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6. Use in the Elderly
PARIET is metabolized mainly in the liver. Since the physiological functions of the liver are often reduced in the elderly, they are more likely to experience adverse reactions. Therefore, if adverse reactions such as gastrointestinal symptoms (see "Adverse Reactions" section) occur, it is advisable to take measures such as instituting a drug-free interval with careful supervision.
7. Use during Pregnancy, Delivery or Lactation
(1) PARIET should only be used in pregnant women or women suspected of being pregnant if the expected therapeutic benefits outweigh the possible risks associated with treatment.
[Fetotoxicity (delayed ossification in rats, weight loss and delayed ossification in rabbits) has been reported with
PARIET
in animal studies (400 mg/kg p.o. in rats, 30 mg/kg i.v. in rabbits).]
(2) It is advisable to avoid administration to nursing mothers. When
PARIET
must be used, breast feeding should be discontinued during treatment.
[In an animal study (in rats), it has been reported that PARIET is excreted in breast milk.]
8. Pediatric Use
The safety of PARIET in children has not been established (no clinical experience).
9. Precautions concerning Use
(1) Administration
Since PARIET is an enteric coated tablet, patients should be instructed not to chew or crush the tablet, but swallow it whole.
(2) Caution in handing over drug
For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove, the drug from the package prior to use. [It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, causing perforation and
resulting in serious complications such as mediastinitis.]
10. Other Precautions
(I) It has been reported that in a carcinogenicity study in which 5mg/kg/day or greater of sodium rabeprazole was administered orally to rats for 2 years, carcinoids were observed in the stomachs of female rats.
(2) Increases in thyroid weight and blood thyroxine
levels have been reported in animal studies (rats, oral administration of
25mg/kg/day or greater). Therefore, thyroid function should be carefully
monitored during the administration of PARIET
[PHARMACOKINETICS]
1. Blood concentrations
The changes over time in the mean plasma sodium rabeprazole concentration when administered orally to healthy adult male volunteers at a dose of 20 mg during fasting or after a meal are shown in the figure below. Mean values of pharmacokinetic parameters determined for individual subjects during fasting and postprandial administration of
PARIET are presented in the table below. Tmax was prolonged by 1.7 hr after postprandial administration compared to administration during fasting, and inter-individual variations in absorption were observed.
Plasma sodium
rabeprazole concentration after oral administration of
PARIET
20 mg
during fasting or after a meal
Effect of food on pharmacokinetic parameters
| Dose |
Cmax (ng/mL) |
tmax (hr) |
AUC (ng hr/mL) |
t½ (hr) |
| Fasting |
437 ± 237 |
3.6 ± 0.9 |
937 ± 617 |
1.49 ± 0.68 |
| Postprandial |
453 ± 138 |
5.3 ± 1.4 |
901 ± 544 |
1.07 ± 0.47 |
(Mean ± S.D., n=12
)
The following table shows the mean values of pharmacokinetic parameters when sodium rabeprazole was administered orally to
healthy adult male volunteers at doses of 10 mg and 20 mg during
fasting.
Pharmacokinetic parameters after single oral
administration of PARIET to healthy adult male volunteers
| Dose |
Cmax (ng/mL) |
tmax (hr) |
AUC (ng hr/mL) |
t½ (hr) |
| 10 mg |
247 ± 24 |
3.8 ± 0.5 |
440 ± 24 |
0.85 ± 0.04 |
| 20 mg |
406 ± 64 |
3.1 ± 0.2 |
809 ± 186 |
1.02 ± 0.16 |
(Mean ± S.E., n=6
)
2. Metabolism
When
PARIET was administered orally to healthy adult male volunteers at single doses of 10 mg and--20 --- g, the main metabolite recognized in plasma was its thioether-form product produced by non-enzymatic reduction reaction. Other metabolites were the demethylated products due to demethylation which involving the hepatic enzymatic metabolism of cytochrome P450C19 (CYP2C19), and the sulfone-form products due to sulfonation
involving 3A4 (CYP3A4).
3. Urinary excretion
No unchanged drug was detected in the urine of healthy adult male volunteers up to 24 hr after oral administration of 20 mg of sodium rabeprazole, and about 29-40% of the dose was excreted in the urine as the carboxylic acid form and its glucuronide, and about 13-19% of the dose was present as the mercapturate conjugated-form.
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