Capecitabine - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Cardiotoxicity : May be more common in patients with a prior history of coronary artery disease.

Withhold capecitabine tablets for cardiotoxicity as appropriate.

The safety of resumption of capecitabine tablets in patients with cardiotoxicity that has resolved has not been established. ( 2.5 , 5.3 ) • Diarrhea : Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.4 ) • Dehydration : Optimize hydration before starting capecitabine tablets.

Monitor hydration status and kidney function at baseline and as clinically indicated.

Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.5 ) • Renal Toxicity : Monitor renal function at baseline and as clinically indicated.

Optimize hydration before starting capecitabine tablets.

Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.6 ) • Serious Skin Toxicities : Monitor for new or worsening serious skin reactions.

Permanently discontinue capecitabine tablets in patients who experience a severe cutaneous adverse reaction. • Palmar-Plantar Erythrodysesthesia Syndrome : Withhold capecitabine tablets then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.8 ) • Myelosuppression : Monitor complete blood count at baseline and before each cycle. capecitabine tablets is not recommended in patients with baseline neutrophil counts <1.5 x 10 9 /L or platelet counts <100 x 10 9 /L.

For grade 3 or 4 myelosuppression, withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on occurrence. ( 2.5 , 5.9 ) • Hyperbilirubinemia : Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (<3 x ULN), using the percent of current dose as shown in column 3 of Table 1 ( 2.5 , 5.10 ) ] • Embryo-Fetal Toxicity : Can cause fetal harm.

Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.11 , 8.1 , 8.3 ) 5.1 Serious Adverse Reactions or Death from Dihydropyrimidine Dehydrogenase (DPD) Deficiency Patients with certain homozygous or compound heterozygous variants in the DPYD gene known to result in complete or near complete absence of DPD activity (complete DPD deficiency) are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to capecitabine tablets (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity).

Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious, or fatal, adverse reactions.

Prior to initiating capecitabine tablets, test patients for genetic variants of the DPYD gene unlessimmediate treatment is necessary [see Clinical Pharmacology ].

Serious adverse reactions may still occur even if no DPYD variants are identified.

Avoid use of capecitabine tablets in patients with certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency.

Withhold or permanently discontinue capecitabine tablets based on clinical assessment of the onset, duration, and severity of adverse reactions in patients with evidence of acute early-onset orunusually severe reactions.

No capecitabine tablets dose has been proven safe for patients with complete DPD deficiency.

For patients with partial DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment.

An FDA-authorized test for the detection of genetic variants of the DPYD gene to identifypatients at risk of serious adverse reactions with capecitabine tablets treatment is not currently available.

Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify).

5.2 Increased Risk of Bleeding With Concomitant Use of Vitamin K Antagonists Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine tablets concomitantly with vitamin K antagonists, such as warfarin.

Clinically significant increases in PT and INR have been reported in patients who were on stable doses of oral vitamin K antagonists at the time capecitabine tablets was introduced.

These events occurred within several days and up to several months after initiating capecitabine tablets and, in a few cases, within 1 month after stopping capecitabine tablets.

These events occurred in patients with and without liver metastases.

Monitor INR more frequently and adjust the dose of the vitamin K antagonist as appropriate [see Drug Interactions ].

5.3 Cardiotoxicity Cardiotoxicity can occur with capecitabine tablets.