PRECAUTIONS
General
Immediate hypersensitivity reactions: Anaphylaxis has been reported with use of intravenous pantoprazole. This may require emergency medical treatment.
Injection site reactions: Thrombophlebitis was associated with the administration of intravenous pantoprazole.
Hepatic effects: Mild, transient transaminase elevations have been observed in clinical studies. The clinical significance of this finding in a large population of subjects administered intravenous pantoprazole is unknown. (See ADVERSE REACTIONS section).
Symptomatic response to therapy with pantoprazole does not preclude the presence of gastric malignancy.
As with any other intravenous product containing edetate disodium (the salt form of EDTA) which is a potent chelator of metal ions including zinc, zinc supplementation should be considered in patients treated with PROTONIX I.V. for Injection who are prone to zinc deficiency. Caution should be used when other EDTA containing products are also co-administered intravenously.
Treatment with PROTONIX® I.V. (pantoprazole sodium) for Injection should be discontinued as soon as the patient is able to resume treatment with PROTONIX Delayed-Release Tablets.
Drug Interactions
Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. (See CLINICAL PHARMACOLOGY, Drug-Drug Interactions.)
Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin (see below), midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when co-administered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time.
Based on information about other proton pump inhibitors, concomitant administration of pantoprazole may reduce the plasma levels of atazanavir. Appropriate clinical monitoring is recommended.
Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (e.g., ketoconazole, ampicillin esters, and iron salts).
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with 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 at 40 mg/day. In the gastric fundus, treatment at 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 at 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 at 50 mg/kg/day, and benign polyps and adenocarcinomas of the gastric fundus at 200 mg/kg/day. In the liver, treatment at 0.5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment at 200 mg/kg/day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats.
Sporadic occurrences of hepatocellular adenomas and a hepatocellular carcinoma were observed in Sprague-Dawley rats exposed to pantoprazole in 6-month and 12-month oral toxicity studies.
In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with doses of 5 to 50 mg/kg/day, approximately 1 to 10 times the recommended human dose based on body surface area. In the gastric fundus, treatment at 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, 0.5 to 15 times the recommended human dose based on body surface area. In the liver, treatment at 150 mg/kg/day produced increased incidences of hepatocellular adenomas and carcinomas in female mice. Treatment at 5 to 150 mg/kg/day also produced gastric fundic ECL cell hyperplasia.
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. A 26-week p53 +/- transgenic mouse carcinogenicity study was not positive.
Pantoprazole 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) was found to have no effect on fertility and reproductive performance.
Pregnancy
Teratogenic Effects
Pregnancy Category B
Teratology studies have been performed in rats at intravenous doses up to 20 mg/kg/day (4 times the recommended human dose based on body surface area) and rabbits at intravenous doses up to 15 mg/kg/day (6 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Pantoprazole and its metabolites are excreted in the milk of rats. Pantoprazole excretion in human milk has been detected in a study of a single nursing mother after a single 40 mg oral dose. The clinical relevance of this finding is not known. Many drugs which are excreted in human milk have a potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for pantoprazole in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Use in Women
No gender-related differences in the safety profile of intravenous pantoprazole were seen in international trials involving 166 men and 120 women with erosive esophagitis associated with GERD. Erosive esophagitis healing rates in the 221 women treated with oral pantoprazole in U.S. clinical trials were similar to those found in men. The incidence rates of adverse events were also similar between men and women.
Use in Elderly
No age-related differences in the safety profile of intravenous pantoprazole were seen in international trials involving 86 elderly (≥ 65 years old) and 200 younger (< 65 years old) patients with erosive esophagitis associated with GERD. Erosive esophagitis healing rates in the 107 elderly patients (≥ 65 years old) treated with oral pantoprazole in U.S. clinical trials were similar to those found in patients under the age of 65. The incidence rates of adverse events and laboratory abnormalities in patients aged 65 years and older were similar to those associated with patients younger than 65 years of age.
Laboratory Tests
There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results.
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