Pantoprazole Sodium Delayed-release (Page 5 of 10)

8.5 Geriatric Use

In short-term US clinical trials, EE healing rates in the 107 elderly patients (≥65 years old) treated with pantoprazole sodium was similar to those found in patients under the age of 65. The incidence rates of adverse reactions and laboratory abnormalities in patients aged 65 years and older were similar to those associated with patients younger than 65 years of age.

10 OVERDOSAGE

Experience in patients taking very high doses of pantoprazole sodium (greater than 240 mg) is limited. Spontaneous post-marketing reports of overdose are generally within the known safety profile of pantoprazole sodium.

Pantoprazole is not removed by hemodialysis. In case of overdosage, treatment should be symptomatic and supportive.

Single oral doses of pantoprazole at 709 mg/kg, 798 mg/kg, and 887 mg/kg were lethal to mice, rats, and dogs, respectively. The symptoms of acute toxicity were hypoactivity, ataxia, hunched sitting, limb-splay, lateral position, segregation, absence of ear reflex, and tremor.

If overexposure to pantoprazole sodium occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

11 DESCRIPTION

The active ingredient in pantoprazole sodium delayed-release tablets, a PPI, 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 432.37. The structural formula is:

1
(click image for full-size original)

Pantoprazole sodium is a white to off-white powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium, USP is freely soluble in water, in methanol, and in dehydrated alcohol; practically insoluble in hexane and dichloromethane.

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 and approximately 220 hours at pH 7.8.

Pantoprazole Sodium Delayed-Release Tablets, USP contains the following inactive ingredients: calcium stearate, crospovidone, hypromellose, ferric oxide red, ferrosoferric oxide black, mannitol, methacrylic acid- ethyl acrylate copolymer, polyethylene glycol, silicon dioxide, sodium carbonate, sucrose, talc, and triethyl citrate.

Imprinting ink contains ammonium hydroxide, ferrosoferric oxide black, isopropyl alcohol, N-butyl alcohol, propylene glycol and shellac glaze.

Meets USP Dissolution Test 3.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pantoprazole is a 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 (20 mg to 120 mg).

12.2 Pharmacodynamics

Pantoprazole sodium for delayed-release oral suspension, 40 mg has been shown to be comparable to pantoprazole delayed-release tablets in suppressing pentagastrin-stimulated MAO in patients (n = 49) with GERD and a history of EE. In this multicenter, pharmacodynamics crossover study, a 40 mg oral dose of pantoprazole sodium for delayed-release oral suspension administered in a teaspoonful of applesauce was compared with a 40 mg oral dose of pantoprazole sodium delayed-release tablets after administration of each formulation once daily for 7 days. Both medications were administered thirty minutes before breakfast. Pentagastrin-stimulated (MAO) was assessed from hour 23 to 24 at steady state.

Antisecretory Activity

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 subjects. 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 significantly greater increases in gastric pH 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 in Table 5.

Table 5: Effect of Single Daily Doses of Oral Pantoprazole on Intragastric pH

–––––––––—––––––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

Serum Gastrin Effects

Fasting serum gastrin levels were assessed in two double-blind studies of the acute healing of 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 short-term treatment with pantoprazole sodium, elevated gastrin levels return to normal by at least 3 months.

Enterochromaffin-Like (ECL) Cell Effects

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 PPIs. 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 Nonclinical Toxicology (13.1)].

Endocrine Effects

In a clinical pharmacology study, pantoprazole sodium 40 mg given once daily for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T3 ), thyroxine (T4 ), thyroid-stimulating hormone (TSH), thyronine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, and growth hormone.

In a 1-year study of GERD patients treated with pantoprazole sodium 40 mg or 20 mg, there were no changes from baseline in overall levels of T3 , T4 , and TSH.

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