 |
| Pariet |
DT CaSa an rooc stmuatec ac s&Dretlon i nors arer tne trst case ot
raoeprazole scwim are 69% and 82% respectively and the duration of inhibition lasts up to 48 hours. The inhibitory effect of rabeprazole sodium on acid secretion Increases slightly with repeated once-daily dosing, achieving steady state inhibition after three days. When the drug is discontinued, secretory activity normalises over 2 to 3 days.
Helicobacter pylon is associated with acid peptic disease including duoderial ulcer (DU) and gastric ulcer (GU). H. pylon is implicated as a major contributing factor in the development of gasmtis and ulcers in such patients. Recent evidence also suggests a causative link between H. pylon and gastric carcinoma.
Rabeprazoe has been shown to nave a bactericidal effect on H. pylon in vitro. Eradication of H. pylon with Pariet (rabeprazole) and antimicrobials is associated with high rates of healing of mucosal lesions. Clinical experience from controlled randomised clinical trials indicate that rabeprazole 20 mg twice daily in combination with two antibiotics e.g. clarithromycin and amoxycillin or cartt’romvci and rnetrondazole (given at aoproved dose levels for 1 week achieve >80% H. pylon eradication rate in patients with gastro-cluodenal ulcers. As expected, there was a trend towards significantly lower eradication rates in patients with baseline metronidazole resistant H. pylon iso- lates arid a trend towards the development of secondary resistance. Hence, local information on the prevalence of resistance and local therapeutic guidelines should be taken in account in the choice of an appropriate combination regimen for H. pylon eradication therapy. Further more, in patients with persistent infection, potential development of secondary resistance (in patients with primary susceptible strains) to an antibacterial agent should be taken into account in the considerations for a new re-treatment regimen.
Serum Gaslrin Effects
In clirücal studies patients were treated once daily with 10 or 20 rng rabeprazole sodium, for up to 43 months duration. Serum gastrin levels increased duTing the first 2 to 8 weeks reflecting the rhibitory effects on acid secretion and remained stable while treatment was continued. Gastrin values returned to pre-treatment levels, usually within 1 to 2 weeks after discontinuation of therapy. Human gastric biopsy specimens from the antrum and the fundus from over 500 patients receiving
- - rabeprazole or comparator treatment for up to 8 weeks have not detected changes in ECL cell histology, degree of gastritis, incidence of atrophic gastritis, intestinal metaplasia or distribution of H. pylon infection. In over 250 patients followed for 36 months of continuous therapy, no significant change c fWdrgs present at basene was observed.
OtPef Effects
Systemic effects of rabepcazoe sodium in the CNS, cardiovascular and respiratory systems have not been found to date. Rabepiazole sodium, given in oral doses of 20 mg for 2 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol. oestrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle stimulating hormone (FSH), luteinising hormone (LH), renin, aldosterone or somatotrophic hormone.
Pharmacokinetic properties
Absorption
Pariet is an enteric-coated (gastro-resistant) tablet formulation of rabeprazole sodium. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole therefore begins only after the tablet leaves the stomach. Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hours after a 20 mg dose. Peak plasma concentrations (Cmax) of rabeprazole and AUC are linear over the dose range of 10 mg to 40 mg. Absolute bioavailability of an oral 20 mg dose (compared to intravenous administration) is about 52% due in large part to presystemic metabolism. Additionally the bioavailability does not appear to increase with repeat administration, In healthy subjects the plasma half-life s approximately one hour (range 0.7 to 1.5 hours), and the total body clearance is estimated to be 283 ± 98 mI/mm. Neither food nor the time of day of administration of the treatment affect the absorption of rabeprazole sodium.
Distribution
Rabeprazole is approximately 97% bound to human plasma proteins.
Metabolism and excretion
In humans the thioether (Ml) and carboxylic acid (M6) are the main plasma metabolites with the suiphone (M2), desmethyl-thioether (M4) and mercapturic acid conjugate (M5) minor metabolites observed at lower levels. Only the desmethyl metabolite (M3) has a small amount of anti-secretory activity, but it is not present in plasma.
Following a single 20 mg 14C labelled oral dose of rabeprazole sodium, no unchanged drug was excreted in the urine. Approximately 90% of the dose was eliminated in urine mainly as the two metabolites: a mercapturic acid conjugate (M5) and a arboxylic acid (M6), plus two unknown metabolites. The remainder of the dose was recovered in faeces.
Gender
Adjusted for body mass and height, there are no significant genoer oifferences in pnarmacokinetic parameters following a single 20 mg dose of rabeprazole.
Renal dysfunction
In patients with stable, end-stage, renal failure requiring maintenance haemodialysis (creatinine clearance 5m1/min/1 .73m2), the disposition of rabeprazole was very similar to that in healthy voh.enteers. The AUC and the Cm in these patients was about 35% lower than the corresponding parameters in healthy volunteers, The mean half-life of rabeprazole was 0.82 hours in healthy volunteers, 0.95 hours in patients during haemodialysis and 3.6 hours post dialysis. The clearance of the drug in patients with renal disease requiring maintenance haemodialysis was approximately twice that in healthy volunteers.
Hepatic dysfunction
Following a single 20 mg dose of rabeprazoe to patients with chronic nild to moderate hepatic impairment the AUC doubled aria there was a 2-3 fold increase in half-life of rabeprazole compared to the healthy volunteers. However, following a 20 mg dose daily for 7 days the AUC had increased to only 1.5-fold and the Cmax to only 1.2-fold. The half-life of rabeprazole in patients with hepatic impairment was 12.3 hours compared to 2.1 hours in healthy volunteers. The pharmacodynamic response (gastric pH control) in the two groups was clinically comparable.
Elderly
Elimination of rabeprazole was somewhat decreased in the elderly. Following 7 days of daily dosing with 20 mg of rabeprazole sodium, the AUC approximately doubled, the C increased by 60% and t, increased by approximately 30% as compared to young healthy volunteers. However there was no evidence of rabeprazole-accumulation.
CYP2C19 Polyrnoiphsm
Fo&wng a 20 mg daily dose of rabeprazole for 7 days, CYP2C19 slow metabolisers. had AUG 3IC t which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabusers whilst C1 had increased by only 40%.
Preclinical safety data -
Pre-clinical effects were observed only at exposures sufficiently in excess of the maximum human exposure iia! make concerns for human safety negIgible in respect of animal data.
Studies on mutagenicity gave equivocal results. Tests in mouse lymphoma cell line were positive, but in vivo micronucleus and in vivo and in vitro DNA repair tests were negative. Carcinogenicity studies revealed no special hazard for humans.
PHARMACEUTICAL PARTICULARS
List of excipients
Mannitol, magnesium oxi&, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose. rnaesium stearate, ethylcellulose, hypromellose phthalate, diacetylated monoglycerides, talc, titaniumn cboxide yeow ion oxide (20 mg only), red iron oxide (10 mg od. carnauba wax and ink.
Special precautions for storage
Do not store above 25C. Do not refngera’te.
After opening, store in the original package (aluminium poucfl) and use within three months. Do not
store above 25CC. Do not refrigerate. —
Keep out of reach of children.
Nature and contents of container
Primary packaging:
Unit dose blister strips (PVC/PVdC/PE-5ply laminate/aluminium foil strip) of 7 0(14 tablets.
Secondary packaging:
Aluminium pouch containing multiples of 7 or 14 tablet unit dose blister strips and a silica gel desiccant pouch.
Alternative packaging Format:
Primary packaging:
Helicobacter pylon is associated with acid peptic disease including duoderial ulcer (DU) and gastric ulcer (GU). H. pylon is implicated as a major contributing factor in the development of gasmtis and ulcers in such patients. Recent evidence also suggests a causative link between H. pylon and gastric carcinoma.
Rabeprazoe has been shown to nave a bactericidal effect on H. pylon in vitro. Eradication of H. pylon with Pariet (rabeprazole) and antimicrobials is associated with high rates of healing of mucosal lesions. Clinical experience from controlled randomised clinical trials indicate that rabeprazole 20 mg twice daily in combination with two antibiotics e.g. clarithromycin and amoxycillin or cartt’romvci and rnetrondazole (given at aoproved dose levels for 1 week achieve >80% H. pylon eradication rate in patients with gastro-cluodenal ulcers. As expected, there was a trend towards significantly lower eradication rates in patients with baseline metronidazole resistant H. pylon iso- lates arid a trend towards the development of secondary resistance. Hence, local information on the prevalence of resistance and local therapeutic guidelines should be taken in account in the choice of an appropriate combination regimen for H. pylon eradication therapy. Further more, in patients with persistent infection, potential development of secondary resistance (in patients with primary susceptible strains) to an antibacterial agent should be taken into account in the considerations for a new re-treatment regimen.
Serum Gaslrin Effects
In clirücal studies patients were treated once daily with 10 or 20 rng rabeprazole sodium, for up to 43 months duration. Serum gastrin levels increased duTing the first 2 to 8 weeks reflecting the rhibitory effects on acid secretion and remained stable while treatment was continued. Gastrin values returned to pre-treatment levels, usually within 1 to 2 weeks after discontinuation of therapy. Human gastric biopsy specimens from the antrum and the fundus from over 500 patients receiving
- - rabeprazole or comparator treatment for up to 8 weeks have not detected changes in ECL cell histology, degree of gastritis, incidence of atrophic gastritis, intestinal metaplasia or distribution of H. pylon infection. In over 250 patients followed for 36 months of continuous therapy, no significant change c fWdrgs present at basene was observed.
OtPef Effects
Systemic effects of rabepcazoe sodium in the CNS, cardiovascular and respiratory systems have not been found to date. Rabepiazole sodium, given in oral doses of 20 mg for 2 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol. oestrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle stimulating hormone (FSH), luteinising hormone (LH), renin, aldosterone or somatotrophic hormone.
Pharmacokinetic properties
Absorption
Pariet is an enteric-coated (gastro-resistant) tablet formulation of rabeprazole sodium. This presentation is necessary because rabeprazole is acid-labile. Absorption of rabeprazole therefore begins only after the tablet leaves the stomach. Absorption is rapid, with peak plasma levels of rabeprazole occurring approximately 3.5 hours after a 20 mg dose. Peak plasma concentrations (Cmax) of rabeprazole and AUC are linear over the dose range of 10 mg to 40 mg. Absolute bioavailability of an oral 20 mg dose (compared to intravenous administration) is about 52% due in large part to presystemic metabolism. Additionally the bioavailability does not appear to increase with repeat administration, In healthy subjects the plasma half-life s approximately one hour (range 0.7 to 1.5 hours), and the total body clearance is estimated to be 283 ± 98 mI/mm. Neither food nor the time of day of administration of the treatment affect the absorption of rabeprazole sodium.
Distribution
Rabeprazole is approximately 97% bound to human plasma proteins.
Metabolism and excretion
In humans the thioether (Ml) and carboxylic acid (M6) are the main plasma metabolites with the suiphone (M2), desmethyl-thioether (M4) and mercapturic acid conjugate (M5) minor metabolites observed at lower levels. Only the desmethyl metabolite (M3) has a small amount of anti-secretory activity, but it is not present in plasma.
Following a single 20 mg 14C labelled oral dose of rabeprazole sodium, no unchanged drug was excreted in the urine. Approximately 90% of the dose was eliminated in urine mainly as the two metabolites: a mercapturic acid conjugate (M5) and a arboxylic acid (M6), plus two unknown metabolites. The remainder of the dose was recovered in faeces.
Gender
Adjusted for body mass and height, there are no significant genoer oifferences in pnarmacokinetic parameters following a single 20 mg dose of rabeprazole.
Renal dysfunction
In patients with stable, end-stage, renal failure requiring maintenance haemodialysis (creatinine clearance 5m1/min/1 .73m2), the disposition of rabeprazole was very similar to that in healthy voh.enteers. The AUC and the Cm in these patients was about 35% lower than the corresponding parameters in healthy volunteers, The mean half-life of rabeprazole was 0.82 hours in healthy volunteers, 0.95 hours in patients during haemodialysis and 3.6 hours post dialysis. The clearance of the drug in patients with renal disease requiring maintenance haemodialysis was approximately twice that in healthy volunteers.
Hepatic dysfunction
Following a single 20 mg dose of rabeprazoe to patients with chronic nild to moderate hepatic impairment the AUC doubled aria there was a 2-3 fold increase in half-life of rabeprazole compared to the healthy volunteers. However, following a 20 mg dose daily for 7 days the AUC had increased to only 1.5-fold and the Cmax to only 1.2-fold. The half-life of rabeprazole in patients with hepatic impairment was 12.3 hours compared to 2.1 hours in healthy volunteers. The pharmacodynamic response (gastric pH control) in the two groups was clinically comparable.
Elderly
Elimination of rabeprazole was somewhat decreased in the elderly. Following 7 days of daily dosing with 20 mg of rabeprazole sodium, the AUC approximately doubled, the C increased by 60% and t, increased by approximately 30% as compared to young healthy volunteers. However there was no evidence of rabeprazole-accumulation.
CYP2C19 Polyrnoiphsm
Fo&wng a 20 mg daily dose of rabeprazole for 7 days, CYP2C19 slow metabolisers. had AUG 3IC t which were approximately 1.9 and 1.6 times the corresponding parameters in extensive metabusers whilst C1 had increased by only 40%.
Preclinical safety data -
Pre-clinical effects were observed only at exposures sufficiently in excess of the maximum human exposure iia! make concerns for human safety negIgible in respect of animal data.
Studies on mutagenicity gave equivocal results. Tests in mouse lymphoma cell line were positive, but in vivo micronucleus and in vivo and in vitro DNA repair tests were negative. Carcinogenicity studies revealed no special hazard for humans.
PHARMACEUTICAL PARTICULARS
List of excipients
Mannitol, magnesium oxi&, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose. rnaesium stearate, ethylcellulose, hypromellose phthalate, diacetylated monoglycerides, talc, titaniumn cboxide yeow ion oxide (20 mg only), red iron oxide (10 mg od. carnauba wax and ink.
Special precautions for storage
Do not store above 25C. Do not refngera’te.
After opening, store in the original package (aluminium poucfl) and use within three months. Do not
store above 25CC. Do not refrigerate. —
Keep out of reach of children.
Nature and contents of container
Primary packaging:
Unit dose blister strips (PVC/PVdC/PE-5ply laminate/aluminium foil strip) of 7 0(14 tablets.
Secondary packaging:
Aluminium pouch containing multiples of 7 or 14 tablet unit dose blister strips and a silica gel desiccant pouch.
Alternative packaging Format:
Primary packaging:
Ur dose blister strips (aluminium/aluminium) of 7 or 14 tablets.
DATE OF CPARTIAL1 REVISION OF ThE TEXT
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