Pantoprazole 40 mg · Dry-powder injectables

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).

Pantoprazole peak serum concentration (C max) and area under the serum concentration-time curve (AUC) increase in a manner proportional to intravenous doses from 10 mg to 80 mg. Pantoprazole does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following the administration of pantoprazole sodium for injection, the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. In CYP2C19 extensive metabolizers [see Clinical Pharmacology ( 12.5)] with normal liver function receiving a 40 mg dose of pantoprazole sodium for injection by constant rate over 15 minutes, the peak concentration (C max) is 5.52 ±1.42 mcg/mL and the total area under the plasma concentration versus time curve (AUC) is 5.4 ±1.5 mcg hr/mL. The total clearance is 7.6 to 14 L/h.

Distribution — The apparent volume of distribution of pantoprazole is approximately 11 to 23.6 L, distributing mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin.

Metabolism — 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 (e.g., 3% of Whites and African-Americans and 17 to 23% of Asians). Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values from 3.5 to 10 hours, they still have minimal accumulation (23% or less) with once daily dosing.

Excretion — After administration of a single intravenous dose of 14C-labeled pantoprazole sodium to healthy, extensive CYP2C19 metabolizers, 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.

Geriatric Patients — After repeated intravenous administration in elderly subjects (65 to 76 years of age), the AUC and elimination half-life values of pantoprazole were similar to those observed in younger subjects.

Male and Female Patients — After oral administration there was a modest increase in the AUC and C maxof pantoprazole in women compared to men. However, weight-normalized clearance values are similar in women and men.

Patients with Renal Impairment — In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole were similar to those of healthy subjects.

Patients with Hepatic Impairment — In patients with mild to severe hepatic impairment (Child-Pugh Class A to C), maximum pantoprazole concentrations increased only slightly (1.5-fold) relative to healthy subjects when pantoprazole sodium was administered orally. Although serum half-life values increased to 7 to 9 hours and AUC values increased by 5- to 7-fold in hepatic-impaired patients, these increases were no greater than those observed in CYP2C19 poor metabolizers, where no dosage adjustment is warranted. These pharmacokinetic changes in hepatic-impaired patients result in minimal drug accumulation following once daily, multiple-dose administration. Oral pantoprazole doses higher than 40 mg per day have not been studied in hepatically impaired patients.

Effect of Other Drugs on Pantoprazole — Pantoprazole is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6 and 2C9.

In in vivodrug-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.

Clopidogrel — Clopidogrel is metabolized to its active metabolite in part by CYP2C19. In a crossover clinical study, 66 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with oral pantoprazole (80 mg at the same time as clopidogrel) for 5 days.