PANTOPRAZOLE SODIUM DELAYED-RELEASE- pantoprazole sodium tablet, delayed release
Contract Pharmacy Services-PA
The active ingredient in pantoprazole sodium delayed-release tablets is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical formula is C16 H14 F2 N3 NaO4 S x 1.5 H2 O, with a molecular weight of 432.4. The structural formula is:
Pantoprazole sodium sesquihydrate is a white to off-white crystalline powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium sesquihydrate is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n‑hexane.
The stability of the compound in aqueous solution is pH-dependent. The rate of degradation increases with decreasing pH. At ambient temperature, the degradation half-life is approximately 2.8 hours at pH 5.0 and approximately 220 hours at pH 7.8.
Pantoprazole sodium is supplied as a delayed-release tablet for oral administration, available in 2 strengths. Each delayed-release tablet contains 45.1 mg or 22.6 mg of pantoprazole sodium sesquihydrate (equivalent to 40 mg or 20 mg pantoprazole, respectively) with the following inactive ingredients: calcium stearate, crospovidone, hypromellose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate. Pantoprazole Sodium Delayed‑Release tablets (40 mg and 20 mg) complies with USP dissolution test 2.
Pantoprazole sodium is prepared as an enteric-coated tablet so that absorption of pantoprazole begins only after the tablet leaves the stomach. Peak serum concentration (Cmax ) and area under the serum concentration time curve (AUC) increase in a manner proportional to oral and intravenous doses from 10 mg to 80 mg. Pantoprazole does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following oral or intravenous administration, the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. In extensive metabolizers (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Metabolism) with normal liver function receiving an oral dose of the enteric-coated 40 mg pantoprazole tablet, the peak concentration (Cmax ) is 2.5 μg/mL, the time to reach the peak concentration (tmax ) is 2.5 h and the total area under the plasma concentration versus time curve (AUC) is 4.8 μg·hr/mL. When pantoprazole is given with food, its tmax is highly variable and may increase significantly. Following intravenous administration of pantoprazole to extensive metabolizers, its total clearance is 7.6-14.0 L/h and its apparent volume of distribution is 11.0-23.6 L.
The absorption of pantoprazole is rapid, with a Cmax of 2.5 μg/mL that occurs approximately 2.5 hours after administration of a single or multiple oral 40-mg doses of pantoprazole sodium delayed-release tablets. Pantoprazole is well absorbed; it undergoes little first-pass metabolism resulting in an absolute bioavailability of approximately 77%. Pantoprazole absorption is not affected by concomitant administration of antacids. Administration of pantoprazole with food may delay its absorption up to 2 hours or longer; however, the Cmax and the extent of pantoprazole absorption (AUC) are not altered. Thus, pantoprazole may be taken without regard to timing of meals.
The apparent volume of distribution of pantoprazole is approximately 11.0-23.6 L, distributing mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin.
Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. CYP2C19 displays a known genetic polymorphism due to its deficiency in some sub-populations (eg, 3% of Caucasians and African-Americans and 17%-23% of Asians). Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values of 3.5 to 10.0 hours, they still have minimal accumulation (≤ 23%) with once daily dosing.
After a single oral or intravenous dose of 14 C-labeled pantoprazole to healthy, normal metabolizer volunteers, approximately 71% of the dose was excreted in the urine with 18% excreted in the feces through biliary excretion. There was no renal excretion of unchanged pantoprazole.
Only slight to moderate increases in pantoprazole AUC (43%) and Cmax (26%) were found in elderly volunteers (64 to 76 years of age) after repeated oral administration, compared with younger subjects. No dosage adjustment is recommended based on age.
The pharmacokinetics of pantoprazole have not been investigated in patients < 18 years of age.
There is a modest increase in pantoprazole AUC and Cmax in women compared to men. However, weight-normalized clearance values are similar in women and men. No dosage adjustment is needed based on gender (see PRECAUTIONS, Use in Women).
In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole were similar to those of healthy subjects. No dosage adjustment is necessary in patients with renal impairment or in patients undergoing hemodialysis.
In patients with mild to severe hepatic impairment, maximum pantoprazole concentrations increased only slightly (1.5-fold) relative to healthy subjects. Although serum half-life values increased to 7-9 hours and AUC values increased by 5- to 7-fold in hepatic-impaired patients, these increases were no greater than those observed in slow CYP2C19 metabolizers, where no dosage frequency adjustment is warranted. These pharmacokinetic changes in hepatic-impaired patients result in minimal drug accumulation following once daily multiple-dose administration. No dosage adjustment is needed in patients with mild to severe hepatic impairment. Doses higher than 40 mg/day have not been studied in hepatically-impaired patients.
Pantoprazole is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6, and 2C9. In in vivo drug-drug interaction studies with CYP2C19 substrates (diazepam [also a CYP3A4 substrate] and phenytoin [also a CYP3A4 inducer]), nifedipine, midazolam, and clarithromycin (CYP3A4 substrates), metoprolol (a CYP2D6 substrate), diclofenac, naproxen and piroxicam (CYP2C9 substrates), and theophylline (a CYP1A2 substrate) in healthy subjects, the pharmacokinetics of pantoprazole were not significantly altered. It is, therefore, expected that other drugs metabolized by CYPs 2C19, 3A4, 2D6, 2C9, and 1A2 would not significantly affect the pharmacokinetics of pantoprazole. In vivo studies also suggest that pantoprazole does not significantly affect the kinetics of other drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, naproxen, piroxicam, and oral contraceptives [levonorgestrel/ethinyl estradiol]) metabolized by CYPs 2C19, 3A4, 2C9, 2D6, and 1A2. Therefore, it is expected that pantoprazole would not significantly affect the pharmacokinetics of other drugs metabolized by these isozymes. Dosage adjustment of such drugs is not necessary when they are coadministered with pantoprazole. In other in vivo studies, digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically relevant interactions with pantoprazole. Although no significant drug-drug interactions have been observed in clinical studies, the potential for significant drug-drug interactions with more than once daily dosing with high doses of pantoprazole has not been studied in poor metabolizers or individuals who are hepatically impaired.
Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by covalently binding to the (H+ ,K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. The binding to the (H+ ,K+)-ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all doses tested.
Under maximal acid stimulatory conditions using pentagastrin, a dose-dependent decrease in gastric acid output occurs after a single dose of oral (20-80 mg) or a single dose of intravenous (20-120 mg) pantoprazole in healthy volunteers. Pantoprazole given once daily results in increasing inhibition of gastric acid secretion. Following the initial oral dose of 40 mg pantoprazole, a 51% mean inhibition was achieved by 2.5 hours. With once a day dosing for 7 days the mean inhibition was increased to 85%. Pantoprazole suppressed acid secretion in excess of 95% in half of the subjects. Acid secretion had returned to normal within a week after the last dose of pantoprazole; there was no evidence of rebound hypersecretion.
In a series of dose-response studies pantoprazole, at oral doses ranging from 20 to 120 mg, caused dose-related increases in median basal gastric pH and in the percent of time gastric pH was > 3 and > 4. Treatment with 40 mg of pantoprazole produced optimal increases in gastric pH which were significantly greater than the 20-mg dose. Doses higher than 40 mg (60, 80, 120 mg) did not result in further significant increases in median gastric pH. The effects of pantoprazole on median pH from one double-blind crossover study are shown below.
|–––––––—––––––––Median pH on day 7—–––––––––––––|
|Time||Placebo||20 mg||40 mg||80 mg|
|8 a.m. — 8 a.m. (24 hours)||1.3||2.9*||3.8*#||3.9*#|
|8 a.m. — 10 p.m. (Daytime)||1.6||3.2*||4.4*#||4.8*#|
|10 p.m. — 8 a.m. (Nighttime)||1.2||2.1*||3.0*||2.6*|
|* Significantly different from placebo# Significantly different from 20 mg|
Fasting serum gastrin levels were assessed in two double-blind studies of the acute healing of erosive esophagitis (EE) in which 682 patients with gastroesophageal reflux disease (GERD) received 10, 20, or 40 mg of pantoprazole sodium for up to 8 weeks. At 4 weeks of treatment there was an increase in mean gastrin levels of 7%, 35%, and 72% over pretreatment values in the 10, 20, and 40 mg treatment groups, respectively. A similar increase in serum gastrin levels was noted at the 8 week visit with mean increases of 3%, 26%, and 84% for the three pantoprazole dose groups. Median serum gastrin levels remained within normal limits during maintenance therapy with pantoprazole sodium delayed-release tablets.
In long-term international studies involving over 800 patients, a 2- to 3-fold mean increase from the pretreatment fasting serum gastrin level was observed in the initial months of treatment with pantoprazole at doses of 40 mg per day during GERD maintenance studies and 40 mg or higher per day in patients with refractory GERD. Fasting serum gastrin levels generally remained at approximately 2 to 3 times baseline for up to 4 years of periodic follow-up in clinical trials.
Following healing of gastric or duodenal ulcers with pantoprazole treatment, elevated gastrin levels return to normal by at least 3 months.
In 39 patients treated with oral pantoprazole 40 mg to 240 mg daily (majority receiving 40 mg to 80 mg) for up to 5 years, there was a moderate increase in ECL-cell density starting after the first year of use which appeared to plateau after 4 years.
In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) to pantoprazole at doses of 0.5 to 200 mg/kg/day resulted in dose-related increases in gastric ECL-cell proliferation and gastric neuroendocrine (NE)-cell tumors. Gastric NE-cell tumors in rats may result from chronic elevation of serum gastrin concentrations. The high density of ECL cells in the rat stomach makes this species highly susceptible to the proliferative effects of elevated gastrin concentrations produced by proton pump inhibitors. However, there were no observed elevations in serum gastrin following the administration of pantoprazole at a dose of 0.5 mg/kg/day. In a separate study, a gastric NE-cell tumor without concomitant ECL-cell proliferative changes was observed in 1 female rat following 12 months of dosing with pantoprazole at 5 mg/kg/day and a 9 month off-dose recovery (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility).
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