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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
XELODA (NDA-020896)
(CAPECITABINE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/14/2022 (SUPPL-44)
12/14/2022 (SUPPL-45)
12/14/2022 (SUPPL-46)
12/14/2022 (SUPPL-47)
12/14/2022 (SUPPL-48)
12/14/2022 (SUPPL-49)
12/14/2022 (SUPPL-50)
12/14/2022 (SUPPL-51)
05/19/2021 (SUPPL-43)
6 Adverse Reactions
6.5 Postmarketing ExperienceAdditions underlined
The following adverse reactions have been observed in the postmarketing setting: angioedema, hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [see Warnings and Precautions (5.5)], cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens- Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [see Warnings and Precautions (5.7)], persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints [see Warnings and Precautions (5.7)]
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions underlined
…
Hypersensitivity and Angioedema
Advise patients that XELODA may cause severe hypersensitivity reactions and angioedema. Advise patients who have known hypersensitivity to capecitabine or 5-fluorouracil to inform their healthcare provider [see Contraindications (4)]. Instruct patients who develop hypersensitivity reactions or mucocutaneous symptoms (e.g., urticaria, rash, erythema, pruritus, or swelling of the face, lips, tongue or throat which make it difficult to swallow or breathe) to stop taking XELODA and immediately contact their healthcare provider or to go to an emergency room. [see Adverse Reactions (6)].
…
Additions underlined
…
What is XELODA?
XELODA is a prescription medicine used to treat people with:
cancer of the colon that has spread to lymph nodes in the area close to the colon (Dukes’ C stage), after they have surgery.
cancer of the colon or rectum (colorectal) that has spread to other parts of the body (metastatic), as your first treatment of your cancer at this stage.
…
What are the possible side effects of XELODA?
XELODA can cause serious side effects including:
…
Diarrhea. Diarrhea is common with XELODA and can sometimes be severe. Stop taking XELODA and call your healthcare provider right away if the number of bowel movements you have in a day increases by 4 or more bowel movements than is usual for you or bowel movements at night. Ask your healthcare provider about what medicines you can take to treat your diarrhea. If you have severe bloody diarrhea with severe abdominal pain and fever, stop taking Xeloda and call your healthcare provider or go to the nearest hospital emergency room right away.
Heart problems. XELODA can cause heart problems including: heart attack and decreased blood flow to the heart, chest pain, irregular heartbeats, changes in the electrical activity of your heart seen on an electrocardiogram (ECG), problems with your heart muscle, heart failure, and sudden death. Stop taking XELODA and call your healthcare provider or go to the nearest hospital emergency room right away if you get any new symptoms of a heart problem including:
chest pain o dizziness
shortness of breath o lightheadedness
…
Increased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with XELODA and can also sometimes be severe. Your healthcare provider will check you for these problems during treatment with XELODA.
…
Severe allergic reactions can happen with XELODA. Tell your healthcare provider if you have ever had an allergic reaction to capecitabine or 5-fluorouracil. See “Do not take XELODA if you:”. Stop taking XELODA and call your healthcare provider right away or go to an emergency room if you have any of the following symptoms of a severe allergic reaction:
red itchy welts on your skin (hives)
skin redness
swelling of your face, lips, tongue or throat
rash
itching
trouble swallowing or breathing
02/22/2019 (SUPPL-42)
6 Adverse Reactions
6.4 Clinically Relevant Adverse Events in < 5% of Patients
6.5 Postmarketing Experience
In both of these sections there have been extensive revisions made to column-like sections; please refer to label for complete information.
Additions and/or revisions underlined:
The following adverse reactions have been observed in the postmarketing setting: hepatic failure, lacrimal duct stenosis …persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints.
In instances of exposure to crushed XELODA tablets, the following adverse reactions have been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting, and nausea.
7 Drug Interactions
7.1 Drug-Drug InteractionsNewly added information:
Allopurinol
Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites [see Clinical Pharmacology (12.3)], which may decrease XELODA efficacy. Avoid the use of allopurinol during treatment with XELODA.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or revisions underlined:
Diarrhea
Inform patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever to stop taking XELODA. Advise patients on the use of antidiarrheal treatments (e.g., loperamide) to manage diarrhea [see Warnings and Precautions (5.2)].
Cardiotoxicity
Advise patients of the risk of cardiotoxicity and to immediately contact their healthcare provider or to go to an emergency room for new onset of chest pain, shortness of breath, dizziness, or lightheadedness [see Warnings and Precautions (5.3)].
Dehydration and Renal Failure
Instruct patients experiencing grade 2 or higher dehydration (IV fluids indicated < 24 hours) to stop taking XELODA immediately and to call their healthcare provider to correct the dehydration. Advise patients to not restart XELODA until rehydrated and any precipitating causes have been corrected or controlled [see Warnings and Precautions (5.5)].
Important Administration Instructions
Advise patients to swallow XELODA tablets whole with water within 30 minutes of a meal. Advise patients and caregivers not to crush or cut XELODA tablets. Advise patients if they cannot swallow XELODA tablets whole, to inform their healthcare provider [see Dosage and Administration (2.1)].
Nausea
Instruct patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater to stop taking XELODA immediately and to contact their healthcare provider for management of nausea [see Adverse Reactions (6.1)].
Vomiting
Instruct patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater to stop taking XELODA immediately and to contact their healthcare provider for management of vomiting [see Adverse Reactions (6.1)].
Hand-and-Foot Syndrome
Instruct patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients’ activities of daily living) or greater to stop taking XELODA immediately and to contact their healthcare provider. Inform patients that initiation of symptomatic treatment is recommended and hand-and-foot syndrome can lead to loss of fingerprints which could impact personal identification [see Adverse Reactions (6.1)].
Additions and/or revisions underlined:
Before taking XELODA, tell your healthcare provider about all your medical conditions, including if you:
See “What is the most important information I should know about XELODA?”
are pregnant or plan to become pregnant …
Females who are able to become pregnant should use effective birth control during treatment and for 6 months after the final dose. Talk to your healthcare provider about birth control choices that may be right for you during treatment with XELODA.
Males who have female partners who are able to become pregnant should use effective birth control during treatment and for 3 months after the final dose.
Other
Update reflects labeling change from February 2019.
12/14/2016 (SUPPL-39)
5 Warnings and Precautions
5.6 Embryo-Fetal Toxicity(additions underlined)
Based on findings from animal reproduction studies and its mechanism of action, XELODA may cause fetal harm when given to a pregnant woman . Limited available data are not sufficient to inform use of XELODA in pregnant women. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively . Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of XELODA.
(addition underlined)
Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with XELODA . XELODA should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to XELODA treatment.
Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving XELODA monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient’s activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. Persistent or severe hand-and-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints which could impact patient identification. If grade 2 or 3 hand-and-foot syndrome occurs, administration of XELODA should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of XELODA should be decreased.
6 Adverse Reactions
6.4 Clinically Relevant Adverse Events in less than 5% of Patients(addition underlined)
Postmarketing: hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [see Warnings and Precautions (5.5)], cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) , persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints.
8 Use in Specific Populations
8.1 Pregnancy(PLLR conversion)
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 andembryo 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.
(PLLR conversion)
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
mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk.
(PLLR conversion)
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 . 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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(additions underlined)
Hand-and-Foot Syndrome
Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients’ activities of daily living) or greater should be instructed to stop taking XELODA immediately. Initiation of symptomatic treatment is recommended. Hand-and-foot syndrome can lead to loss of fingerprints which could impact your identification..
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with XELODA and for 6 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy .
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with XELODA and for 3 months after the last dose .
Lactation
Advise females not to breastfeed during treatment with XELODA and for 2 weeks after the last dose