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Pantoprazole


Special Alerts

EDTA-Stabilized Formulation for I.V. Use - April, 2004

A new formulation pantoprazole for I.V. administration will be available in June, 2004. This new formulation does not require an in-line filter. Caution should be used in dispensing and administering I.V. pantoprazole to clearly identify which formulation is being used.


Pronunciation

 (pan TOE pra zole)


U.S. Brand Names

 Protonix®


Generic Available

 No


Canadian Brand Names

 Panto™ IV; Pantoloc™; Protonix®


Use

Oral: Treatment and maintenance of healing of erosive esophagitis associated with GERD; reduction in relapse rates of daytime and nighttime heartburn symptoms in GERD; hypersecretory disorders associated with Zollinger-Ellison syndrome or other neoplastic disorders

I.V.: Short-term treatment (7-10 days) of patients with gastroesophageal reflux disease (GERD) and a history of erosive esophagitis; hypersecretory disorders associated with Zollinger-Ellison syndrome or other neoplastic disorders


Use - Unlabeled/Investigational

 Peptic ulcer disease, active ulcer bleeding (parenteral formulation); adjunct treatment with antibiotics for Helicobacter pylori eradication


Pregnancy Risk Factor

 B


Pregnancy Implications

 There are no adequate and well-controlled studies in pregnant women. Use in pregnancy only if clearly needed.


Lactation

 Enters breast milk/not recommended


Contraindications

 Hypersensitivity to pantoprazole, substituted benzamidazoles (ie, esomeprazole, lansoprazole, omeprazole, rabeprazole), or any component of the formulation


Warnings/Precautions

 Symptomatic response does not preclude gastric malignancy. Not indicated for maintenance therapy; safety and efficacy for use beyond 16 weeks have not been established. Prolonged treatment (typically >3 years) may lead to vitamin B12 malabsorption. Intravenous preparation contains edetate sodium (EDTA); use caution in patients who are risk for zinc deficiency if other EDTA-containing solutions are coadministered. Safety and efficacy in pediatric patients have not been established.


Adverse Reactions

1% to 10%:

Cardiovascular: Chest pain (I.V. 6%)

Central nervous system: Pain, migraine, anxiety, dizziness, headache (I.V. >1%)

Dermatologic: Rash (I.V. 6%), pruritus (I.V. 4%)

Endocrine & metabolic: Hyperglycemia (1%), hyperlipidemia

Gastrointestinal: Diarrhea (4%), constipation, dyspepsia, gastroenteritis, nausea, rectal disorder, vomiting, abdominal pain (I.V. 12%)

Genitourinary: Urinary frequency, urinary tract infection

Hepatic: Liver function test abnormality, increased SGPT

Local: Injection site pain (>1%)

Neuromuscular & skeletal: Weakness, back pain, neck pain, arthralgia, hypertonia

Respiratory: Bronchitis, increased cough, dyspnea, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection

Miscellaneous: Flu syndrome, infection

<1%: Abnormal vision, acne, albuminuria, alkaline phosphatase increased, allergic reaction, alopecia, amblyopia, anemia, angina pectoris, anorexia, aphthous stomatitis, appetite increased, arrhythmia, arthritis, asthma, balanitis, bone pain, breast pain, bursitis, cataract, CHF, cholecystitis, cholelithiasis, cholestatic jaundice, colitis, confusion, contact dermatitis, convulsion, creatinine increased, cystitis, deafness, decreased reflexes, dehydration, depression, diabetes mellitus, diplopia, dry mouth, dry skin, duodenitis, dysarthria, dysmenorrhea, dysphagia, dysuria, ear pain, ecchymosis, eczema, ECG abnormality, eosinophilia, epididymitis, epistaxis, extraocular palsy, fever, fungal dermatitis, gastrointestinal carcinoma, gastrointestinal hemorrhage, gastrointestinal moniliasis, generalized edema, gingivitis, glaucoma, glossitis, glycosuria, goiter, gout, halitosis, hallucinations, hematuria, hemorrhage, hepatitis, herpes simplex, herpes zoster, hypercholesterolemia, hyperkinesia, hypertension, hyperuricemia, hypotension, impaired urination, impotence, kidney calculus, kidney pain, laryngitis, leg cramps, leukocytosis, leukopenia, libido decreased, lichenoid dermatitis, maculopapular rash, mouth ulceration, myalgia, myocardial ischemia, neck rigidity, neoplasm, nervousness, neuralgia, neuritis, nocturia, oral moniliasis, otitis externa, pain, palpitation, paresthesia, pneumonia, pyelonephritis, rectal hemorrhage, retinal vascular disorder, scrotal edema, skin ulcer, somnolence, stomach ulcer, stomatitis, diaphoresis, syncope, tachycardia, taste perversion, tenosynovitis, thrombocytopenia, thrombosis, tongue discoloration, transaminases increased, tremor, urethritis, urticaria, thrombophlebitis (I.V.), vaginitis, vasodilation, vertigo, voice alteration

Postmarketing and/or case reports: Anaphylaxis, angioedema, anterior ischemic optic neuropathy, blurred vision, CPK increased, erythema multiforme, hepatic failure, hypokinesia, interstitial nephritis, jaundice, optic neuropathy, pancytopenia, rhabdomyolysis, salivation increased, speech disorder, Stevens-Johnson syndrome, pancreatitis, tinnitus, toxic epidermal necrolysis


Overdosage/Toxicology

 Treatment of an overdose would include appropriate supportive treatment. No adverse events were seen with ingestions of 400 and 600 mg doses. Pantoprazole is not removed by hemodialysis.


Drug Interactions

 Substrate of CYP2C19 (major), 3A4 (minor); Inhibits 2C8/9 (moderate); Induces CYP1A2 (weak), 3A4 (weak)

CYP2C8/9 substrates: Pantoprazole may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, and warfarin.

CYP2C19 inducers: May decrease the levels/effects of pantoprazole. Example inducers include aminoglutethimide, carbamazepine, phenytoin, and rifampin.

Iron salts: Oral absorption may be reduced by pantoprazole.

Itraconazole and ketoconazole: Proton pump inhibitors may decrease the absorption of itraconazole and ketoconazole.

Protease inhibitors: Proton pump inhibitors may decrease absorption of some protease inhibitors (atazanavir and indinavir).

Warfarin: Increased anticoagulant effects/INR have been reported with concurrent use (postmarketing case reports); monitor INR closely.


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may cause gastric mucosal irritation).

Herb/Nutraceutical: Prolonged treatment (typically >3 years) may lead to vitamin B12 malabsorption.


Stability

Oral: Store tablet at 15°C to 30°C (59°F to 77°F)

I.V.: Store at 2°C to 8°C (36°F to 46°F); protect from light. Reconstitute with 10 mL 0.9% sodium chloride (final concentration 4 mg/mL); stable up to 2 hours at room temperature; protection from light not required. When diluted in 100 mL D5W, LR, or NS, may be stored at room temperature for up to 12 hours (original formulation) or up to 22 hours (EDTA-stabilized formulation). Reconstituted solution may be given intravenously (over 2 minutes) or may be added to 100 mL D5W, 0.9% sodium chloride, or lactated Ringer's (for 15-minute infusion); use diluted solution within 12 hours.


Compatibility

 Stable in D5W, LR, NS

Y-site administration: Incompatible: Midazolam, zinc


Mechanism of Action

 Suppresses gastric acid secretin by inhibiting the parietal cell H + /K + ATP pump


Pharmacodynamics/Kinetics

Absorption: Well absorbed

Distribution: Vd: 11-24 L

Protein binding: 98%, primarily to albumin

Metabolism: Extensively hepatic; CYP2C19 (demethylation), CYP3A4; no evidence that metabolites have pharmacologic activity

Bioavailability: 77%

Half-life elimination: 1 hour

Time to peak: Oral: 2.5 hours

Excretion: Urine (71%); feces (18%)


Dosage

 Adults:

Oral:

Erosive esophagitis associated with GERD:

Treatment: 40 mg once daily for up to 8 weeks; an additional 8 weeks may be used in patients who have not healed after an 8-week course

Maintenance of healing: 40 mg once daily

Note: Lower doses (20 mg once daily) have been used successfully in mild GERD treatment and maintenance of healing

Hypersecretory disorders (including Zollinger-Ellison): Initial: 40 mg twice daily; adjust dose based on patient needs; doses up to 240 mg/day have been administered

Helicobacter pylori eradication (unlabeled use): Doses up to 40 mg twice daily have been used as part of combination therapy

I.V.:

Erosive esophagitis associated with GERD: 40 mg once daily for 7-10 days

Hypersecretory disorders: 80 mg twice daily; adjust dose based on acid output measurements; 160-240 mg/day in divided doses has been used for a limited period (up to 7 days)

Prevention of rebleeding in peptic ulcer bleed (unlabeled use): 80 mg, followed by 8 mg/hour infusion for 72 hours

Elderly: Dosage adjustment not required

Dosage adjustment in renal impairment: Not required; pantoprazole is not removed by hemodialysis

Dosage adjustment in hepatic impairment: Not required


Administration

I.V.: Flush I.V. line before and after administration. Solutions prepared from original formulation must be infused through an inline filter. Solutions prepared from the EDTA-stabilized formulation do not require an in-line filter (per manufacturer).

2-minute infusion: The volume of reconstituted solution (4 mg/mL) to be injected may be administered intravenously over at least 2 minutes.

15-minute infusion: Infuse over 15 minutes at a rate not to exceed 3 mg/minute.

Oral: Tablets should be swallowed whole, do not crush or chew. Best if taken before breakfast.


Monitoring Parameters

 Hypersecretory disorders: Acid output measurements, target level <10 mEq/hour (<5 mEq/hour if prior gastric acid-reducing surgery)


Test Interactions

 False-positive urine screening tests for tetrahydrocannabinol (THC) have been noted in patients receiving proton pump inhibitors, including pantoprazole.


Dietary Considerations

Oral: May be taken with or without food; best if taken before breakfast.

I.V.: Due to EDTA in preparation, zinc supplementation may be needed in patients prone to zinc deficiency.


Patient Education

 Take as directed; do not alter dosage without consulting prescriber. Take at similar time each day. Swallow tablet whole (do not crush or chew). Avoid alcohol. You may experience dizziness, headache, or anxiety (use caution when driving or engaging in dangerous activities until response to medication is known); vomiting or loss of appetite (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); or diarrhea (boiled milk, yogurt, or buttermilk may help). Report persistent abdominal discomfort; chest pain or palpitations; acute headache; unresolved diarrhea; excessive fatigue; increased muscle, joint, or body pain; shortness of breath or wheezing; cold or flu symptoms; changes in urinary pattern; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Breast-feeding is not recommended.


Anesthesia and Critical Care Concerns/Other Considerations

 Intravenous omeprazole has been studied in prevention of rebleeding in ulcer patients who are at high risk for rebleeding (endoscopic findings of active bleeding or nonbleeding visible vessel) after successful hemostasis (Lin HJ, 1998; Lau JYW, 2000). Lin and his group treated 100 ulcer patients (actively bleeding ulcers or ulcers with nonbleeding visible vessels) endoscopically and then randomized them to cimetidine (300 mg bolus followed by 50 mg/hour infusion) or omeprazole (40 mg bolus, ~7 mg/hour infusion) for 72 hours. Patients were discharged on the oral form of the drug arm they were assigned to. The omeprazole group maintained an intragastric pH >6 for about 84% of the infusion duration, while the cimetidine group maintained their pH >6 only about 50% of the time. Rebleeding occurred significantly more often in the cimetidine group. Lau and his colleagues treated patients with actively bleeding ulcers or ulcers with nonbleeding visible vessels with an epinephrine infusion followed by thermocoagulation. They were then randomized to omeprazole (80 mg bolus followed by a continuous infusion of 8 mg/hour for 72 hours) or placebo. All patients were discharged on oral omeprazole (20 mg/day) for 8 weeks and received H. pylori treatment if indicated. The primary goal was to evaluate the rate of rebleeding during the first 30 days after endoscopy. Two hundred and forty patients were enrolled with randomization of 120 into each group. Bleeding recurred in significantly more patients receiving placebo than omeprazole infusion. The authors concluded that after endoscopic therapy, omeprazole reduces the risk of rebleeding in patients with actively bleeding ulcers or ulcers with nonbleeding visible vessels.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 May cause anxiety or dizziness; may rarely produce confusion, depression, dysarthria, hallucinations, nervousness, or somnolence


Mental Health: Effects on Psychiatric Treatment

 None reported


Dosage Forms

 [DSC] = Discontinued product; Note: Strength expressed as base:

Injection, powder for reconstitution, as sodium: 40 mg [original formulation] [DSC]

Injection, powder for reconstitution, as sodium: 40 mg [contains edetate sodium 1 mg]

Tablet, delayed release, as sodium: 20 mg, 40 mg


Extemporaneously Prepared

 A 2 mg/mL pantoprazole oral liquid can be prepared with twenty pantoprazole 40 mg tablets, 340 mL sterile water, and 33.6 g of sodium bicarbonate powder. Remove the Protonix imprint from each of the tablets on a paper towel dampened with ethanol (improves the look of product). Let tablets air dry. Grind the tablets into a coarse powder, transfer to a 600 mL beaker and add 340 mL of sterile water for irrigation and place beaker on a magnetic stirrer. Add 16.8 g of sodium bicarbonate powder and stir for about 20 minutes until the tablet remnants have disintegrated. While stirring, add another 16.8 g of sodium bicarbonate powder and stir for about 5 minutes until powder has dissolved. Add enough sterile water for irrigation to bring the final volume to 400 mL. Mix well. Transfer to amber-colored bottle. Stable for 62 days under refrigeration. Shake well before use.

Dentinger PJ, Swenson CF, and Anaizi NH, "Stability of Pantoprazole in an Extemporaneously Compounded Oral Liquid," Am J Health-Syst Pharm , 2002, 59:953-6.


References

Bardhan KD, Dillon J, Axon AT, et al, "Triple Therapy for Helicobacter pylori Eradication: A Comparison of Pantoprazole Once Versus Twice Daily," Aliment Pharmacol Ther , 2000, 14(1):59-67.

Brunner G, Luna P, Hartmann M, et al, "Optimizing the Intragastric pH as a Supportive Therapy in Upper GI Bleeding," Yale J Biol Med , 1996, 69(3):225-31.

Cockayne SE, Glet RJ, Gawkrodger DJ, et al, "Severe Erythrodermic Reactions to the Proton Pump Inhibitors Omeprazole and Lansoprazole," Br J Dermatol ,1999, 141(1):173-5.

Escourrou J, Deprez P, Saggioro A, et al, "Maintenance Therapy With Pantoprazole 20 mg Prevents Relapse of Reflux Oesophagitis," Aliment Pharmacol Ther , 1999, 13(11):1481-91.

Jung R and MacLaren R, "Proton-Pump Inhibitors for Stress Ulcer Prophylaxis in Critically Ill Patients," Ann Pharmacother , 2002, 36(12):1929-37.

Lau JY, Sung JJ, Lee KK, et al, "Effect of Intravenous Omeprazole on Recurrent Bleeding After Endoscopic Treatment of Bleeding Peptic Ulcers," N Engl J Med , 2000, 343(5):310-6.

Lew EA, Pisegna JR, Starr JA, et al, "Intravenous Pantoprazole Rapidly Controls Gastric Acid Hypersecretion in Patients With Zollinger-Ellison Syndrome," Gastroenterology , 2000, 118(4):696-704.

Lin HJ, Lo WC, Lee FY, et al, "A Prospective Randomized Comparative Trial Showing That Omeprazole Prevents Rebleeding in Patients With Bleeding Peptic Ulcer After Successful Endoscopic Therapy," Arch Intern Med , 1998, 158(1):54-8.

Morgan D, "Intravenous Proton-Pump Inhibitors in the Critical Care Setting," Crit Care Med , 2002, 30(6 Suppl):369-72.

Natsch S, Vinks MH, Voogt AK, et al, "Anaphylactic Reactions to Proton-Pump Inhibitors," Ann Pharmacother , 2000, 34(4):474-6.

Perri F, Festa V, Clemente R, et al, "Randomized Study of Two "Rescue" Therapies for Helicobacter pylori -infected Patients After Failure of Standard Triple Therapies," Am J Gastroenterol , 2001, 96(1):58-62.

Poole P, "Pantoprazole," Am J Health-Syst Pharm , 2001, 58:999-1008.

Vcev A, Stimac D, Ivandic A, et al, "Pantoprazole, Amoxycillin, and Either Azithromycin or Clarithromycin for Eradication of Helicobacter pylori in Duodenal Ulcer," Aliment Pharmacol Ther , 2000, 14(1):69-72.

Wolfe MM and Sachs G, "Acid Suppression: Optimizing Therapy for Gastroduodenal Ulcer Healing, Gastroesophageal Reflux Disease, and Stress-Related Erosive Syndrome," Gastroenterology , 2000,118(2 Suppl 1):9-31.


International Brand Names

 Anagastra® (ES); Apton® (PT); Controloc® (CZ, HR, HU, IL, PL, RO, SG, SI, TH, YU, ZA); Eupantol® (FR); Gastromax® (AR); Inipomp® (FR); Noprop® (BR); Pangest® (AR); Pantecta® (CR, DO, ES, GT, HN, IT, PA, SV); Panthec® (TR); Panto Byk® (LU); Pantocal® (BR); Pantocarm® (ES); Pantoc® (PT); Pantodac® (IN); Pantodar® (JO, LB, RO); Panto™ IV (CA); Pantoloc® (AT); Pantoloc™ (CA); Pantoloc® (DK, SE, ZA); Pantopan® (IT); Pantop® (AR); Pantorc® (IT); Pantozol® (BE, BR, CH, DE, ID, LU, MX, NL); Pantpas® (TR); Pantus® (AR); Peptazol® (AR, IT); Protium® (GB, IE); Protonix® (CA); Rifun® (DE); Somac® (AU, FI, NO, NZ); Ulcemex® (CL); Ulcotenal® (ES); ZacPac® (DE); Ziprol® (BR); Zurcal® (AR, AT, BR, CH, CL, CO, EC, MX, PT); Zurcale® (BE)


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