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pantoprazole sod dr 40 mg tab (generic protonix)

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Uses

Gastroesophageal Reflux

Pantoprazole sodium is used orally for the short-term (up to 8 weeks) treatment and symptomatic relief of erosive esophagitis in patients with gastroesophageal reflux disease (GERD). Pantoprazole sodium also is used orally as maintenance therapy following healing of erosive esophagitis to reduce recurrence of the disease. Pantoprazole sodium is used IV for up to 7-10 days in the treatment of GERD in patients with a history of erosive esophagitis. IV pantoprazole should be discontinued as soon as the patient is able to initiate or resume treatment with oral pantoprazole. Potential benefits in gastroesophageal reflux and esophagitis result principally from reduced acidity of gastric contents induced by the drug and resultant reduced irritation of esophageal mucosa; the drug can effectively relieve symptoms of esophagitis (e.g., heartburn, regurgitation) and promote healing of ulcerative and erosive lesions.

Suppression of gastric acid secretion is considered by the American College of Gastroenterology (ACG) to be the mainstay of treatment for GERD, and a proton-pump inhibitor or histamine H2-receptor antagonist is used to achieve acid suppression, control symptoms, and prevent complications of the disease. Because GERD is considered to be a chronic disease, the ACG states that many patients with GERD require long-term, even lifelong, treatment. The ACG states that proton-pump inhibitors are more effective (i.e., provide more frequent and more rapid symptomatic relief and healing of esophagitis) than histamine H2-receptor antagonists in the treatment of GERD, and are effective and appropriate as maintenance therapy in many patients with the disease. Proton-pump inhibitors also provide greater control of acid reflux than do prokinetic agents (e.g., cisapride [no longer commercially available in the US], metoclopramide) without the risk of severe adverse effects associated with these agents.

Safety and efficacy of oral pantoprazole for treating GERD and erosive esophagitis (grade 2 or greater on the Hetzel-Dent scale) were established in 2 short-term (up to 8 weeks), controlled studies in adults; pantoprazole was more effective than placebo or nizatidine in healing lesions and providing symptomatic relief. In other studies, pantoprazole was more effective than famotidine or ranitidine and at least as effective as omeprazole.

Safety and efficacy of oral pantoprazole as maintenance therapy following healing of erosive esophagitis were established in two 12-month controlled studies in adults. Pantoprazole (40 mg daily) was more effective than ranitidine (150 mg twice daily) in maintaining healing and decreasing the number of daytime and nocturnal heartburn episodes.

Safety and efficacy of IV pantoprazole for short-term (up to 7-10 days) use in the treatment of GERD in patients with a history of erosive esophagitis have been established in several studies. In a controlled study in adults receiving oral pantoprazole prior to study entry, the degree of inhibition of gastric acid secretion following substitution of IV pantoprazole (40 mg once daily for 7 days) was similar to that achieved following oral administration of the drug at the same daily dosage. In 2 controlled studies evaluating short-term (up to 7 days) use of IV pantoprazole as initial treatment for GERD in adults, the degree of inhibition of gastric acid secretion following IV administration of pantoprazole 40 mg once daily was similar to that achieved following oral administration of pantoprazole at the same daily dosage. In addition, relief of GERD symptoms and healing of esophageal lesions were comparable for IV and oral administration of pantoprazole.

Safety and efficacy of IV pantoprazole use for more than 10 days have not been established.

For further information on the treatment of GERD,

Pathologic GI Hypersecretory Conditions

Pantoprazole sodium is used orally or IV for the treatment of pathologic GI hypersecretory conditions associated with Zollinger-Ellison syndrome or other neoplastic conditions. The drug reduces the volume of gastric acid output and hydrogen ion concentration of gastric secretions in patients with these conditions.

In an uncontrolled study in a limited number of patients with pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome with or without multiple endocrine neoplasia type I), oral administration of pantoprazole at dosages of 80-240 mg daily maintained gastric acid secretion below 5 or 10 mEq/hour in patients who had or had not undergone gastric acid-reducing surgery, respectively. The drug was well tolerated at these dosages for more than 2 years in some patients.

Administration of IV pantoprazole in a limited number of patients with Zollinger-Ellison syndrome (with or without multiple endocrine neoplasia type I) resulted in control of gastric acid secretion to 10 mEq/hour or less with substantial reductions in hydrogen ion concentration and volume of gastric secretions within 45 minutes of drug administration. In another study, control of gastric acid secretion was maintained or improved in a limited number of patients switched from an oral proton-pump inhibitor to IV pantoprazole. In both studies, IV pantoprazole 160 or 240 mg daily in divided doses for up to 6 days maintained basal gastric acid secretion below target levels (10 mEq/hour in patients without or 5 mEq/hour in those with prior gastric acid-reducing surgery) for at least 24 hours in all patients and through the end of treatment (3-7 days) in nearly all patients. Dosage was individualized in both studies, but a regimen of 80 mg every 12 hours controlled gastric acid secretion in more than 80% of patients. There was no evidence of tolerance once acid secretion was controlled.

Crohn's Disease-associated Ulcers

Although evidence currently is limited, proton-pump inhibitors have been used for gastric acid-suppressive therapy as an adjunct in the symptomatic treatment of upper GI Crohn's disease, including esophageal, gastroduodenal, and jejunoileal disease. Most evidence of efficacy to date has been from case studies in patients with Crohn's-associated peptic ulcer disease unresponsive to other therapies (e.g., H2-receptor antagonists, cytoprotective agents, antacids, and/or sucralfate).

For further information on the management of Crohn's Disease,

Other Uses

Pantoprazole also has been used orally for treatment of gastric or duodenal ulcers. The recommended dosage of IV pantoprazole does not raise gastric pH sufficiently to contribute to the treatment of some conditions (e.g., life-threatening GI bleeding), and the drug's safety and efficacy in the treatment of conditions other than GERD or pathologic GI hypersecretory conditions associated with Zollinger-Ellison syndrome or other neoplastic conditions have not been established.

Dosage and Administration

Reconstitution and Administration

Pantoprazole sodium is administered orally or IV; the drug is not intended for other parenteral routes of administration. Pantoprazole is administered once daily in the management of gastroesophageal reflux disease (GERD) and erosive esophagitis; in the management of pathologic GI hypersecretory conditions, pantoprazole generally is given twice daily, although the drug may be given IV every 8 hours if necessary.

For the treatment of GERD, one vial of pantoprazole sodium for injection should be reconstituted with 10 mL of 0.9% sodium chloride injection to provide a solution containing about 4 mg/mL of pantoprazole; the reconstituted solution may be stored for up to 24 hours at room temperature and does not need to be protected from light prior to IV injection over not less than 2 minutes. Alternatively, the reconstituted solution may be stored for up to 6 hours at room temperature prior to further dilution with 100 mL of 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection to provide a final concentration of about 0.4 mg/mL. The diluted solution may be stored at room temperature but must be used within 24 hours after initial reconstitution. Neither the reconstituted nor diluted solution needs to be protected from light. The diluted solution may be infused IV over a period of about 15 minutes (about 2.7 mg of the drug or 7 mL of solution per minute).

For the treatment of hypersecretory conditions, each of two 40-mg (of pantoprazole) vials of pantoprazole sodium for injection should be reconstituted with 10 mL of 0.9% sodium chloride injection; the total volume (approximately 20 mL) of reconstituted solution may be stored for up to 24 hours at room temperature and does not need to be protected from light prior to IV injection over not less than 2 minutes. Alternatively, the contents of both vials may be combined and stored for up to 6 hours at room temperature prior to further dilution with 80 mL of 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection to a final volume of about 100 mL, providing a final concentration of about 0.8 mg/mL. The diluted solution may be stored at room temperature but must be used within 24 hours after initial reconstitution. Neither the reconstituted nor diluted solution needs to be protected from light. The diluted solution may be infused IV over a period of about 15 minutes (about 5.3 mg of the drug or 7 mL of solution per minute).

Health-care personnel (e.g., pharmacists, nurses) preparing reconstituted solutions using spiked IV system adapters should use caution because of the potential for breakage of the glass vial.(See Glass Vial Breakage under Cautions: Warnings/Precautions.)

Pantoprazole sodium should be administered IV through a dedicated IV line or via a Y-site. Parenteral pantoprazole sodium solutions should be inspected visually for particulate matter and discoloration prior to and during administration whenever solution and container permit. Pantoprazole sodium for injection is incompatible by Y-site administration with midazolam hydrochloride injection and may be incompatible with solutions containing zinc. Y-site administration of IV pantoprazole should be discontinued immediately if precipitation or discoloration occurs.

Pantoprazole sodium delayed-release tablets should be swallowed intact and not split, crushed, or chewed. For patients unable to swallow the 40-mg tablets, a 40-mg dose may be administered using two 20-mg tablets. Food may delay the rate but does not affect the extent of GI absorption of the tablets; therefore, pantoprazole delayed-release tablets may be administered without regard to meals. Antacids do not affect the absorption of pantoprazole and may be administered concomitantly with the delayed-release tablets.

Pantoprazole delayed-release oral suspension should be administered 30 minutes before a meal. Pantoprazole sodium delayed-release granules for oral suspension should be mixed with applesauce or apple juice prior to administration; the granules should not be mixed with any other foods or liquids (including water). The delayed-release granules in the suspension should be swallowed intact and not crushed or chewed. The contents of a single-dose packet of pantoprazole sodium delayed-release granules for oral suspension should be sprinkled onto one teaspoonful of applesauce and administered within 10 minutes of preparation. After swallowing the pantoprazole and applesauce mixture, the patient should take sips of water, repeated as necessary, to ensure complete delivery of the dose. Alternatively, the contents of a single-dose packet may be sprinkled into 5 mL of apple juice; the resulting suspension should be stirred for 5 seconds and then swallowed immediately. The granules will not dissolve. The container should be rinsed once or twice with apple juice and the rinsings swallowed immediately to ensure complete delivery of the dose. The contents of a packet of delayed-release granules for oral suspension should not be divided to prepare a dose that is smaller than the full labeled dose (e.g., a 40-mg packet should not be used to prepare a 20-mg dose for a pediatric patient who is unable to swallow the delayed-release tablets).

Pantoprazole delayed-release oral suspension also can be administered via a nasogastric or gastrostomy tube (16 French or larger). The plunger should be removed from a 60-mL syringe and the catheter tip of the syringe attached to the nasogastric or gastrostomy tube; then, the contents of a single-dose packet of pantoprazole sodium delayed-release granules for oral suspension should be emptied into the barrel of the syringe while the syringe is held as high as possible to prevent bending of the tubing. A volume of 10 mL of apple juice should be added to the syringe and the syringe gently tapped or shaken to facilitate emptying; the syringe and tubing should be rinsed with 10 mL of apple juice at least 2 more times (until no granules remain).

For the treatment of pathologic hypersecretory conditions associated with Zollinger-Ellison syndrome or other neoplastic conditions, pantoprazole sodium for injection is administered IV every 8 or 12 hours. The frequency of administration may be individualized based on acid output measurements. Patients with Zollinger-Ellison syndrome may be vulnerable to serious complications of increased gastric acid secretion, even after a brief loss of gastric acid suppression. Therefore, transition from oral to IV and IV to oral formulations of gastric acid inhibitors should be performed in such a manner to ensure continuity of gastric acid suppression effects.

Dosage

Dosage of pantoprazole sodium is expressed in terms of pantoprazole.

Gastroesophageal Reflux

For the treatment of erosive esophagitis associated with GERD, the recommended adult oral dosage of pantoprazole is 40 mg daily. The duration of therapy is 8 weeks, and therapy may be extended for an additional 8 weeks if esophageal healing is incomplete. For maintenance therapy following healing of erosive esophagitis, the recommended adult oral dosage of pantoprazole is 40 mg once daily. Although the American College of Gastroenterology (ACG) states that chronic, even lifelong, therapy with a proton-pump inhibitor is appropriate in many patients with GERD, the manufacturer states that the safety and efficacy of continuing pantoprazole maintenance therapy for more than 1 year has not been established.

For the treatment of GERD associated with a history of erosive esophagitis, the recommended adult IV dosage of pantoprazole is 40 mg once daily. Treatment with IV pantoprazole should be discontinued as soon as the patient is able to initiate or resume treatment with the oral drug; safety and efficacy of IV pantoprazole use for more than 10 days have not been established.

For the treatment of erosive esophagitis associated with GERD in children 5 years of age or older, the recommended oral dosage of pantoprazole is 20 mg once daily in children weighing at least 15 kg but less than 40 kg and 40 mg once daily in children weighing 40 kg or more. Treatment may be continued for up to 8 weeks; safety beyond 8 weeks has not been established in pediatric patients.

Pathologic GI Hypersecretory Conditions

For the treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine neoplasia type I), the recommended adult oral dosage of pantoprazole is 40 mg twice daily. Dosages should be individualized and continued for as long as clinically necessary. Oral dosages up to 240 mg daily have been administered, and some patients have received the drug for more than 2 years.

The recommended adult IV dosage of pantoprazole for the treatment of pathologic GI hypersecretory conditions is 80 mg administered IV every 12 hours. In patients requiring a higher daily dosage, 80 mg administered IV every 8 hours is expected to maintain acid output below 10 mEq/hour. Safety and efficacy of dosages exceeding 240 mg daily, and use of IV pantoprazole for longer than 6 days have not been established.

Special Populations

Dosage adjustment is not necessary in patients with renal impairment, patients undergoing hemodialysis, patients with hepatic impairment, or in geriatric patients. However, dosages exceeding 40 mg daily have not been studied in patients with hepatic impairment.

Reduction of pantoprazole dosage should be considered in pediatric patients who are poor metabolizers of cytochrome P-450 (CYP) 2C19 substrates, since exposure to the drug is increased by more than sixfold compared with that in extensive or moderate metabolizers. However, no dosage adjustment is required in adults who are poor metabolizers of CYP2C19 substrates, since minimal (23% or less) accumulation of the drug occurs with once-daily dosing.

Cautions

Contraindications

Known hypersensitivity to pantoprazole, any other ingredient in the formulation, or other substituted benzimidazoles (e.g., esomeprazole, lansoprazole, omeprazole, rabeprazole).

Warnings/Precautions

Sensitivity Reactions

Anaphylaxis has been reported with the use of IV pantoprazole sodium. Immediate medical intervention and drug discontinuance are required if anaphylaxis or other severe hypersensitivity reaction occurs.

Gastric Malignancy

Symptomatic response to therapy with pantoprazole does not preclude the presence of gastric neoplasm. Because of the chronic nature of the disease, there may be a potential for prolonged administration of pantoprazole in patients with gastroesophageal reflux disease (GERD); in long-term animal studies, pantoprazole caused rare types of GI tumors, although the relevance of these findings to humans is unknown.

Atrophic Gastritis

Atrophic gastritis occasionally has been noted in gastric corpus biopsy specimens from patients receiving long-term treatment with pantoprazole, especially those infected with Helicobacter pylori.

Clostridium difficile Infection

Available data suggest a possible association between use of proton-pump inhibitors and risk of Clostridium difficile infection, including C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis). In most observational studies to date, the risk of C. difficile infection in patients exposed to proton-pump inhibitors has ranged from 1.4-2.75 times that in patients not exposed to proton-pump inhibitors; however, some observational studies have found no increase in risk. Although many of the cases occurred in patients who had other risk factors for CDAD, including advanced age, comorbid conditions, and/or use of broad-spectrum anti-infectives, the US Food and Drug Administration (FDA) concluded that a contributory role for proton-pump inhibitors could not be definitively ruled out. The mechanism by which proton-pump inhibitors might increase the risk of CDAD has not been elucidated. Although it has been suggested that reduction of gastric acidity by gastric antisecretory agents might facilitate colonization with C. difficile, some studies have raised questions about this proposed mechanism or have suggested that the observed association is the result of confounding with other risk factors for CDAD. FDA also is reviewing the risk of CDAD in patients exposed to histamine H2-receptor antagonists.

CDAD can be serious in patients who have one or more risk factors for C. difficile infection and are receiving concomitant therapy with a proton-pump inhibitor; colectomy and, rarely, death have been reported. FDA recommends that patients receive proton-pump inhibitors at the lowest effective dosage and for the shortest possible time appropriate for their clinical condition. Patients experiencing persistent diarrhea should be evaluated for CDAD and should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.

Musculoskeletal Effects

Findings from several observational studies suggest that therapy with proton-pump inhibitors, particularly in high dosages (i.e., multiple daily doses) and/or for prolonged periods of time (i.e., one year or longer), may be associated with an increased risk of osteoporosis-related fractures of the hip, wrist, or spine. The magnitude of risk is unclear; causality has not been established. FDA is continuing to evaluate this safety concern. Although controlled studies are required to confirm these findings, patients should receive proton-pump inhibitors at the lowest effective dosage and for the shortest possible time appropriate for their clinical condition. Individuals who are at risk for osteoporosis-related fractures should receive an adequate intake of calcium and vitamin D and should have their bone health assessed and managed according to current standards of care.

Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients receiving long-term therapy (for at least 3 months or, in most cases, for longer than one year) with proton-pump inhibitors, including pantoprazole. Clinically serious adverse effects associated with hypomagnesemia, which are similar to manifestations of hypocalcemia, include tetany, seizures, tremors, carpopedal spasm, arrhythmias (e.g., atrial fibrillation, supraventricular tachycardia), and abnormal QT interval. Other reported adverse effects include paresthesia, muscle weakness, muscle cramps, lethargy, fatigue, and unsteadiness. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuance of the proton-pump inhibitor. Following discontinuance of the proton-pump inhibitor, hypomagnesemia resolved within a median of one week; upon rechallenge, hypomagnesemia recurred within a median of 2 weeks.

In patients expected to receive long-term therapy with a proton-pump inhibitor or in those receiving a proton-pump inhibitor concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), clinicians should consider measurement of serum magnesium concentrations prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter. (.)

Cyanocobalamin Malabsorption

Hypochlorhydria or achlorhydria resulting from daily treatment with acid-suppressive drugs over a long period (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin. Cyanocobalamin deficiency has been reported rarely. The possibility of such malabsorption should be considered if manifestations of cyanocobalamin deficiency occur.

Injection Site Reactions

Injection site reactions, including thrombophlebitis and abscess, have been associated with IV administration of pantoprazole.

Edetate Disodium Content

Pantoprazole sodium for injection contains edetate disodium (disodium EDTA), which is a potent metal ion (e.g., zinc) chelator. Zinc supplementation should be considered during IV pantoprazole therapy in patients who are prone to zinc deficiency and caution should be exercised when IV pantoprazole is used concomitantly with other IV preparations that contain edetate disodium.

Laboratory Test Interferences

Cannabinoid Tests

False-positive results for urine screening tests for tetrahydrocannabinol (THC) have been reported in patients receiving proton-pump inhibitors, including pantoprazole. An alternative confirmatory test should be considered to verify positive urine THC screening results in these patients.

Respiratory Effects

Administration of proton-pump inhibitors has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia). For further precautionary information about this adverse effect,

Glass Vial Breakage

The manufacturer and the US Food and Drug Administration (FDA) have received reports of glass vial breakage during attempts to connect pantoprazole sodium vials to spiked IV system adapters. Such breakage may be a safety issue for health-care personnel (e.g., pharmacists, nurses) attempting to connect these system components either manually or with mechanical assistance, but is not considered by the manufacturer to be a quality issue for pantoprazole sodium for injection. Although the manufacturer is reviewing the use of pantoprazole sodium vials with such systems in order to understand the problem, the manufacturer has not performed studies with these systems to date and currently does not recommend use of spiked IV system adapters with pantoprazole sodium vials. The manufacturer of pantoprazole sodium states that if a decision is made to use spiked adapters, the manufacturer of the adapters should be contacted to provide assistance.

Specific Populations

Pregnancy

Category B.

Lactation

Pantoprazole is distributed into milk; discontinue nursing or the drug because of potential risk in nursing infants.

Pediatric Use

Efficacy and safety of oral pantoprazole for short-term treatment of erosive esophagitis associated with GERD in pediatric patients 1-16 years of age are supported by controlled clinical trials in adults and additional safety, efficacy, and pharmacokinetic studies in pediatric patients. However, because an appropriate dosage formulation is not available for children younger than 5 years of age, oral pantoprazole is labeled for use only in children 5 years of age or older. Safety and efficacy of oral pantoprazole for uses other than treatment of erosive esophagitis have not been established in pediatric patients.

Oral pantoprazole was evaluated in several clinical trials in pediatric patients 1-16 years of age with endoscopically diagnosed or symptomatic GERD, including a limited number of patients with endoscopically diagnosed erosive esophagitis. Because these clinical trials had no placebo or active comparator group and provided no evidence of a dose-related response to the pantoprazole dosages studied, the results were inconclusive regarding efficacy of pantoprazole for the treatment of symptomatic GERD in pediatric patients. Adverse effects reported in more than 4% of patients included upper respiratory tract infection, headache, fever, diarrhea, vomiting, rash, and abdominal pain. Following oral administration of a single 40-mg dose of pantoprazole, exposure to the drug was about 39% higher in children 6-11 years of age and about 10% higher in adolescents 12-16 years of age compared with adults.

Efficacy of oral pantoprazole in infants younger than 1 year of age has not been established. In a treatment-withdrawal study in infants 1-11 months of age with symptomatic GERD, pantoprazole was not more effective than placebo.

Safety and efficacy of IV pantoprazole in pediatric patients have not been established.

Geriatric Use

There are no substantial differences in safety and efficacy relative to younger adults. No dosage adjustment is necessary in geriatric patients.

Common Adverse Effects

Adverse effects occurring in more than 2% of patients receiving oral pantoprazole and reported more frequently with pantoprazole than with placebo include headache, diarrhea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia.

Adverse effects occurring in more than 1% of patients receiving IV pantoprazole and that generally had an unclear relationship to the drug include headache, injection site reaction (including thrombophlebitis and abscess), abdominal pain, constipation, dyspepsia, nausea, diarrhea, insomnia, dizziness, and rhinitis.

Drug Interactions

Drugs Affecting Hepatic Microsomal Isoenzymes

Pharmacokinetic interaction unlikely. Pantoprazole is extensively metabolized, mainly via hepatic cytochrome P-450 (CYP) 2C19 isoenzyme; CYP3A4, CYP2D6, and CYP2C9 isoenzymes metabolize the drug to a much lesser extent. However, no clinically important drug interactions between pantoprazole and other drugs metabolized by the same isoenzymes were identified in clinical studies. Pantoprazole may have a lower potential for drug interactions than lansoprazole, omeprazole, and rabeprazole.

Drugs that Cause Hypomagnesemia

Potential pharmacologic interaction (possible increased risk of hypomagnesemia). In patients receiving diuretics (i.e., loop or thiazide diuretics) or other drugs that may cause hypomagnesemia, monitoring of magnesium concentrations should be considered prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter.(See Hypomagnesemia under Cautions: Warnings/Precautions.)

Gastric pH-Dependent Drugs

Pharmacokinetic interaction theoretically possible when pantoprazole is used concomitantly with gastric pH-dependent drugs (e.g., ampicillin esters, iron salts, ketoconazole); increased or decreased drug absorption at increased gastric pH values.

Antiretroviral Agents

Atazanavir

Potential pharmacokinetic interaction with atazanavir (possible altered oral absorption of atazanavir at increased gastric pH, resulting in decreased plasma atazanavir concentrations). Concomitant use of omeprazole 40 mg once daily and atazanavir (with or without low-dose ritonavir) results in a substantial decrease in plasma concentrations of atazanavir and possible loss of the therapeutic effect of the antiretroviral agent or development of drug resistance. The manufacturer of pantoprazole states that concomitant use with atazanavir is not recommended. If atazanavir is administered in a treatment-naive patient receiving a proton-pump inhibitor, a ritonavir-boosted regimen of 300 mg of atazanavir once daily with ritonavir 100 mg once daily with food is recommended. The dose of the proton-pump inhibitor should be administered approximately 12 hours before ritonavir-boosted atazanavir; the dose of the proton-pump inhibitor should not exceed omeprazole 20 mg daily (or equivalent). Concomitant use of proton-pump inhibitors with atazanavir is not recommended in treatment-experienced patients.

Fosamprenavir

Concomitant use of esomeprazole with fosamprenavir (with or without ritonavir) did not substantially affect concentrations of amprenavir (active metabolite of fosamprenavir). No dosage adjustment is required when proton-pump inhibitors are used concomitantly with fosamprenavir (with or without ritonavir).

Lopinavir

Concomitant use of omeprazole with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) did not have a clinically important effect on plasma concentrations or area under the concentration-time curve (AUC) of lopinavir. No dosage adjustment is required when proton-pump inhibitors are used concomitantly with lopinavir/ritonavir.

Nelfinavir

Potential pharmacokinetic interaction (decreased plasma nelfinavir concentrations). Concomitant use of omeprazole 40 mg once daily (given 30 minutes before a nelfinavir dose) and nelfinavir 1.25 g twice daily decreased peak plasma concentrations and AUCs of nelfinavir by 37 and 36%, respectively, and of its major active metabolite M8 by 89 and 92%, respectively. The manufacturer of pantoprazole states that concomitant use of proton-pump inhibitors with nelfinavir is not recommended.

Raltegravir

Pharmacokinetic interaction with omeprazole (substantially increased peak plasma concentration and AUC of raltegravir); however, no dosage adjustment is recommended when proton-pump inhibitors are used concomitantly with raltegravir.

Rilpivirine

Pharmacokinetic interaction with omeprazole (decreased plasma concentrations and AUC of rilpivirine). Concomitant use of other proton-pump inhibitors also may result in decreased plasma concentrations of rilpivirine. Concomitant use of rilpivirine and proton-pump inhibitors is contraindicated.

Saquinavir

Potential pharmacokinetic interaction (increased peak plasma concentration and AUC of saquinavir). Concomitant use of omeprazole 40 mg once daily and ritonavir-boosted saquinavir (saquinavir 1 g twice daily and ritonavir 100 mg twice daily) increased the peak plasma concentration and AUC of saquinavir by 75 and 82%, respectively. Caution is advised if proton-pump inhibitors are used concomitantly with ritonavir-boosted saquinavir, and patients should be monitored for saquinavir toxicity.

Clopidogrel

Potential pharmacokinetic interaction (decreased plasma concentration of the active metabolite of clopidogrel) and pharmacodynamic interaction (reduced antiplatelet effects) between proton-pump inhibitors and clopidogrel. Clopidogrel is metabolized to its active metabolite by cytochrome P-450 (CYP) isoenzyme 2C19 (CYP2C19). Concurrent use of omeprazole or esomeprazole, which inhibit CYP2C19, with clopidogrel reduces exposure to the active metabolite of clopidogrel and decreases platelet inhibitory effects. Although the clinical importance has not been fully elucidated, a reduction in the effectiveness of clopidogrel in preventing cardiovascular events is possible. Proton-pump inhibitors vary in their potency for inhibiting CYP2C19. The change in inhibition of adenosine diphosphate (ADP)-induced platelet aggregation associated with concomitant use of proton-pump inhibitors is related to the change in exposure to the active metabolite of clopidogrel. In pharmacokinetic and pharmacodynamic studies in healthy individuals, concomitant use of dexlansoprazole, lansoprazole, or pantoprazole had less effect on the antiplatelet activity of clopidogrel than did concomitant use of omeprazole or esomeprazole. Use of pantoprazole (80 mg daily, administered at the same time as clopidogrel) concomitantly with clopidogrel (300-mg loading dose followed by 75 mg daily) for 5 days reduced exposure to the active metabolite of clopidogrel by about 14% compared with use of clopidogrel alone. The observed effects of pantoprazole on metabolite exposure and clopidogrel-induced platelet inhibition were not considered clinically important, and the manufacturer of pantoprazole states that no adjustment of clopidogrel dosage is necessary if clopidogrel is used concomitantly with recommended dosages of pantoprazole.

The decision to use a proton-pump inhibitor concomitantly with clopidogrel should be based on the assessed risks and benefits in individual patients. The American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) states that the reduction in GI bleeding risk with proton-pump inhibitors is substantial in patients with risk factors for GI bleeding (e.g., advanced age; concomitant use of warfarin, corticosteroids, or nonsteroidal anti-inflammatory agents [NSAIAs]; H. pylori infection) and may outweigh any potential reduction in the cardiovascular efficacy of antiplatelet treatment associated with a drug-drug interaction. In contrast, ACCF/ACG/AHA states that patients without such risk factors receive little if any absolute risk reduction from proton-pump inhibitor therapy, and the risk/benefit balance may favor use of antiplatelet therapy without a proton-pump inhibitor in these patients.

If concomitant therapy with a proton-pump inhibitor and clopidogrel is considered necessary, use of an agent with little or no CYP2C19-inhibitory activity should be considered. Alternatively, treatment with a histamine H2-receptor antagonist (ranitidine, famotidine, nizatidine) may be considered, although such agents may not be as effective as a proton-pump inhibitor in providing gastric protection; cimetidine should not be used since it also is a potent CYP2C19 inhibitor. There currently is no evidence that histamine H2-receptor antagonists (other than cimetidine) or other drugs that reduce gastric acid (e.g., antacids) interfere with the antiplatelet effects of clopidogrel. For further information on interactions between proton-pump inhibitors and clopidogrel, .

Digoxin

Hypomagnesemia (e.g., resulting from long-term use of proton-pump inhibitors) sensitizes the myocardium to digoxin and, thus, may increase the risk of digoxin-induced cardiotoxic effects. In patients receiving digoxin, monitoring of magnesium concentrations should be considered prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter.

Methotrexate

Potential pharmacokinetic interaction (increased serum methotrexate concentrations, possibly resulting in toxicity) when proton-pump inhibitors, including pantoprazole, are used concomitantly with methotrexate. Increased serum concentrations and delayed clearance of methotrexate and/or its metabolite hydroxymethotrexate, with or without symptoms of methotrexate toxicity, have been reported in patients receiving methotrexate (usually at doses of 300 mg/m to 12 g/m) concomitantly with a proton-pump inhibitor. Although most of the reported cases occurred in patients receiving high doses of methotrexate, toxicity also has been reported in patients receiving low dosages of methotrexate (e.g., 15 mg per week) concomitantly with a proton-pump inhibitor. No formal studies of interactions between high-dose methotrexate and proton-pump inhibitors have been conducted to date.

The manufacturer of pantoprazole states that temporary discontinuance of proton-pump inhibitor therapy may be considered in some patients receiving high-dose methotrexate therapy. Some clinicians recommend either withholding proton-pump inhibitor therapy for several days before and after methotrexate administration or substituting a histamine H2-receptor antagonist for the proton-pump inhibitor when acid suppressive therapy is indicated during methotrexate therapy. Pending further evaluation, some clinicians state that these recommendations should extend to patients receiving low-dose methotrexate.

Sucralfate

Potential delayed absorption and decreased bioavailability of proton-pump inhibitor (e.g., lansoprazole, omeprazole); administer proton-pump inhibitor at least 30 minutes before sucralfate.

Warfarin

Potential increased international normalized ratio (INR) and prothrombin time when warfarin is used concomitantly with proton-pump inhibitors, including pantoprazole. Potential for abnormal bleeding and death; monitor for INR and prothrombin time increases when pantoprazole is used concomitantly with warfarin.

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