INHIBITORS OF H+,K+-ATPase ( Proton pump inhibitors )

By:

Muhammad Iqdam Muhammad

INTRODUCTION The proton pump inhibitors omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole inhibit gastric acid by blocking the hydrogen-potassium adenosine tri phosphatase enzyme system (the proton pump) of the gastric parietal cell. Proton pump inhibitors are effective short-term treatments for gastric and duodenal ulcers; they are also used in combination with anti bacterials for the eradication of Helicobacter pylori (see table (1) antibiotic regimen for H. pylori eradication). An initial short course of a proton pump inhibitor is the treatment of choice in gastro-oesophageal reflux disease with severe symptoms; patients with endoscopically confirmed erosive, ulcerative, or stricturing oesophagitis usually need to be maintained on a proton pump inhibitor. Proton pump inhibitors are also used in the prevention and treatment of NSAID-associated ulcers In patients who need to continue NSAID treatment after an ulcer has healed, the dose of proton pump inhibitor should normally not be reduced because asymptomatic ulcer deterioration may occur. Omeprazole is effective in the treatment of the Zollinger-Ellison syndrome (including cases resistant to other treatment); lansoprazole is also indicated for this condition Mehcanism of Action The ultimate mediator of acid secretion is the H+,K+- ATPase ("proton pump") of the apical membrane of the parietal cell (see Figure 1). Since this pump is unique to parietal cells, a number of specific inhibitors of it have been developed; a family of substituted benzimidazoles were discovered first, and two of these compounds, lansoprazole and omeprazole (Figure 2), have been released for clinical use in the United States. These agents offer a means to inhibit acid secretion to any desired level. They are especially useful in patients with hypergastrinemia and may be valuable in those whose peptic ulcer disease is not well controlled by H2 antagonists. Proton pump inhibitors contain a sulfinyl group in a bridge between substituted benzimidazole and pyridine rings (see Figure 2). At neutral pH, omeprazole and lansoprazole are chemically stable, lipid-soluble, weak bases that are devoid of inhibitory activity. These neutral weak bases reach parietal cells from the blood and diffuse into the secretory canaliculi, where the drugs become protonated and thereby trapped. The protonated agent rearranges to form a sulfenic acid and a sulfenamide. The sulfenamide interacts covalently with sulfhydryl groups at critical sites in the extracellular (luminal) domain of the membrane-spanning H+,K+-ATPase (Figure 2). Full

inhibition occurs with two molecules of inhibitor bound per molecule of enzyme. Omeprazole and lansoprazole must thus be considered as prodrugs that need to be activated to be effective. The specificity of the effects of proton pump inhibitors derive from the selective distribution of H+,K+ATPase, from the requirement for acidic conditions to catalyze generation of the reactive inhibitor, and from trapping of the protonated drug and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme. Administration of omeprazole (Figure 2) results in permanent inhibition of enzyme activity in vivo; secretion of acid resumes only after insertion of new molecules of H+,K+ATPase into the luminal membrane. Lansoprazole has a similar mechanism of action. However, some data suggest that the inhibitory effect of lansoprazole may be reversed by a mechanism involving cellular glutathione and that de novo synthesis of the proton pump is not essential to restore acid secretion. Newer H+,K+-ATPase agents are being developed that do not covalently bind to the enzyme. Pharmacological Properties The pharmacological effects of omeprazole (prilosec) and lansoprazole (prevacid) result from inhibition of gastric acid secretion. These agents produce only small and inconsistent changes in the volume of gastric juice and in the secretion of pepsin and intrinsic factor and do not affect gastric motility. The following discussion focuses on omeprazole; however, the therapeutic effects of omeprazole and lansoprazole are similar. Because omeprazole is an irreversible inhibitor of the H+,K+-ATPase, this agent produces a doserelated inhibition of gastric acid secretion that persists after the drug disappears from the plasma (Figure 3). The acid inhibitory effect of lansoprazole also lasts longer than would be predicted from its plasma elimination half-life. Omeprazole and lansoprazole are available for oral administration as delayed-release capsules. It is clinically important to note that, while both are stable at neutral pH, they are destroyed by gastric acid. Therefore, if their microencapsulation is disrupted before swallowingfor example, if the patient breaks open the gelatin-coated capsule and swallows the enteric-coated grainsthe neutral pH in the mouth and esophagus will break down the microencapsulation, and the drug will be exposed to degradation by gastric acid in the stomach. When the delayed-release capsule is taken appropriately, it releases omeprazole or lansoprazole after the granules leave the stomach; the drug is rapidly absorbed in the intestine. When given in a sufficient dosage (e.g., 20 mg per day for 7 days), omeprazole can reduce the daily production of acid by more than 95%; pretreatment values are not achieved until 4 or 5 days after withdrawal of the drug, presumably reflecting the time required to synthesize and insert new molecules of H+,K+-ATPase into the membrane. One consequence of profound reduction in gastric acidity is increased secretion of gastrin; patients who take the usual therapeutic dose of omeprazole or lansoprazole have a modest hyper gastrinemia. Prolonged administration of very high doses of omeprazole to experimental animals causes hyperplasia of oxyntic mucosal cells, presumably because of trophic effects of gastrin on these cells; carcinoid tumors also are produced in rats. Although no evidence of mucosal proliferation has been found in human subjects with long-term administration (up to 6 years), some clinicians are unwilling to administer omeprazole for long-term therapy if a suitable alternative therapy is available. The pharmacological properties of omeprazole have been reviewed. Absorption and Fate Orally administered omeprazole is absorbed rapidly but to a variable extent; its bioavailability depends on dose and gastric pH and may reach 70% with repeated administration. These properties presumably reflect the lability of the drug in acid and its impact on gastric pH. It is extensively (more than 95%) bound to plasma protein. Omeprazole is cleared from the circulation by hepatic metabolism with a half-time of 30 to 90 minutes; most of the metabolites are excreted in the urine. Lansoprazole has an oral bioavailability of about 80% and a plasma half-life of about 1.5 hours. Its absorption is reduced if given with food.

Drug Interactions Since omeprazole and lansoprazole interact with cytochrome P450 in vitro, inhibition of hepatic metabolism of certain drugs may be of potential importance. Omeprazole reduces the metabolism of phenytoin, diazepam, and the R isomer of warfarin. Clinically significant interactions of lansoprazole with these drugs in vivo have not been demonstrated Therapeutic Uses Inhibitors of H+,K+-ATPase ( proton pump inhibitors ) promote healing of : Ulcers in the stomach, duodenum, and esophagus. They are of particular value in the treatment of patients who do not respond adequately to H2 receptor antagonists, especially those with Zollinger-Ellison syndrome Peptic Ulcers and Reflux Esophagitis. Omeprazole (20 mg/day) produces relief of symptoms and healing in about 90% of patients with duodenal ulcer in 4 weeks. Lansoprazole (15 to 30 mg daily) produces similar effects. In treating gastric ulcer, higher daily doses (40 mg) of omeprazole produce healing in about 90% of patients in 8 weeks. Omeprazole frequently is effective in healing peptic ulcers that are unresponsive to H2 antagonists. Relapse is a problem when therapy is discontinued, and low-dose maintenance therapy, e.g., using 20 mg of omeprazole for 3 days each week, reduces recurrence of active disease. Overall, the rates of healing and relapse for omeprazole are roughly equivalent to those for the H2 receptor antagonists. As with the H2 receptor antagonists, concurrent treatment to eradicate H. pylori in infected patients is likely to contribute to reduced recurrence. Omeprazole is more effective than H2 receptor antagonists in treating gastroesophageal reflux, which may require long-term treatment. Typically, higher doses of omeprazole (20 to 60 mg daily) are used for this indication than for treatment of peptic ulcers. Lansoprazole has been shown to be effective in patients with reflux esophagitis who were not responsive to an H2 receptor antagonist. If the tone of the lower esophageal sphincter is reduced or if esophageal peristalsis is impaired, prokinetic agents such as metoclopramide or cisapride may be useful as a therapeutic strategy. Zollinger-Ellison Syndrome: The peptic and esophageal ulceration associated with gastrin-producing tumors is often difficult to treat. Omeprazole or lansoprazole is the treatment of choice for this condition. The goal of therapy is to reduce the basal secretion of acid to below 10 mEq per hour. This usually requires administration of at least 60 to 70 mg of omeprazole per day and from 15 mg every other day to 180 mg every day of lansoprazole. 90% of patients are controlled with daily doses of 120 mg. CAUTIONS Proton pump inhibitors should be used with caution in patients with liver disease, in pregnancy and in breast-feeding. Proton pump inhibitors may mask symptoms of gastric cancer; particular care is required in those whose symptoms change and in those over 45 years of age; the presence of gastric malignancy should be excluded before treatment. SIDE-EFFECTS Side-effects of the proton pump inhibitors include dry mouth, gastro-intestinal disturbances (including diarrhoea, nausea and vomiting, constipation, flatulence, abdominal pain), liver dysfunction, taste disturbance, hypersensitivity reactions (including rash, urticaria, angioedema, bronchospasm, anaphylaxis), peripheral oedema, depression, dizziness, drowsiness, headache, insomnia, fever, haematological changes (including agranulocytosis, leucocytosis, leucopenia, pancytopenia, thrombocytopenia), interstitial nephritis, muscle and joint pain, blurred vision, photosensitivity, pruritus, severe skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis,

bullous eruption), sweating, malaise. Proton pump inhibitors decrease gastric acidity and may increase the risk of gastro-intestinal infections.

Omeprazole
DEFINITION Omeprazole sodium contains not less than 98.0 per cent and not more than the equivalent of 101.0 per cent of sodium (RS)-5-methoxy-2-[[ (4-methoxy 3,5 dimethylpyridin -2-yl)methyl] sulphinyl] 1H- benzimidazole , calculated with reference to the anhydrous substance. CHARACTERS A white or almost white powder, hygroscopic, freely soluble in water and in alcohol, soluble in propylene glycol, very slightly soluble in methylene chloride.

Prilosec
Classification Gastrointestinal Agents. Antiulcer Agents. Prescription only. Pregnancy category C.
Description: Omeprazole is an oral anti ulcer agent. It is indicated in the treatment of gastro esophageal reflux disease, gastric and duodenal ulcers, and gastric hyper secretory conditions including Zollinger- Ellison syndrome, systemic mastocytosis, and multiple endocrine adenoma. Omeprazole belongs to a new class of anti secretory agents, the substituted benzimidazoles, which suppress gastric acid secretion by inhibiting the H+/K+ ATPase enzyme system of parietal cells. Unlike other anti ulcer agents, omeprazole does not antagonize H or cholinergic receptors. Omeprazole has a long duration of action and a high level of potency, allowing for once-daily administration. Investigations are currently underway to assess the efficacy of omeprazole in combination with either amoxicillin or clarithromycin for the treatment of peptic ulcer disease. Omeprazole was approved by the FDA in September 1989. Mechanism of Action: Following activation in an acidic pH, omeprazole binds irreversibly to the H+/K+ ATPase pump on the secretory surface of the parietal cell membrane. Subsequently, the secretion of hydrogen ions into the gastric lumen is inhibited. Omeprazole is characterized as a gastric acid pump inhibitor because it blocks the final step of gastric acid production. It inhibits both basal

and stimulus-induced acid secretion. Omeprazole is an extremely potent drug. Intragastric pH of patients receiving omeprazole is often higher and affected longer than during therapy with H2antagonists. Omeprazole is also more effective than either H2-antagonists or sucralfate in the treatment of gastro esophageal reflux disease (GERD). Serum gastrin levels increase during the initial 12 weeks of therapy, and median increases in gastrin are greater than the increases produced by H2-receptor antagonists. Gastrin levels return to baseline within 12 weeks following discontinuance of therapy. Gastrin levels in patients with Zollinger- Ellison syndrome are not affected. Animal data suggest that prolonged elevations of serum gastrin may be associated with tumors. Finally, omeprazole also inhibits the hepatic cytochrome P-450 oxidase system (see Drug Interactions). Pharmacokinetics: Omeprazole is administered orally and should be taken prior to meals, preferably in the morning. Omeprazole is enteric-coated, and absorption begins only after the granules have passed through the stomach. Due to a significant first-pass effect, bioavailability following oral doses of 2040 mg is 30 40%, but it may approach 100% in patients with hepatic impairment. The drug is rapidly absorbed following oral administration and distributes throughout the body tissues, concentrating in the gastric parietal cells. It is not known if it crosses the placenta or is excreted into breast milk (see Contraindications). The drugs onset of action is 1 hour, and the duration of inhibition is greater than 72 hours. Omeprazole is 95% bound to plasma proteins. Extensive hepatic metabolism occurs, and the metabolites have minimal anti secretory activity. The plasma half-life in healthy patients is 0.51 hour, while the half-life in patients with chronic hepatic disease is approximately 3 hours. Secretory activity returns to normal 35 days after therapy is discontinued. Approximately 7280% of a dose is excreted renally, and 1823% is excreted in the feces. Indications Duodenal ulcer. multiple endocrine adenoma syndrome. esophagitis . systemic mastocytosis. gastric ulcer . Zollinger-Ellison syndrome. gastroesophageal reflux disease (GERD). Dosage: For the short-term treatment of or for long-term maintenence therapy of gastroesophageal reflux disease (GERD) or severe erosive esophagitis: Oral dosage: Adults: For treatment of acute disease, 20 mg PO once daily for 48 weeks. To prevent relapse, which occurs commonly, 20 mg PO once daily indefinitely. Children: Safety and efficacy in children have not been established. For the long-term treatment of gastric hypersecretory conditions, including ZollingerEllison syndrome, systemic mastocytosis, and multiple endocrine adenoma syndrome: Oral dosage: Adults: 60 mg PO given in single or multiple daily doses, adjusted as needed, and continued for as long as necessary. Maximum daily dose: 120 mg PO tid. Children: Safety and efficacy in children have not been established. For the short-term treatment of active gastric ulcer or active duodenal ulcer: Oral dosage: Adults: 20 mg PO once daily increased to 40 mg PO once daily if necessary for 48 weeks. Children: Safety and efficacy in children have not been established.

Contraindications/Precautions Pregnancy Breast-feeding Hepatic disease Gastric carcinoma Pregnancy Omeprazole is classified as pregnancy category C. It is not known whether this drug crosses the placenta. Omeprazole should be used during pregnancy only when clearly needed. Breast-feeding Omeprazole concentrations have been measured in breast milk of a woman following oral administration of 20 mg. The peak concentration of omeprazole in breast milk was less than 7% of the peak serum concentration. The concentration will correspond to 0.004 mg of omeprazole in 200 mL of milk. In rats, omeprazole administration during late gestation and lactation at doses of 13.8 to 138 mg/kg/day (about 5.6 to 56 times the human dose of 20 mg per day, based on body surface area) resulted in decreased weight gain in pups. Because omeprazole is excreted in human milk, because of the potential for serious adverse reactions in nursing infants from omeprazole, and because of the potential for tumorigenicity shown for omeprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In addition, sodium bicarbonate should be used with caution in nursing mothers. Hepatic disease: Omeprazole should be administered with caution to patients with hepatic disease since clearance of the drug can be prolonged. Dosage adjustments, however, are generally not needed. In addition, omeprazole has been associated with hepatitis and, in rare instances, hepatic failure. Gastric carcinoma Omeprazole decreases intragastric acidity. Subsequently, the number of bacteria in gastric secretions and, correspondingly, the amount of carcinogenic N-nitroso compounds produced by these bacteria increase. Long-term results of clinical studies involving patients with Zollinger-Ellison syndrome have shown a small increase in risk for gastric carcinomas; however, further research is needed. Also, it recently has been shown that omeprazole can cause malabsorption of vitamin B12.. Special Populations Geriatric The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly subjects, versus 58% in young subjects given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole and no unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of young subjects) and its plasma half-life averaged one hour, similar to that of young healthy subjects. Gender There are no known differences in the absorption or excretion of omeprazole between males and females. Hepatic insufficiency In patients with chronic hepatic disease, the bioavailability of omeprazole increased to approximately 100% compared to an I.V. dose, reflecting decreased first-pass effect, and the mean plasma half-life of the drug increased to nearly 3 hours compared to the mean half life of 1 hour in healthy subjects. Plasma clearance averaged 70 mL/min, compared to a value of 500-600 mL/min in normal subjects.

 Renal insufficiency In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73m 2 , the disposition of omeprazole was very similar to that in healthy volunteers, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. Asians In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of approximately four fold was noted in Asian subjects compared to Caucasians. Dose adjustment, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired and Asian subjects should be considered.

Drug Drug Interactions: Omeprazole has the following interaction information:

Adverse Reactions: Constipation Hepatitis Diarrhea Neutropenia Headache Pancytopenia Hemolysis Pernicious anemia Hepatic failure Thrombocytopenia Few adverse effects have been associated with omeprazole. Headache has been reported in 6.9% of patients. Frequently reported gastrointestinal disturbances include diarrhea (3%) and constipation (1.1%). Other GI effects, such as abdominal pain and nausea/vomiting, may not be statistically significant when compared with placebo. In rare instances, hematologic abnormalities have been reported during omeprazole therapy (<1%) and warrant medical attention. These effects include pancytopenia, hemolysis with anemia, leukocytosis, neutropenia, and thrombocytopenia. In a study of healthy volunteers, it was shown that omeprazole caused a significant reduction in cyanocobalamin (vitamin B12) absorption. Since neurologic manifestations can appear in the absence of hematologic changes, patients should be monitored for signs of pernicious anemia. Potential side effects Mild This medication can cause headache, diarrhea, or constipation. Side effects are uncommon and generally are mild. Consult your doctor if they are bothersome. Serious/limiting (notify your doctor immediately) Serious side effects are rare, occurring in 1% or fewer of patients, but they can include liver damage or anemia or other blood disorders. Contact your doctor immediately if you experience painful urination, blood in urine, unusual bleeding or bruising, shortness of breath, chest pain or tightness, skin rash, sore throat, or fever. Animal studies of omeprazole suggested an increased risk of developing stomach cancers after prolonged use, but there currently is no evidence of this problem in humans. Because of these risks, however, the drug is approved for use for only 8 weeks or less. Discuss this issue with your doctor if treatment beyond 8 weeks is needed. Over dosage Reports have been received of over dosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience. (See ADVERSE REACTIONS .) Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone. Over dosage No specific antidote for omeprazole over dosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of over dosage, treatment should be symptomatic and supportive. As with the management of any overdose, the possibility of multiple drug ingestion should be considered. Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were lethal to mice, rats, and

dogs, respectively. Animals given these doses showed sedation, ptosis, tremors, convulsions, and decreased activity, body temperature, and respiratory rate and increased depth of respiration. Product Identification Prilosec Capsules Merck & Co. Available as 20 mg of omeprazole in a sustained release formulation. 20 mg capsule hard gelatin purple "MSD 742" "PRILOSEC 20"

Esomeprazole

NEXIUM
DESCRIPTION The active ingredient in NEXIUM (esomeprazolemagnesium) Delayed-Release Capsules is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5- Dimethyl -2pyridinyl) methyl]sulfinyl]-1 H -benzimidazole-1-yl) magnesium trihydrate, a compound that inhibits gastric acid secretion. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers. Its empirical formula is (C 17 H 18 N 3 O 3 S) 2 Mg 3 H 2 O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis. The structural formula is: The magnesium salt is a white to slightly colored crystalline powder. It contains 3 moles of water of solvation and is slightly soluble in water.

Pantoprazole

PROTONIX delay
DESCRIPTION The active ingredient in PROTONIX (pantoprazole sodium) Delayed-Release Tablets & I.V. is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4 dimethoxy -2 pyridinyl) methyl] sulfinyl]-1 H benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical formula is C 16 H 14 F 2 N 3 NaO 4 S x 1.5 H 2 O, 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 nhexane.

PROTONIX I.V.
DESCRIPTION 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. Mechanism of Action: Pantoprazole is a proton pump inhibitor (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 anti secretory effect that persists longer than 24 hours for all doses tested

Pharmacokinetics: 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 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 g/mL and the total area under the plasma concentration versus time curve (AUC) is 5.4 g hr/mL. The total clearance is 7.6-14.0 L/h and the apparent volume of distribution is 11.0-23.6 L. Distribution The apparent volume of distribution of pantoprazole is approximately 11.0-23.6 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 Caucasians and African-Americans and 17-23% of Asians). Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values from 3.5 to 10.0 hours, they still have minimal accumulation (</=23%) with once daily dosing. Elimination After administration of a single intravenous dose of 14 C-labeled pantoprazole to healthy, normal metabolizer subjects, 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. Indications Treatment of Gastroesophageal Reflux Disease Associated With a History of Erosive Esophagitis PROTONIX I.V. for Injection is indicated for short-term treatment (7 to 10 days) of patients having gastroesophageal reflux disease (GERD) with a history of erosive esophagitis, as an alternative to oral

therapy in patients who are unable to continue taking PROTONIX (pantoprazole sodium) DelayedRelease Tablets. Safety and efficacy of PROTONIX I.V. for Injection as an initial treatment of patients having GERD with a history of erosive esophagitis have not been demonstrated. Pathological Hypersecretion Associated with Zollinger-Ellison Syndrome PROTONIX I.V. for Injection is indicated for the treatment of pathological hypersecretory conditions associated with Zollinger-Ellison Syndrome or other neoplastic conditions. Dosage& Administration : 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 resume treatment with PROTONIX Delayed-Release Tablets. Also, data on the safe and effective dosing for conditions other than those described in INDICATIONS 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. Treatment of Gastroesophageal Reflux Disease Associated With a History of Erosive Esophagitis The recommended adult dose, as an alternative to continued oral therapy 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 having GERD with a history of erosive esophagitis for more than 10 days have not been demonstrated (see INDICATIONS). Fifteen Minute Infusion PROTONIX I.V. for Injection should be reconstituted with 10 mL of 0.9% Sodium Chloride Injection, USP, and further diluted (admixed) with 100 mL of 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's Injection, USP, to a final concentration of approximately 0.4 mg/mL. The reconstituted solution may be stored for up to 2 hours at room temperature prior to further dilution; the admixed solution may be stored for up to 22 hours at room temperature prior to intravenous infusion. Both the reconstituted solution and the admixed solution do not need to be protected from light. PROTONIX I.V. for Injection admixtures should be administered intravenously over a period of approximately 15 minutes at a rate of approximately 7 mL/min.

Two Minute Infusion

PROTONIX I.V. for Injection should be reconstituted with 10 mL of 0.9% Sodium Chloride Injection, USP, to a final concentration of approximately 4 mg/mL. The reconstituted solution may be stored for up to 2 hours at room temperature prior to intravenous infusion and does not need to be protected from light. PROTONIX I.V. for Injection should be administered intravenously over a period of at least 2 minutes.

Pathological Hypersecretion Associated with Zollinger-Ellison Syndrome 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. 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. Fifteen Minute Infusion Each vial of PROTONIX I.V. for Injection should be reconstituted with 10 mL of 0.9% Sodium Chloride Injection, USP. The contents of the two vials should be combined and further diluted (admixed) with 80 mL of 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's Injection, USP, to a total volume of 100 mL with a final concentration of approximately 0.8 mg/mL. The reconstituted solution may be stored for up to 2 hours at room temperature prior to further dilution; the admixed solution may be stored for up to 22 hours at room temperature prior to intravenous infusion. Both the reconstituted solution and the admixed solution do not need to be protected from light. PROTONIX I.V. for Injection should be administered intravenously over a period of approximately 15 minutes at a rate of approximately 7 mL/min. Two Minute Infusion PROTONIX I.V. for Injection should be reconstituted with 10 mL of 0.9% Sodium Chloride Injection, USP, pervial to a final concentration of approximately 4 mg/mL. The reconstituted solution may be stored for up to 2 hours at room temperature prior to intravenous infusion and does not need to be protected from light. The total volume from both vials should be administered intravenously over a period of at least 2 minutes. Over dosage 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 were lethal to mice, rats and dogs, respectively. The symptoms of acute toxicity were hypo activity, ataxia, hunched sitting, limb-splay, lateral position, segregation, absence of ear reflex, and tremor. Drug-Drug Interactions 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, 2C9, 2D6 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.

Special Populations
Geriatric After repeated I.V. administration in elderly subjects (65 to 76 years of age), pantoprazole AUC and elimination half-life values were similar to those observed in younger subjects. No dosage adjustment is recommended based on age. Pediatric The pharmacokinetics of pantoprazole have not been investigated in patients <18 years of age. Gender After oral administration there is a modest increase in pantoprazole AUC and C max in women compared to men. However, weight-normalized clearance values are similar in women and men. No dosage adjustment is warranted based on gender Renal Impairment In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole were similar to those of healthy subjects. No dosage adjustment is necessary in patients with renal impairment or in patients undergoing hemodialysis. Hepatic Impairment Oral administration studies (absolute bioavailability is approximately 70%) were performed in patients with mild to severe hepatic impairment. Maximum pantoprazole concentrations increased only slightly (1.5-fold) relative to healthy subjects. Although serum elimination 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 slow CYP2C19 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 equal to or less than 21%. No dosage adjustment is needed in patients with mild to severe hepatic impairment. Doses higher than 40 mg/day have not been studied in hepatically-impaired patients.

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

PRECAUTIONS General
Immediate hypersensitivity reactions: Anaphylaxis has been reported with use of intravenous pantoprazole. Thismay 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. 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 potentchelator of metal ions including zinc, zinc supplementation should be considered in patients treated withPROTONIX I.V. for Injection who are prone to zinc deficiency. Caution should be used when other EDTAcontaining products are also co-administered intravenously. Treatment with PROTONIX I.V. (pantoprazole sodium) for Injection should be discontinued as soon as thepatient is able to resume treatment with PROTONIX Delayed-Release Tablets.

Fig.1 Physiological and pharmacological regulation of gastric secretions: the basis for therapy of peptic ulcer disease. This schematic shows the interactions among an endocrine cell that secretes histamine (enterochromaffin-like [ECL] cell), an acid-secreting cell (parietal cell), and a cell that secretes the cytoprotective factors mucus and bicarbonate (superficial epithelial cell). Physiological pathways are in solid black and may be stimulated (+) or inhibited (-). Physiological agonists stimulate transmembrane receptors: muscarinic (M) and nicotinic (N) receptors for acetylcholine (ACh); G, gastrin receptor; H2, histamine (HIST) receptor; PG, prostaglandin E2 receptor. Actions of drugs are indicated by dashed lines. A blue X indicates a point of pharmacological antagonism. A light blue dashed line and arrow indicate a drug action that mimics or enhances a physiological pathway. Drugs currently used in treating peptic ulcer disease are shown in dark blue. NSAIDs are non steroidal anti inflammatory drugs such as aspirin and are ulcerogenic. (1) and (3) indicate possible input by cholinergic postganglionic fibers. (2) shows neural input from the vagus nerve.

Figure 2. Inhibitors of the gastric H+,K+-ATPase. A. Structures of lansoprazole and omeprazole. B. Mechanism of irreversible inhibition of H+,K+-ATPase by pump inhibitors. In the acidic environment of the parietal cell canaliculi, these "pro-drugs" are converted to sulfenamides that interact covalently with sulfhydryl groups in the extracellular (luminal) domain of the proton pump.

Figure 3. Inhibitory effect of omeprazole on secretion of gastric acid. Maximal secretory responses were elicited in healthy human beings by infusing pentagastrin over a 1hour period before and at various intervals after a single oral dose of omeprazole. Note the profound and prolonged inhibition.