Interactions : אינטראקציות

4.5. Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
Interaction with other medicinal products
Brivudine
A clinically significant interaction between brivudine and fluoropyrimidines (e.g. capecitabine, 5-Fluorouracil, tegafur), resulting from the inhibition of dihydropyrimidine dehydrogenase by brivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, brivudine must not be administered concomitantly with capecitabine (see section 4.3 and 4.4). There must be at least a 4-week waiting period between end of treatment with brivudine and start of capecitabine therapy. Treatment with brivudine can be started 24 hours after the last dose of capecitabine.
Cytochrome P-450 2C9 substrates
Other than warfarin, no formal interaction studies between capecitabine and other CYP2C9 substrates have been conducted. Care should be exercised when capecitabine is co-administered with 2C9 substrates (e.g., phenytoin). See also interaction with coumarin-derivative anticoagulants below, and section 4.4.
Coumarin-derivative anticoagulants
Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These reactions occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within one month after stopping capecitabine. In a clinical pharmacokinetic interaction study, after a single 20 mg dose of warfarin, capecitabine treatment increased the AUC of S-warfarin by 57% with a 91% increase in INR value. Since metabolism of R-warfarin was not affected, these results indicate that capecitabine down-regulates isozyme 2C9, but has no effect on isozymes 1A2 and 3A4.
Patients taking coumarin-derivative anticoagulants concomitantly with capecitabine should be monitored regularly for alterations in their coagulation parameters (PT or INR) and the anticoagulant dose adjusted accordingly.
Phenytoin
Increased phenytoin plasma concentrations resulting in symptoms of phenytoin intoxication in single cases have been reported during concomitant use of capecitabine with phenytoin. Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations.
Folinic acid/ folic acid
A combination study with capecitabine and folinic acid indicated that folinic acid has no major effect on the pharmacokinetics of capecitabine and its metabolites. However, folinic acid has an effect on the pharmacodynamics of capecitabine and its toxicity may be enhanced by folinic acid: the maximum tolerated dose (MTD) of capecitabine alone using the intermittent regimen is 3000 mg/m2 per day whereas it is only 2000 mg/m2 per day when capecitabine was combined with folinic acid (30 mg orally bid). The enhanced toxicity may be relevant when switching from 5-FU/LV to a capecitabine regimen.
This may also be relevant with folic acid supplementation for folate deficiency due to the similarity between folinic acid and folic acid.

     Antacid
The effect of an aluminium hydroxide and magnesium hydroxide-containing antacid on the pharmacokinetics of capecitabine was investigated. There was a small increase in plasma concentrations of capecitabine and one metabolite (5’-DFCR); there was no effect on the 3 major metabolites (5’-DFUR, 5-FU and FBAL).
Allopurinol
Interactions with allopurinol have been observed for 5-FU; with possible decreased efficacy of 5- FU.
Concomitant use of allopurinol with capecitabine should be avoided.
Interferon alpha
The MTD of capecitabine was 2000 mg/m2 per day when combined with interferon alpha-2a (3 MIU/m2 per day) compared to 3000 mg/m2 per day when capecitabine was used alone.
Radiotherapy
The MTD of capecitabine alone using the intermittent regimen is 3000 mg/m2 per day, whereas, when combined with radiotherapy for rectal cancer, the MTD of capecitabine is 2000 mg/m2 per day using either a continuous schedule or given daily Monday through Friday during a 6-week course of radiotherapy.
Oxaliplatin
No clinically significant differences in exposure to capecitabine or its metabolites, free platinum or total platinum occurred when capecitabine was administered in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab.
Bevacizumab
There was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites in the presence of oxaliplatin.
Food interaction
In all clinical trials, patients were instructed to administer capecitabine within 30 minutes after a meal.
Since current safety and efficacy data are based upon administration with food, it is recommended that Capecitabine Teva be administered with food. Administration with food decreases the rate of capecitabine absorption (see section 5.2).