PROTONIX^® I.V.
(pantoprazole sodium)
for Injection

The active ingredient in PROTONIX^® I.V. (pantoprazole sodium) for Injection is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C₁₆H₁₄F₂N₃NaO₄S, with a molecular weight of 405.4. The structural formula is:

Pantoprazole sodium is a white to off-white crystalline powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium 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. The reconstituted solution of PROTONIX I.V. for Injection is in the pH range 9.0 to 10.5.

PROTONIX I.V. for Injection is supplied as a freeze-dried powder in a clear glass vial fitted with a rubber stopper and crimp seal containing pantoprazole sodium, equivalent to 40 mg of pantoprazole, edetate disodium (1 mg), and sodium hydroxide to adjust pH.

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 PROTONIX I.V. for Injection, the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. In extensive metabolizers (see CLINICAL PHARMACOLOGY, Metabolism) with normal liver function receiving a 40 mg dose of PROTONIX I.V. for Injection by constant rate over 15 minutes, the peak concentration (C_max) is 5.52 μg/mL and the total area under the plasma concentration versus time curve (AUC) is 5.4 μg · hr/mL. The total clearance is 7.6-14.0 L/h and the apparent volume of distribution is 11.0-23.6 L.

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, 2D6, 2C9 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 co-administered 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.

PROTONIX I.V. for Injection is indicated for short-term treatment (7 to 10 days) of patients with gastroesophageal reflux disease (GERD) and a history of erosive esophagitis.

PROTONIX I.V. for Injection is indicated for the treatment of pathological hypersecretory conditions associated with Zollinger-Ellison Syndrome or other neoplastic conditions.

PROTONIX I.V. for Injection is contraindicated in patients with known hypersensitivity to the formulation.

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.

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).

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.

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.

Safety and effectiveness in pediatric patients have not been established.

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.

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.

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.

Intravenous pantoprazole has been studied in clinical trials in several populations including patients with GERD and a history of erosive esophagitis, patients with Zollinger-Ellison Syndrome, patients involved in clinical trials for other disorders which may respond to proton pump inhibitor therapy, and healthy subjects. Adverse experiences occurring in >1% of patients treated with intravenous pantoprazole (n=836) in domestic or international clinical trials are shown below by body system. In most instances, the relationship to pantoprazole was unclear.

BODY AS A WHOLE: abdominal pain, headache, injection site reaction (including thrombophlebitis and abscess).

DIGESTIVE SYSTEM: constipation, dyspepsia, nausea, diarrhea.

NERVOUS SYSTEM: insomnia, dizziness.

RESPIRATORY SYSTEM: rhinitis.

Head-to-head comparative studies between PROTONIX I.V. for Injection and oral PROTONIX, other proton pump inhibitors (oral or I.V.), or H2 receptor antagonists (oral or I.V.) have been limited. The available information does not provide sufficient evidence to distinguish the safety profile of these regimens.

In short-term clinical trials in patients with erosive esophagitis associated with GERD treated with oral pantoprazole, the following adverse events, regardless of causality, occurred at a rate of ≥1%.

BODY AS A WHOLE: headache, asthenia, back pain, chest pain, neck pain, flu syndrome, infection, pain.

CARDIOVASCULAR SYSTEM: migraine.

DIGESTIVE SYSTEM: diarrhea, flatulence, abdominal pain, eructation, constipation, dyspepsia, gastroenteritis, gastrointestinal disorder, nausea, rectal disorder, vomiting.

HEPATO-BILIARY SYSTEM: liver function tests abnormal, SGPT increased.

METABOLIC AND NUTRITIONAL: hyperglycemia, hyperlipemia.

MUSCULOSKELETAL SYSTEM: arthralgia.

NERVOUS SYSTEM: insomnia, anxiety, dizziness, hypertonia.

RESPIRATORY SYSTEM: bronchitis, cough increased, dyspnea, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection.

SKIN AND APPENDAGES: rash.

UROGENITAL SYSTEM: urinary frequency, and urinary tract infection.

Additional adverse experiences occurring in <1% of patients with erosive esophagitis associated with GERD receiving oral pantoprazole based on pooled results from either short-term domestic or international trials are shown below within each body system. In most instances, the relationship to pantoprazole was unclear.

BODY AS A WHOLE: abscess, allergic reaction, chills, cyst, face edema, fever, generalized edema, heat stroke, hernia, laboratory test abnormal, malaise, moniliasis, neoplasm, non-specified drug reaction.

CARDIOVASCULAR SYSTEM: abnormal electrocardiogram, angina pectoris, arrhythmia, cardiovascular disorder, chest pain substernal, congestive heart failure, hemorrhage, hypertension, hypotension, myocardial ischemia, palpitation, retinal vascular disorder, syncope, tachycardia, thrombophlebitis, thrombosis, vasodilatation.

DIGESTIVE SYSTEM: anorexia, aphthous stomatitis, cardiospasm, colitis, dry mouth, duodenitis, dysphagia, enteritis, esophageal hemorrhage, esophagitis, gastrointestinal carcinoma, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, glossitis, halitosis, hematemesis, increased appetite, melena, mouth ulceration, oral moniliasis, periodontal abscess, periodontitis, rectal hemorrhage, stomach ulcer, stomatitis, stools abnormal, tongue discoloration, ulcerative colitis.

ENDOCRINE SYSTEM: diabetes mellitus, glycosuria, goiter.

HEPATO-BILIARY SYSTEM: biliary pain, hyperbilirubinemia, cholecystitis, cholelithiasis, cholestatic jaundice, hepatitis, alkaline phosphatase increased, gamma glutamyl transpeptidase increased, SGOT increased.

HEMIC AND LYMPHATIC SYSTEM: anemia, ecchymosis, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, leukopenia, thrombocytopenia.

METABOLIC AND NUTRITIONAL: dehydration, edema, gout, peripheral edema, thirst, weight gain, weight loss.

MUSCULOSKELETAL SYSTEM: arthritis, arthrosis, bone disorder, bone pain, bursitis, joint disorder, leg cramps, neck rigidity, myalgia, tenosynovitis.

NERVOUS SYSTEM: abnormal dreams, confusion, convulsion, depression, dry mouth, dysarthria, emotional lability, hallucinations, hyperkinesia, hypesthesia, libido decreased, nervousness, neuralgia, neuritis, paresthesia, reflexes decreased, sleep disorder, somnolence, thinking abnormal, tremor, vertigo.

RESPIRATORY SYSTEM: asthma, epistaxis, hiccup, laryngitis, lung disorder, pneumonia, voice alteration.

SKIN AND APPENDAGES: acne, alopecia, contact dermatitis, dry skin, eczema, fungal dermatitis, hemorrhage, herpes simplex, herpes zoster, lichenoid dermatitis, maculopapular rash, pain, pruritus, skin disorder, skin ulcer, sweating, urticaria.

SPECIAL SENSES: abnormal vision, amblyopia, cataract specified, deafness, diplopia, ear pain, extraocular palsy, glaucoma, otitis externa, taste perversion, tinnitus.

UROGENITAL SYSTEM: albuminuria, balanitis, breast pain, cystitis, dysmenorrhea, dysuria, epididymitis, hematuria, impotence, kidney calculus, kidney pain, nocturia, prostatic disorder, pyelonephritis, scrotal edema, urethral pain, urethritis, urinary tract disorder, urination impaired, vaginitis.

In addition, the following adverse experiences occurred at a rate of <1% in long-term clinical trials in patients treated with oral pantoprazole: atrial fibrillation/flutter, myocardial infarction, neuropathy, photosensitivity reaction. In most instances, the relationship to pantoprazole was unclear.

The postmarketing safety profile of intravenous pantoprazole is not substantially different from that of oral pantoprazole (described below).

There have been spontaneous reports of adverse events with postmarketing use of intravenous or oral pantoprazole. These reports include the following:

BODY AS A WHOLE: anaphylaxis (including anaphylactic shock), angioedema (Quincke's edema).

DIGESTIVE SYSTEM: increased salivation, nausea, pancreatitis.

HEMIC AND LYMPHATIC SYSTEM: pancytopenia.

HEPATO-BILIARY SYSTEM: hepatocellular damage leading to jaundice and hepatic failure.

MUSCULOSKELETAL SYSTEM: elevated CPK (creatine phosphokinase), rhabdomyolysis.

NERVOUS SYSTEM: confusion, hypokinesia, speech disorder, vertigo.

SKIN AND APPENDAGES: severe dermatologic reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN, some fatal).

SPECIAL SENSES: anterior ischemic optic neuropathy, blurred vision, tinnitus.

UROGENITAL SYSTEM: interstitial nephritis.

In U.S. clinical trials of patients with GERD and a history of erosive esophagitis and international clinical trials of patients with erosive esophagitis associated with GERD, the overall percentages of transaminase elevations did not increase during treatment with intravenous pantoprazole. For other laboratory parameters, there were no clinically important changes identified.

In two U.S. controlled trials of oral pantoprazole in patients with erosive esophagitis associated with GERD, 0.4% of the patients on 40 mg oral pantoprazole experienced SGPT elevations of greater than three times the upper limit of normal at the final treatment visit. Except in those patients where there was a clear alternative explanation for a laboratory value change, such as intercurrent illness, the elevations tended to be mild and sporadic. The following changes in laboratory parameters were reported as adverse events: creatinine increased, hypercholesterolemia, and hyperuricemia.

Experience in patients taking very high doses of pantoprazole is limited. There have been spontaneous reports of overdosage with pantoprazole, including a suicide in which pantoprazole 560 mg and undetermined amounts of chloroquine and zopiclone were also ingested. There have also been spontaneous reports of patients taking similar amounts of pantoprazole (400 and 600 mg) with no adverse effects.

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

Single intravenous doses of pantoprazole at 378, 230, and 266 mg/kg (38, 46, and 177 times the recommended human dose based on body surface area) 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.

PROTONIX I.V. for Injection may be administered intravenously through a dedicated line or through a Y-site. The intravenous line should be flushed before and after administration of PROTONIX I.V. for Injection with either 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's Injection, USP. When administered through a Y-site, PROTONIX I.V. for Injection is compatible with the following solutions: 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's Injection, USP.

Midazolam HCl has been shown to be incompatible with Y-site administration of PROTONIX I.V. for Injection. PROTONIX I.V. for Injection may not be compatible with products containing zinc. When PROTONIX I.V. for Injection is administered through a Y-site, immediately stop use if precipitation or discoloration occurs.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to and during administration whenever solution and container permit.

Treatment with PROTONIX I.V. for Injection should be discontinued as soon as the patient is able to be treated with PROTONIX Delayed-Release Tablets. Also, data on the safe and effective dosing for conditions other than those described in INDICATIONS AND USAGE, such as life-threatening upper gastrointestinal bleeds, are not available. PROTONIX I.V. 40 mg once daily does not raise gastric pH to levels sufficient to contribute to the treatment of such life-threatening conditions.

Parenteral routes of administration other than intravenous are not recommended.

No dosage adjustment is necessary in patients with renal impairment, hepatic impairment, or for elderly patients. Doses higher than 40 mg/day have not been studied in hepatically-impaired patients. No dosage adjustment is necessary in patients undergoing hemodialysis.

The recommended adult dose is 40 mg pantoprazole given once daily by intravenous infusion for 7 to 10 days. Safety and efficacy of PROTONIX I.V. for Injection as a treatment of patients with GERD and a history of erosive esophagitis for more than 10 days have not been demonstrated (see INDICATIONS AND USAGE).

The dosage of PROTONIX I.V. for Injection in patients with pathological hypersecretory conditions associated with Zollinger-Ellison Syndrome or other neoplastic conditions varies with individual patients. The recommended adult dosage is 80 mg q12h. The frequency of dosing can be adjusted to individual patient needs based on acid output measurements. In those patients who need a higher dosage, 80 mg q8h is expected to maintain acid output below 10 mEq/h. Daily doses higher than 240 mg or administered for more than 6 days have not been studied. (See Clinical Studies section.) Transition from oral to I.V. and from I.V. to oral formulations of gastric acid inhibitors should be performed in such a manner to ensure continuity of effect of suppression of acid secretion. Patients with Zollinger-Ellison Syndrome may be vulnerable to serious clinical complications of increased acid production even after a short period of loss of effective inhibition.

PROTONIX^® I.V. (pantoprazole sodium) for Injection is supplied as a freeze-dried powder containing 40 mg of pantoprazole per vial.

PROTONIX I.V. for Injection is available as follows:

NDC 0008-0923-51 One carton containing 1 vial of PROTONIX I.V. for Injection (each vial containing 40-mg pantoprazole).

Store PROTONIX I.V. for Injection vials at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F). [See USP Controlled Room Temperature.] Protect from light.

Caution: the reconstituted product should not be frozen.

U.S. Patent No. 4,758,579

Marketed by Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101
under license from
ALTANA Pharma
D78467 Konstanz, Germany

W10447C015
ET01
Rev 04/07