Protonix Information
Protonix (Pantoprazole) Indications And Usage
Protonix (Pantoprazole) For Delayed-Release Oral Suspension and Protonix (Pantoprazole) Delayed-Release Tablets are indicated for:
Protonix (Pantoprazole) Dosage Forms And Strengths
Delayed-Release Tablets:
For Delayed-Release Oral Suspension:
Protonix (Pantoprazole) Contraindications
Protonix (Pantoprazole) is contraindicated in patients with known hypersensitivity to any component of the formulation [see ] or any substituted benzimidazole.
Protonix (Pantoprazole) Warnings And Precautions
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. [See Adverse Reactions 6.2)]
Protonix (Pantoprazole) Adverse Reactions
The adverse reaction profiles for Protonix (Pantoprazole) (pantoprazole sodium) For Delayed-Release Oral Suspension and Protonix (Pantoprazole) (pantoprazole sodium) Delayed-Release Tablets are similar.
The following adverse reactions have been identified during postapproval use of Protonix (Pantoprazole) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
These adverse reactions are listed below by body system:
General Disorders and Administration Conditions:
Hepatobiliary Disorders:
Immune System Disorders:
Investigations:
Metabolism and Nutritional Disorders:
Musculoskeletal Disorders:
Psychiatric Disorders:
Skin and Subcutaneous Tissue Disorders:
Protonix (Pantoprazole) Overdosage
Experience in patients taking very high doses of Protonix (Pantoprazole) (> 240 mg) is limited. Spontaneous post-marketing reports of overdose are generally within the known safety profile of Protonix (Pantoprazole) .
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.
Protonix (Pantoprazole) Description
The active ingredient in Protonix (Pantoprazole) (pantoprazole sodium) For Delayed-Release Oral Suspension and Protonix (Pantoprazole) (pantoprazole sodium) Delayed-Release Tablets is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1-benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical formula is CHFNNaOS x 1.5 HO, with a molecular weight of 432.4. The structural formula is:
Pantoprazole sodium sesquihydrate is a white to off-white crystalline powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium sesquihydrate 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. At ambient temperature, the degradation half-life is approximately 2.8 hours at pH 5 and approximately 220 hours at pH 7.8.
Protonix (Pantoprazole) (pantoprazole sodium) is supplied as a for delayed-release oral suspension, available in one strength (40 mg), and as a delayed-release tablet, available in two strengths (20 mg and 40 mg).
Each Protonix (Pantoprazole) (pantoprazole sodium) Delayed-Release Tablet contains 45.1 mg or 22.56 mg of pantoprazole sodium sesquihydrate (equivalent to 40 mg or 20 mg pantoprazole, respectively) with the following inactive ingredients: calcium stearate, crospovidone, hypromellose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate. Protonix (Pantoprazole) Delayed-Release Tablets (40 mg and 20 mg) complies with USP dissolution test 2.
Protonix (Pantoprazole) (pantoprazole sodium) For Delayed-Release Oral Suspension, 40 mg, contains the active ingredient pantoprazole sodium sesquihydrate in the form of enteric‑coated granules in unit dose packets. Each unit dose packet contains enteric-coated granules containing 45.1 mg pantoprazole sodium sesquihydrate (equivalent to 40 mg of pantoprazole) with the following inactive ingredients: crospovidone, hypromellose, methacrylic acid copolymer, microcrystalline cellulose, polysorbate 80, povidone, sodium carbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate, and yellow ferric oxide.
Protonix (Pantoprazole) Clinical Pharmacology
Protonix (Pantoprazole) Delayed-Release Tablets are prepared as enteric-coated tablets so that absorption of pantoprazole begins only after the tablet leaves the stomach. Peak serum concentration (C) and area under the serum concentration time curve (AUC) increase in a manner proportional to oral and intravenous doses from 10 mg to 80 mg. Pantoprazole does not accumulate, and its pharmacokinetics are unaltered with multiple daily dosing. Following oral or intravenous administration, the serum concentration of pantoprazole declines biexponentially, with a terminal elimination half-life of approximately one hour.
In extensive metabolizers with normal liver function receiving an oral dose of the enteric-coated 40 mg pantoprazole tablet, the peak concentration (C) is 2.5 μg/mL; the time to reach the peak concentration (t) is 2.5 h, and the mean total area under the plasma concentration versus time curve (AUC) is 4.8 μg•h/mL (range 1.4 to 13.3 μg•h/mL). Following intravenous administration of pantoprazole to extensive metabolizers, its total clearance is 7.6‑14.0 L/h, and its apparent volume of distribution is 11.0‑23.6 L.
A single oral dose of Protonix (Pantoprazole) For Delayed-Release Oral Suspension, 40 mg, was shown to be bioequivalent when administered to healthy subjects (N = 22) as granules sprinkled over a teaspoonful of applesauce, as granules mixed with apple juice, or mixed with apple juice followed by administration through a nasogastric tube. The plasma pharmacokinetic parameters from a crossover study in healthy subjects are summarized in Table 5.
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 10.0 hours in adults, they still have minimal accumulation (≤ 23%) 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.
Protonix (Pantoprazole) Nonclinical Toxicology
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.
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.
A 26-week p53 +/- transgenic mouse carcinogenicity study was not positive.
Pantoprazole was positive in the human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects, and in the Chinese hamster ovarian cell/HGPRT forward mutation assay for mutagenic effects. Equivocal results were observed in the rat liver DNA covalent binding assay. Pantoprazole was negative in the Ames mutation assay, the unscheduled DNA synthesis (UDS) assay with rat hepatocytes, the AS52/GPT mammalian cell-forward gene mutation assay, the thymidine kinase mutation test with mouse lymphoma L5178Y cells, and the 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).
Protonix (Pantoprazole) Clinical Studies
Protonix (Pantoprazole) Delayed-Release Tablets were used in the following clinical trials.
Two independent, multicenter, randomized, double-blind, comparator-controlled trials of identical design were conducted in adult GERD patients with endoscopically confirmed healed erosive esophagitis to demonstrate efficacy of Protonix (Pantoprazole) in long-term maintenance of healing. The two US studies enrolled 386 and 404 patients, respectively, to receive either 10 mg, 20 mg, or 40 mg of Protonix (Pantoprazole) Delayed-Release Tablets once daily or 150 mg of ranitidine twice daily. As demonstrated in Table 9, Protonix (Pantoprazole) 40 mg and 20 mg were significantly superior to ranitidine at every timepoint with respect to the maintenance of healing. In addition, Protonix (Pantoprazole) 40 mg was superior to all other treatments studied.
Protonix (Pantoprazole) 40 mg was superior to ranitidine in reducing the number of daytime and nighttime heartburn episodes from the first through the twelfth month of treatment. Protonix (Pantoprazole) 20 mg, administered once daily, was also effective in reducing episodes of daytime and nighttime heartburn in one trial, as presented in Table 10.
In a multicenter, open-label trial of 35 patients with pathological hypersecretory conditions, such as Zollinger-Ellison syndrome, with or without multiple endocrine neoplasia‑type I, Protonix (Pantoprazole) successfully controlled gastric acid secretion. Doses ranging from 80 mg daily to 240 mg daily maintained gastric acid output below 10 mEq/h in patients without prior acid-reducing surgery and below 5 mEq/h in patients with prior acid-reducing surgery.
Doses were initially titrated to the individual patient needs, and adjusted in some patients based on the clinical response with time [
]. Protonix (Pantoprazole) was well tolerated at these dose levels for prolonged periods (greater than 2 years in some patients).
Protonix (Pantoprazole) How Supplied/storage And Handling
How Supplied
Protonix (Pantoprazole) (pantoprazole sodium) Delayed-Release Tablets are supplied as 40 mg yellow, oval biconvex delayed-release tablets imprinted with Protonix (Pantoprazole) (brown ink) on one side and are available as follows:
Protonix (Pantoprazole) (pantoprazole sodium) Delayed-Release Tablets are supplied as 20 mg yellow oval biconvex delayed-release tablets imprinted with P20 (brown ink) on one side and are available as follows:
Storage
Store Protonix (Pantoprazole) For Delayed-Release Oral Suspension and Protonix (Pantoprazole) Delayed-Release Tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]
Protonix (Pantoprazole) Patient Counseling Information
See
under license from
Nycomed GmbH
D78467 Konstanz, Germany
LAB-0459-2.0
Revised October2011
Relabeling and Repackaging by:
FDA-APPROVED PATIENT INFORMATION
Protonix (Pantoprazole)
Protonix (Pantoprazole)
Protonix (Pantoprazole)
Protonix (Pantoprazole)
