with water. Do not cut, crush, break, or chew it. If the tablet must be cut or crushed, it should be done by a pharmacist.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For metastatic breast and colorectal cancer:
    • For patients receiving this medicine alone:
      • Adults—Dose is based on body size and must be determined by your doctor. At first, 2500 milligrams (mg) per square meter (m(2)) of body size per day, divided in 2 doses and taken about 12 hours apart. These doses are taken for 2 weeks, followed by 1 week rest, given as 3 weeks cycle. Your doctor may adjust your dose if needed.
      • Children—Use and dose must be determined by your doctor.
    • For patients receiving this medicine with docetaxel:
      • Adults—Dose is based on body surface and must be determined by your doctor. At first, 2500 milligrams (mg) per square meter (m(2)) of body surface area per day, divided in 2 doses and taken about 12 hours apart. These are taken for 2 weeks, followed by 1 week rest, given as 3 weeks cycle Your doctor may adjust your dose if needed.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• If you have an allergy to capecitabine, fluorouracil (5-FU), or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have a dihydropyrimidine dehydrogenase (DPD) deficiency or kidney disease.
• If you are breast-feeding. Do not breast-feed while you take Xeloda and for 2 weeks after your last dose.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Xeloda with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or very bad upset stomach or throwing up.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Chest pain or pressure.
• A heartbeat that does not feel normal.
• Numbness or tingling in the hands or feet.
• Mouth irritation or mouth sores.
• Very bad belly pain.
• Change in eyesight, eye pain, or very bad eye irritation.
• Redness or irritation of the palms of hands or soles of feet.
• Swollen gland.
• Mood changes.
• Swelling, warmth, numbness, change of color, or pain in a leg or arm.

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

Pregnancy

Risk Summary

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

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

Data

Animal Data

Oral administration of capecitabine to pregnant mice during the period of organogenesis at a dose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values that were approximately 0.2 times the AUC values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. Oral administration of capecitabine to pregnant monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality. This dose produced 5'-DFUR AUC values that were approximately 0.6 times the AUC values in patients administered the recommended daily dose.

Lactation

Risk Summary

There is no information regarding the presence of capecitabine in human milk, or on its effects on milk production or the breast-fed infant. Capecitabine metabolites were present in the milk of lactating mice [see Data]. Because of the potential for serious adverse reactions from capecitabine exposure in breast-fed infants, advise women not to breastfeed during treatment with Xeloda and for 2 weeks after the final dose.

Data

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

Females and Males of Reproductive Potential

Pregnancy Testing

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

Contraception

Females

Xeloda can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the final dose of Xeloda.

Males

Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the last dose of Xeloda [see Nonclinical Toxicology (13.1)].

Infertility

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

Pediatric Use

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

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

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

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

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

Geriatric Use

Physicians should pay particular attention to monitoring the adverse effects of Xeloda in the elderly [see Warnings and Precautions (5.11)].

Hepatic Insufficiency

Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with Xeloda. The effect of severe hepatic dysfunction on Xeloda is not known [see Warnings and Precautions (5.12) and Clinical Pharmacology (12.3)].

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-DFUR, and FBAL than in those with normal renal function [see Contraindications (4.2), Warnings and Precautions (5.5), Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].

You should not take Xeloda if you have severe kidney disease or a metabolic disorder called DPD (dihydropyrimidine dehydrogenase) deficiency.

If you take a blood thinner (warfarin, Coumadin, Jantoven), you may need to have more frequent "INR" or prothrombin time tests. Taking a blood thinner can increase your risk of severe bleeding while you are using Xeloda, and for a short time after you stop taking this medicine. This risk is higher in adults older than 60.

If you take a blood thinner (warfarin, Coumadin, Jantoven), you may need to have more frequent "INR" or prothrombin time tests. Taking a blood thinner can increase your risk of severe bleeding while you are using Xeloda, and for a short time after you stop taking this medicine. This risk is higher in adults older than 60.

Other drugs may interact with capecitabine, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.