Pantoprazole Sodium: Package Insert and Label Information (Page 5 of 7)

Patients with Hepatic Impairment

In patients with mild to severe hepatic impairment (Child-Pugh A to C cirrhosis), 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 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. Doses higher than 40 mg/day have not been studied in hepatically impaired patients.

Drug Interaction Studies

Effect of Other Drugs on Pantoprazole

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] and clopidogrel), 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.

Effect of Pantoprazole on Other Drugs

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 pantoprazole (80 mg at the same time as clopidogrel) for 5 days. On Day 5, the mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (geometric mean ratio was 86%, with 90% CI of 79 to 93%) when pantoprazole was coadministered with clopidogrel as compared to clopidogrel administered alone. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 μM ADP) was correlated with the change in the exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear.

Mycophenolate Mofetil (MMF)

Administration of pantoprazole 40 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of pantoprazole to 12 healthy subjects in a cross-over study resulted in a 57% reduction in the C_max and 27% reduction in the AUC of MPA. Transplant patients receiving approximately 2000 mg per day of MMF (n = 12) were compared to transplant patients receiving approximately the same dose of MMF and pantoprazole 40 mg per day (n = 21). There was a 78% reduction in the C_max and a 45% reduction in the AUC of MPA in patients receiving both pantoprazole and MMF [see Drug Interactions (7)].

Other Drugs

In vivo studies also suggest that pantoprazole does not significantly affect the kinetics of the following drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, diclofenac, naproxen, piroxicam, and oral contraceptives [levonorgestrel/ethinyl estradiol]). 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.

Antacids

There was also no interaction with concomitantly administered antacids.

12.5 Pharmacogenomics

CYP2C19 displays a known genetic polymorphism due to its deficiency in some subpopulations (e.g., approximately 3% of Caucasians and African-Americans and 17% to 23% of Asians are poor metabolizers). Although these subpopulations of pantoprazole poor metabolizers have elimination half-life values of 3.5 to 10 hours in adults, they still have minimal accumulation (23% or less) with once-daily dosing. For adult patients who are CYP2C19 poor metabolizers, no dosage adjustment is needed.

Similar to adults, pediatric patients who have the poor metabolizer genotype of CYP2C19 (CYP2C19 *2/*2) exhibited greater than a 6-fold increase in AUC compared to pediatric extensive (CYP2C19 *1/*1) and intermediate (CYP2C19 *1/*x) metabolizers. Poor metabolizers exhibited approximately 10-fold lower apparent oral clearance compared to extensive metabolizers.

For known pediatric poor metabolizers, a dose reduction should be considered.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with pantoprazole doses of 0.5 to 200 mg/kg/day, about 0.1 to 40 times the exposure on a body surface area basis of a 50 kg person dosed with 40 mg/day. In the gastric fundus, treatment with 0.5 to 200 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors in a dose-related manner. In the forestomach, treatment with 50 and 200 mg/kg/day (about 10 and 40 times the recommended human dose on a body surface area basis) produced benign squamous cell papillomas and malignant squamous cell carcinomas. Rare gastrointestinal tumors associated with pantoprazole treatment included an adenocarcinoma of the duodenum with 50 mg/kg/day and benign polyps and adenocarcinomas of the gastric fundus with 200 mg/kg/day. In the liver, treatment with 0.5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment with 200 mg/kg/day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats.

In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with doses of 5 to 50 mg/kg/day of pantoprazole, approximately 1 to 10 times the recommended human dose based on body surface area. In the gastric fundus, treatment with 5 to 50 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors. Dose selection for this study may not have been adequate to comprehensively evaluate the carcinogenic potential of pantoprazole.

In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with doses of 5 to 150 mg/kg/day of pantoprazole, 0.5 to 15 times the recommended human dose based on body surface area. In the liver, treatment with 150 mg/kg/day produced increased incidences of hepatocellular adenomas and carcinomas in female mice. Treatment with 5 to 150 mg/kg/day also produced gastric-fundic ECL cell hyperplasia.

A 26-week p53 +/- transgenic mouse carcinogenicity study was not positive.

Pantoprazole was positive in the in vitro human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects, and in the in vitro Chinese hamster ovarian cell/HGPRT forward mutation assay for mutagenic effects. Equivocal results were observed in the in vivo rat liver DNA covalent binding assay. Pantoprazole was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis (UDS) assay with rat hepatocytes, the in vitro AS52/GPT mammalian cell-forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse lymphoma L5178Y cells, and the in vivo rat bone marrow cell chromosomal aberration assay.

There were no effects on fertility or reproductive performance when pantoprazole was given at oral doses up to 500 mg/kg/day in male rats (98 times the recommended human dose based on body surface area) and 450 mg/kg/day in female rats (88 times the recommended human dose based on body surface area).

14 CLINICAL STUDIES

Pantoprazole sodium delayed-release tablets were used in the following clinical trials.

14.1 Erosive Esophagitis (EE) Associated with Gastroesophageal Reflux Disease (GERD)

Adult Patients

A U.S. multicenter, double-blind, placebo-controlled study of pantoprazole sodium delayed-release tablets 10 mg, 20 mg, or 40 mg once daily was conducted in 603 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above (Hetzel-Dent scale). In this study, approximately 25% of enrolled patients had severe EE of grade 3, and 10% had grade 4. The percentages of patients healed (per protocol, n = 541) in this study are shown in Table 8.

Table 8: Erosive Esophagitis Healing Rates (Per Protocol)

* (p < 0.001) pantoprazole sodium delayed-release tablets versus placebo † (p < 0.05) versus 10 mg pantoprazole sodium delayed-release tablets ‡ (p < 0.05) versus 10 mg or 20 mg pantoprazole sodium delayed-release tablets
Week	Pantoprazole Sodium Delayed-Release Tablets			Placebo(n = 68)
	10 mg daily(n = 153)	20 mg daily(n = 158)	40 mg daily(n = 162)
4	45.6%*	58.4%*†	75.0%*‡	14.3%
8	66.0%*	83.5%*†	92.6%*‡	39.7%

In this study, all pantoprazole sodium delayed-release tablet treatment groups had significantly greater healing rates than the placebo group. This was true regardless of H. pylori status for the 40 mg and 20 mg pantoprazole sodium delayed-release tablet treatment groups. The 40 mg dose of pantoprazole sodium delayed-release tablets resulted in healing rates significantly greater than those found with either the 20 mg or 10 mg dose.

A significantly greater proportion of patients taking pantoprazole sodium delayed-release tablets 40 mg experienced complete relief of daytime and nighttime heartburn and the absence of regurgitation, starting from the first day of treatment, compared with placebo. Patients taking pantoprazole sodium delayed-release tablets consumed significantly fewer antacid tablets per day than those taking placebo.

Pantoprazole sodium delayed-release tablets 40 mg and 20 mg once daily were also compared with nizatidine 150 mg twice daily in a U.S. multicenter, double-blind study of 243 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above. The percentages of patients healed (per protocol, n = 212) are shown in Table 9.

Table 9: Erosive Esophagitis Healing Rates (Per Protocol)

* (p < 0.001) pantoprazole sodium delayed-release tablets versus nizatidine
Week	Pantoprazole Sodium Delayed-Release Tablets		Nizatidine150 mg twice daily (n = 70)
	20 mg daily (n = 72)	40 mg daily (n = 70)
4	61.4%*	64.0%*	22.2%
8	79.2%*	82.9%*	41.4%

Once-daily treatment with pantoprazole sodium delayed-release tablets 40 mg or 20 mg resulted in significantly superior rates of healing at both 4 and 8 weeks compared with twice-daily treatment with 150 mg of nizatidine. For the 40 mg treatment group, significantly greater healing rates compared to nizatidine were achieved regardless of the H. pylori status.

A significantly greater proportion of the patients in the pantoprazole sodium delayed-release tablets treatment groups experienced complete relief of nighttime heartburn and regurgitation, starting on the first day and of daytime heartburn on the second day, compared with those taking nizatidine 150 mg twice daily. Patients taking pantoprazole sodium delayed-release tablets consumed significantly fewer antacid tablets per day than those taking nizatidine.

Pediatric Patients Ages 5 Years Through 16 Years

The efficacy of pantoprazole sodium delayed-release tablets in the treatment of EE associated with GERD in pediatric patients ages 5 years through 16 years is extrapolated from adequate and well-conducted trials in adults, as the pathophysiology is thought to be the same. Four pediatric patients with endoscopically diagnosed EE were studied in multicenter, randomized, double-blind, parallel-treatment trials. Children with endoscopically diagnosed EE (defined as an endoscopic Hetzel-Dent score ≥ 2) were treated once daily for 8 weeks with one of two dose levels of pantoprazole sodium delayed-release tablets (20 mg or 40 mg). All 4 patients with EE were healed (Hetzel-Dent score of 0 or 1) at 8 weeks.

14.2 Long-Term Maintenance of Healing of Erosive Esophagitis

Two independent, multicenter, randomized, double-blind, comparator-controlled trials of identical design were conducted in adult GERD patients with endoscopically confirmed healed EE to demonstrate efficacy of pantoprazole sodium delayed-release tablets in long-term maintenance of healing. The two U.S. studies enrolled 386 and 404 patients, respectively, to receive either 10 mg, 20 mg, or 40 mg of pantoprazole sodium delayed-release tablets once daily or 150 mg of ranitidine twice daily. As demonstrated in Table 10, pantoprazole sodium delayed-release tablets 40 mg and 20 mg were significantly superior to ranitidine at every timepoint with respect to the maintenance of healing. In addition, pantoprazole sodium delayed-release tablets 40 mg were superior to all other treatments studied.

Table 10: Long-Term Maintenance of Healing of Erosive Gastroesophageal Reflux Disease (GERD Maintenance): Percentage of Patients Who Remained Healed

Note: Pantoprazole sodium delayed-release tablets 10 mg were superior (p < 0.05) to ranitidine in Study 2, but not Study 1.
* (p < 0.05 vs. ranitidine) † (p < 0.05 vs. pantoprazole sodium delayed-release tablets 20 mg)
	Pantoprazole Sodium Delayed-Release Tablets 20 mg daily	Pantoprazole Sodium Delayed-Release Tablets 40 mg daily	Ranitidine 150 mg twice daily
Study 1	n = 75	n = 74	n = 75
Month 1	91*	99*	68
Month 3	82*	93*†	54
Month 6	76*	90*†	44
Month 12	70*	86*†	35
Study 2	n = 74	n = 88	n = 84
Month 1	89*	92*†	62
Month 3	78*	91*†	47
Month 6	72*	88*†	39
Month 12	72*	83*	37

Pantoprazole sodium delayed-release tablets 40 mg were superior to ranitidine in reducing the number of daytime and nighttime heartburn episodes from the first through the twelfth month of treatment. Pantoprazole sodium delayed-release tablets 20 mg, administered once daily, were also effective in reducing episodes of daytime and nighttime heartburn in one trial, as presented in Table 11.

Table 11: Number of Episodes of Heartburn (Mean ± SD)

* (p < 0.001 vs. ranitidine, combined data from the two U.S. studies)
		Pantoprazole Sodium Delayed-Release Tablets 40 mg daily	Ranitidine 150 mg twice daily
Month 1	Daytime	5.1 ± 1.6*	18.3 ± 1.6
	Nighttime	3.9 ± 1.1*	11.9 ± 1.1
Month 12	Daytime	2.9 ± 1.5*	17.5 ± 1.5
	Nighttime	2.5 ± 1.2*	13.8 ± 1.3