[Posted 03/02/2011] ISSUE: FDA notified healthcare professionals and the public that prescription proton pump inhibitor (PPI) drugs may cause low serum magnesium levels (hypomagnesemia) if taken for prolonged periods of time (in most cases, longer than one year). Low serum magnesium levels can result in serious adverse events including muscle spasm (tetany), irregular heartbeat (arrhythmias), and convulsions (seizures); however, patients do not always have these symptoms. Treatment of hypomagnesemia generally requires magnesium supplements. In approximately one-quarter of the cases reviewed, magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued.
BACKGROUND: PPIs work by reducing the amount of acid in the stomach and are used to treat conditions such as gastroesophageal reflux disease (GERD), stomach and small intestine ulcers, and inflammation of the esophagus.
RECOMMENDATION: Healthcare professionals should consider obtaining serum magnesium levels prior to initiation of prescription PPI treatment in patients expected to be on these drugs for long periods of time, as well as patients who take PPIs with medications such as digoxin, diuretics or drugs that may cause hypomagnesemia. For patients taking digoxin, a heart medicine, this is especially important because low magnesium can increase the likelihood of serious side effects. Healthcare professionals should consider obtaining magnesium levels periodically in these patients. For additional information, refer to the Data Summary section of the FDA Drug Safety Communication. For more information visit the FDA website at: [Web] and [Web].
[Posted 05/25/2010] FDA notified healthcare professionals and patients of revisions to the prescription and over-the-counter [OTC] labels for proton pump inhibitors, which work by reducing the amount of acid in the stomach, to include new safety information about a possible increased risk of fractures of the hip, wrist, and spine with the use of these medications.
The new safety information is based on FDA's review of several epidemiological studies that found those at greatest risk for these fractures received high doses of proton pump inhibitors or used them for one year or more. The majority of the studies evaluated individuals 50 years of age or older and the increased risk of fracture primarily was observed in this age group. While the greatest increased risk for fractures in these studies involved people who had been taking prescription proton pump inhibitors for at least one year or who had been taking high doses of the prescription medications (not available over-the-counter), as a precaution, the “Drug Facts” label on the OTC proton pump inhibitors (indicated for 14 days of continuous use) also is being revised to include information about this risk. FDA recommends healthcare professionals, when prescribing proton pump inhibitors, should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition.
The safety communication includes a data summary with a table and references which support the epidemiological studies reviewed for this communication. For more information visit the FDA website at: [Web] and [Web].
Orally for short-term treatment of erosive esophagitis in patients with GERD.
Orally to maintain healing and decrease recurrence of erosive esophagitis.
IV for up to 7–10 days in the treatment of GERD in patients with a history of erosive esophagitis. Discontinue IV therapy as soon as patient is able to initiate or resume oral therapy with the drug.
Pathologic GI Hypersecretory Conditions
Orally for long-term treatment of pathologic hypersecretory conditions, including Zollinger-Ellison syndrome.
IV for up to 6 days in the treatment of pathologic hypersecretory conditions associated with Zollinger-Ellison syndrome or other neoplastic conditions.
Duodenal Ulcer
Orally for treatment of duodenal ulcer†.
Gastric Ulcer
Orally for treatment of gastric ulcer†.
Crohn’s Disease-associated Ulcers
Some evidence for use of proton-pump inhibitors (e.g., omeprazole) for gastric acid suppressive therapy as an adjunct in the management of upper GI Crohn’s disease†, including esophageal, gastroduodenal, and jejunoileal disease.
Dosage and Administration
Administration
Administer orally or IV. Administer once daily for GERD. Generally given twice daily for pathologic GI hypersecretory conditions, although may be administered IV every 8 hours if necessary.
Oral Administration
Delayed-release Tablets
Administer delayed-release tablets without regard to meals.
Swallow tablets whole; do not split, crush, or chew. May administer two 20-mg tablets if unable to swallow a 40-mg tablet.
Delayed-release Oral Suspension
Administer delayed-release oral suspension 30 minutes before a meal.
Mix delayed-release granules for oral suspension with applesauce or apple juice; do not mix with any other foods or liquids (including water).
Sprinkle the contents of a single-dose packet of pantoprazole sodium delayed-release granules for oral suspension onto 1 teaspoonful of applesauce and administer within 10 minutes of preparation.
Alternatively, sprinkle the packet contents into 5 mL of apple juice, stir for 5 seconds, and swallow the resulting suspension immediately. Rinse the container once or twice with apple juice; swallow the rinsings immediately to ensure complete delivery of the dose.
Swallow granules in the oral suspension intact; do not crush or chew the granules.
NG Tube
May administer pantoprazole sodium delayed-release granules for oral suspension via a nasogastric tube (16 French or larger).
Remove the plunger from a 60-mL syringe and attach the catheter tip of the syringe to the NG tube. Empty the contents of a single-dose packet of the granules into the syringe barrel while holding the syringe as high as possible to prevent bending of the tubing. Add 10 mL of apple juice to the syringe; gently tap or shake the syringe to facilitate emptying. Rinse the syringe and tubing with 10 mL of apple juice at least 2 more times (until no granules remain). Verify patency of the tubing to ensure complete delivery of the dose.
IV Administration
For solution and drug compatibility information, see Compatibility under Stability.
Administer through a dedicated IV line or a Y-site.
Use of spiked IV system adapters may result in breakage of the glass vial, and currently is not recommended by the manufacturer. (See Glass Vial Breakage under Cautions.)
Administer as reconstituted solution or following further dilution.
Reconstitution
Reconstitute vial containing 40 mg pantoprazole with 10 mL of 0.9% sodium chloride injection to provide a solution containing 4 mg/mL.
Dilution
GERD: Dilute one vial of reconstituted solution containing pantoprazole 4 mg/mL with 100 mL of 5% dextrose injection, 0.9% sodium chloride injection, or lactated Ringer's injection to produce a concentration of about 0.4 mg/mL.
Pathologic hypersecretory conditions: Dilute 2 vials of reconstituted solution containing pantoprazole 4 mg/mL with 80 mL of 5% dextrose injection, 0.9% sodium chloride injection, or lactated Ringer's injection to produce a concentration of 0.8 mg/mL.
Rate of Administration
GERD: Administer 40-mg dose IV as the reconstituted (4 mg/mL) solution over not less than 2 minutes or as the 0.4-mg/mL dilution over about 15 minutes (7 mL/minute).
Pathologic hypersecretory conditions: Administer 80-mg dose IV as the reconstituted (4 mg/mL) solution over not less than 2 minutes or as the 0.8-mg/mL dilution over about 15 minutes (7 mL/minute).
Dosage
Available as pantoprazole sodium; dosage expressed in terms of pantoprazole.
Adults
GERD
IV
40 mg once daily for 7–10 days. Discontinue IV therapy when patient is able to initiate or resume oral therapy; safety and efficacy of IV therapy for >10 days not established.
Treatment of Erosive Esophagitis
Oral
40 mg once daily for up to 8 weeks. If not healed, consider additional 8 weeks of therapy.
Maintenance of Healing of Erosive Esophagitis
Oral
40 mg once daily. Not studied for >1 year of therapy. However, chronic, lifelong therapy with proton-pump inhibitor may be appropriate.
Pathologic GI Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome)
Oral
40 mg twice daily. Adjust dosage according to patient response and tolerance; continue therapy as long as necessary. May require dosages of up to 240 mg daily. Patients with Zollinger-Ellison syndrome have been treated for >2 years.
IV
80 mg every 12 hours. 80 mg every 8 hours is expected to maintain acid output <10 mEq/hour in patients requiring higher dosage. Safety and efficacy of dosages exceeding 240 mg daily or use of IV pantoprazole for >6 days not established.
Special Populations
Hepatic Impairment
No dosage adjustment necessary. Dosage exceeding 40 mg daily not studied in patients with hepatic impairment.
Anaphylaxis reported with IV pantoprazole. Immediately discontinue drug and institute appropriate medical intervention.
General Precautions
GI Effects
Response to pantoprazole does not preclude presence of occult gastric neoplasm.
Atrophic gastritis reported occasionally with long-term pantoprazole use, especially in patients infected with Helicobacter pylori.
Glass Vial Breakage
Breakage of pantoprazole vials reported during attempts to connect the vials to spiked IV system adapters. Potential safety issue for health-care professionals attempting to connect these system components manually or with mechanical assistance. Pantoprazole manufacturer does not recommend use of spiked IV system adapters; if such adapters are used, contact manufacturer of the adapter for assistance.
Injection Site Reactions
Injection site reactions (e.g., thrombophlebitis, abscess) associated with use of IV pantoprazole.
Hepatic Effects
Mild, transient elevations of serum ALT reported with oral therapy; 0.4% incidence of serum ALT increases >3 times the upper limit of normal with pantoprazole dosage of 40 mg daily in short-term studies.
Edetate Disodium Content
Pantoprazole sodium for injection contains edetate disodium (disodium EDTA), a potent metal ion (e.g., zinc) chelator. Consider zinc supplementation in patients prone to zinc deficiency. Use caution with other IV products that contain edetate disodium.
Cyanocobalamin Malabsorption
Deficiency due to malabsorption from prolonged (e.g., >3 years) gastric acid suppression reported rarely. Consider possibility if manifestations of cyanocobalamin deficiency occur.
Respiratory Effects
Administration of proton-pump inhibitors has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia).
Musculoskeletal Effects
Long-term use of proton-pump inhibitors, especially at high dosages, has been associated with an increased risk for hip fracture in patients >50 years of age. Use the lowest effective dosage and increase calcium intake in older patients requiring long-term therapy with these drugs.
Specific Populations
Pregnancy
Category B.
Lactation
Distributed into milk. Discontinue nursing or the drug because of potential risk in nursing infants.
Pediatric Use
Safety and efficacy not established in children <18 years of age.
Geriatric Use
No substantial differences in safety and efficacy relative to younger adults.
Common Adverse Effects
Oral: Short-term (up to 8 weeks): Headache, diarrhea, flatulence, abdominal pain, rash, eructation, insomnia, hyperglycemia. Long-term (up to 12 months): Headache, abdominal pain, nausea, vomiting, abnormal liver function test results.
Possible altered oral absorption of atazanavir, resulting in decreased plasma atazanavir concentrations; possible loss of virologic response
Manufacturer of pantoprazole states that concomitant administration with atazanavir is not recommended
Antiretroviral treatment-naive patients: If a proton-pump inhibitor is used concomitantly with atazanavir, administer ritonavir-boosted atazanavir (atazanavir 300 mg and ritonavir 100 mg once daily with food); administer the proton-pump inhibitor approximately 12 hours before ritonavir-boosted atazanavir
For treatment-naive patients, dosage of proton-pump inhibitor should not exceed omeprazole 20 mg daily (or equivalent)
Antiretroviral treatment-experienced patients: Concomitant use of proton-pump inhibitors with atazanavir not recommended
Inhibition of clopidogrel's antiplatelet effect reported with omperazole; clinical importance not yet determined but reduction in clopidogrel's effectiveness in preventing cardiovascular events is possible
Some clinicians suggest avoidance of routine concomitant administration of proton-pump inhibitors and clopidogrel
Well absorbed from GI tract (absolute bioavailability about 77%). Peak plasma concentrations attained about 2.5 hours after single or multiple 40-mg oral doses (as delayed-release tablets). Time to peak concentration is similar (2–2.5 hours) for delayed-release suspension administered orally or via NG tube.
Administration of delayed-release oral suspension (in apple juice) via NG tube is bioequivalent to oral administration of the same formulation (in applesauce or apple juice). Delayed-release suspension is comparable to delayed-release tablets in degree of inhibition of pentagastrin-stimulated gastric acid secretion.
Onset
51% mean inhibition of gastric acid secretion within 2.5 hours after a single 40-mg oral dose; 85% after daily administration for 7 days.
15–30 minutes after single 20- to 120-mg IV infusion. About 96% suppression of pentagastrin-stimulated acid output within 2 hours after 80-mg IV infusion.
Duration
Acid secretion normalized within one week after discontinuance of oral pantoprazole; no apparent rebound hypersecretion.
24 hours after single IV infusion. Median percentage of time gastric pH ≥4 similar after 40 mg IV or orally daily for 5 days.
Food
Food delays absorption of delayed-release tablets but does not affect extent or peak plasma concentrations.
Special Populations
Pharmacokinetics in patients with severe renal impairment similar to healthy individuals.
Peak plasma concentrations and AUCs increased in patients with mild to severe hepatic impairment, but no more than in slow metabolizers. (See Hepatic Impairment under Dosage and Administration.)
Distribution
Extent
Mainly extracellular. Prolonged binding to gastric parietal proton pump enzyme.
Distributed into milk.
Plasma Protein Binding
98%, principally albumin.
Elimination
Metabolism
Metabolized in the liver, principally by CYP2C19, and to a lesser extent by CYP3A4. Metabolites appear to be inactive.
Elimination Route
Excreted in urine (about 71%) and feces (18%); no unchanged drug excreted in urine.
Half-life
1 hour.
Special Populations
Hepatic impairment increased plasma half-life to 7–9 hours, but no more than in slow metabolizers, and minimal accumulation occurs.
In patients with poor CYP2C19 metabolizer phenotype, metabolism is slower than those with extensive (or rapid) metabolizer phenotype; elimination half-life is 3.5–10 hours, but minimal accumulation occurs.
20–25°C (may be exposed to 15–30°C). Protect from light.
Store reconstituted (4 mg/mL) solution at room temperature for up to 24 hours prior to administration as 4-mg/mL solution. If reconstituted solution will be further diluted, store reconstituted solution for up to 6 hours before dilution; then store diluted (0.4 or 0.8 mg/mL) solution at room temperature and use within 24 hours of initial reconstitution. Do not freeze reconstituted solution. Not necessary to protect reconstituted or diluted solution from light.
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Manufacturer states that pantoprazole sodium may be incompatible with zinc-containing preparations.
Actions
Inhibits basal and stimulated gastric acid secretion.
Concentrates in acid conditions of parietal cell secretory canaliculi; forms active sulfenamide metabolite that irreversibly binds to and inactivates hydrogen-potassium ATPase (proton- or acid pump), blocking final step in secretion of hydrochloric acid. Acid secretion is inhibited until additional hydrogen-potassium ATPase is synthesized, resulting in prolonged duration of action.
Advice to Patients
Importance of swallowing tablets whole, without splitting, crushing, or chewing.
Delayed-release tablets may be administered without regard to meals.
Importance of taking delayed-release suspension 30 minutes before a meal.
Importance of instructing patients regarding proper preparation and administration of the oral suspension.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses. Antacids may be used concomitantly with delayed-release tablets.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Pantoprazole Sodium
Routes
Dosage Forms
Strengths
Brand Names
Manufacturer
Oral
For suspension, delayed-release (containing enteric-coated granules)
40 mg (of pantoprazole) per packet
Protonix®
Wyeth
Tablets, delayed-release (enteric-coated)
20 mg (of pantoprazole)
Protonix®
Wyeth
40 mg (of pantoprazole)
Protonix®
Wyeth
Parenteral
For injection, for IV infusion
40 mg (of pantoprazole)
Protonix® I.V.
Wyeth
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 11/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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