[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].
Short-term treatment of symptomatic GERD (e.g., heartburn).
Short-term treatment of erosive esophagitis (endoscopically diagnosed) in patients with GERD.
Maintain healing and decrease recurrence of erosive esophagitis.
IV as short-term (up to 7 days) alternative to oral therapy for the treatment of erosive esophagitis in adults unable to continue taking the drug orally; safety and efficacy of IV lansoprazole not established for initial treatment.
Duodenal Ulcer
Short-term treatment of active duodenal ulcer (endoscopically or radiographically confirmed).
Treatment of Helicobacter pylori infection and duodenal ulcer disease. Used in conjunction with amoxicillin and clarithromycin (triple therapy) or clarithromycin (dual therapy); has been used in other multidrug regimens†.
Maintenance therapy following duodenal ulcer healing.
Gastric Ulcer
Short-term treatment and symptomatic relief of active benign gastric ulcer.
NSAIA-induced Gastric Ulcer
Short-term treatment of NSAIA-induced gastric ulcer in patients continuing NSAIA use.
Risk reduction in patients with history of gastric ulcer who require NSAIA treatment.
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.
Pathologic GI Hypersecretory Conditions
Long-term treatment of pathologic hypersecretory conditions (e.g., Zollinger-Ellison syndrome with or without multiple endocrine adenoma).
Dosage and Administration
Administration
Oral Administration
Administer orally before a meal.
Antacids may be used concomitantly as needed for pain relief.
Capsules
Swallow capsules intact; do not chew or crush.
Alternatively, open capsule and sprinkle contents on 1 tablespoon of compatible foods (e.g., applesauce, Ensure® pudding, cottage cheese, yogurt, strained pears) or mix with about 60 mL of appropriate juice (e.g., apple juice, orange juice, tomato juice); swallow immediately without chewing. If mixed with juice, rinse glass with ≥120 mL juice and swallow immediately to ensure complete dose ingestion. Do not mix with other foods or liquids.
Granules for Suspension
Mix granules for suspension in 30 mL water, stir well, and swallow immediately. Rinse container with more water and swallow. Do not mix with other liquids. Do not chew or crush.
Orally Disintegrating Tablets
Place orally disintegrating tablets on the tongue and allow to disintegrate (usually in <1 minute) with or without water; swallow particles without chewing.
To administer using an oral syringe, place 15- or 30-mg tablet in oral syringe, draw up about 4 or 10 mL, respectively, of water in the syringe, gently shake syringe to ensure rapid dispersal of particles, and administer within 15 minutes. To ensure complete consumption of dose, draw up an additional 2 mL (15-mg dose) or 5 mL (30-mg dose) of water in syringe, mix gently, and administer remaining contents.
NG Tube
Open capsule and mix contents with about 40 mL apple juice and administer immediately (within 3–5 minutes) through NG tube; flush tube with additional apple juice. Do not mix with other liquids.
Place 15- or 30-mg orally disintegrating tablet in syringe, draw up about 4 or 10 mL, respectively, of water in the syringe, gently shake syringe to ensure rapid dispersal of particles, and administer within 15 minutes through NG tube (8 French or larger). Draw up an additional 5 mL of water in syringe, mix gently, and flush NG tube with syringe contents.
Do not administer granules for suspension through enteral tubes.
IV Administration
For solution compatibility and storage information, see Stability.
Administer by IV infusion over 30 minutes.
Use inline filter provided by manufacturer to remove precipitates that may form when lansoprazole is mixed with IV solutions; follow manufacturer’s instructions for priming the filter and precautions regarding its use.
Separate IV line for lansoprazole administration is not required, but flush the IV line with 5% dextrose, lactated Ringer’s, or 0.9% sodium chloride injection before and after administration.
Do not administer with any other drugs or diluents because of potential incompatibilities.
Reconstitution
Reconstitute vial containing 30 mg of lansoprazole with 5 mL of sterile water for injection to provide a solution containing 6 mg/mL.
Dilution
Dilute reconstituted solution in 50 mL of 5% dextrose, lactated Ringer’s, or 0.9% sodium chloride injection prior to administration.
Dosage
Pediatric Patients
Gastroesophageal Reflux
GERD
Oral
Children 1–11 years of age: Children weighing ≤30 kg: 15 mg once daily for up to 12 weeks. Those weighing >30 kg: 30 mg once daily for up to 12 weeks. Dosage has been increased up to 30 mg twice daily after ≥2 weeks in patients remaining symptomatic.
Children 12–17 years of age: 15 mg daily for up to 8 weeks.
Treatment of Erosive Esophagitis
Oral
Children 1–11 years of age. Children weighing ≤30 kg: 15 mg once daily for up to 12 weeks. Those weighing >30 kg: 30 mg once daily for up to 12 weeks. Dosage has been increased up to 30 mg twice daily after ≥2 weeks in patients remaining symptomatic.
Children 12–17 years of age: 30 mg daily for up to 8 weeks.
Adults
Gastroesophageal Reflux
Chronic, lifelong therapy with proton-pump inhibitor is appropriate for many GERD patients.
GERD
Oral
15 mg once daily for up to 8 weeks.
Treatment of Erosive Esophagitis
Oral
30 mg once daily for up to 8 weeks. May give additional 8 weeks of therapy (up to 16 weeks for a single course) if not healed. If recurs, consider additional 8 weeks of therapy.
IV
30 mg once daily for up to 7 days. Discontinue IV administration as soon as patient can resume oral lansoprazole therapy.
Maintenance of Healing of Erosive Esophagitis
Oral
15 mg once daily. Not studied >1 year.
Duodenal Ulcer
Treatment of Active Duodenal Ulcer
Oral
15 mg once daily for 4 weeks.
Treatment of Helicobacter pylori Infection and Duodenal Ulcer
Oral
Triple therapy: 30 mg every 12 hours for 10 or 14 days in conjunction with amoxicillin and clarithromycin.
Dual therapy: 30 mg every 8 hours for 14 days in conjunction with amoxicillin.
Maintenance of Duodenal Ulcer Healing
Oral
15 mg daily. Safety and efficacy beyond 1 year not established.
Gastric Ulcer
Benign Gastric Ulcer
Oral
30 mg once daily for up to 8 weeks.
NSAIA-induced Gastric Ulcer
Treatment
Oral
30 mg once daily for 8 weeks.
Risk Reduction
Oral
15 mg once daily for up to 12 weeks.
Pathologic GI Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome)
Oral
60 mg once daily initially. Adjust dosage according to patient response and tolerance; continue therapy as long as necessary. May require dosages of up to 90 mg twice daily. Administer daily dosages >120 mg in divided doses. Patients with Zollinger-Ellison syndrome have been treated for up to 4 years.
Special Populations
Hepatic Impairment
Consider dosage reduction in patients with severe hepatic impairment.
Response to lansoprazole therapy does not preclude presence of occult gastric neoplasm.
Phenylketonuria
Each 15- or 30-mg Prevacid® Solu-Tab™ orally disintegrating tablet contains aspartame, which is metabolized in the GI tract to provide 2.5 or 5.1 mg of phenylalanine, respectively.
Respiratory Effects
Administration of proton-pump inhibitors has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia).
Use of Fixed Combination
When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.
Specific Populations
Pregnancy
Category B.
Lactation
Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing or the drug.
Pediatric Use
Safety and efficacy of oral lansoprazole established for short-term treatment of symptomatic GERD and erosive esophagitis in patients 1–17 years of age. Safety and efficacy of oral lansoprazole not established in infants <1 year of age. Safety and efficacy of IV lansoprazole not established in pediatric patients.
Geriatric Use
No substantial differences in efficacy and safety of oral lansoprazole in geriatric patients relative to younger adults. Clinical data regarding use of IV lansoprazole in geriatric patients are limited.
Hepatic Impairment
Increased bioavailability and decreased clearance. Consider dosage reduction in patients with severe hepatic impairment.
Common Adverse Effects
In children 1–11 years of age, constipation and headache. In children 12–17 years of age, headache, abdominal pain, nausea, dizziness. Pediatric adverse effect profile similar to that in adults.
In adults receiving oral lansoprazole, diarrhea, abdominal pain, nausea, constipation. In adults receiving IV lansoprazole, headache, injection site pain, injection site reaction, nausea.
Interactions
Metabolized by CYP2C19 and CYP3A4.
Drugs Metabolized by Hepatic Microsomal Enzymes
Unlikely to have clinically important interaction with drugs metabolized by CYP3A, 1A2, 2C9, 2C19, 2D6.
Well absorbed from GI tract (absolute bioavailability >80%). Peak plasma concentrations attained about 1.7 hours after oral administration.
Onset
Increased gastric pH occurred within 1–2 or 2–3 hours after a single 30- or 15-mg oral dose, respectively.
Duration
Gastric acid secretion normalized over 2–4 days after discontinuance; no apparent rebound.
Food
Absorption (peak plasma concentration, AUC) decreased by 50–70% when administered 30 minutes after food. No substantial food effect when administered before meals.
Special Populations
Peak plasma concentration and time to peak plasma concentration in patients with renal impairment similar to healthy individuals.
Peak plasma concentrations were comparable in patients in Asian and US studies.
Distribution
Extent
Distributed into milk in rats; not known whether distributed into human milk.
Prolonged binding to gastric parietal proton pump enzyme.
Plasma Protein Binding
97%.
Special Populations
Severe renal impairment decreased plasma protein binding by 1–1.5% after administration of 60 mg dose.
Elimination
Metabolism
In parietal cell secretory canaliculi, thought to be transformed into 2 active sulfenamide metabolites not present in systemic circulation. Also metabolized in the liver by CYP3A4 and CYP2C19. Metabolites found in plasma are inactive.
Elimination Route
Excreted principally in feces (about 67%) with remainder in urine; no unchanged drug excreted in urine.
Half-life
<2 hours.
Special Populations
Hepatic impairment increased plasma half-life to 3.2–7.2 hours.
Renal impairment decreased elimination half-life.
Stability
Storage
Oral
Capsules, Granules for Suspension, and Orally Disintegrating Tablets
25°C (may be exposed to 15–30°C).
Prevacid® NapraPAC® Kit
25°C (may be exposed to 15–30°C). Store and dispense in original container.
Prevpac® Kit
20–25°C. Protect from light and moisture.
Parenteral
Powder for IV Infusion
Powder: 25°C (may be exposed to 15–30°C). Protect from light.
Reconstituted solution: 25°C for up to 1 hour before further dilution.
Admixture: 25°C for up to 12 hours (in 50 mL of 5% dextrose injection) or 24 hours (in 50 mL of lactated Ringer’s or 0.9% sodium chloride injection).
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Oral
Capsules
Immediately use extemporaneous mixtures of capsule contents and food or juice. (See Oral Administration under Dosage and Administration.)
Granules for Suspension
Use immediately after mixing with water.
Parenteral
Solution Compatibility
Reconstitute powder with sterile water for injection; use of other diluents may result in precipitate or particulate formation. Further dilution in 5% dextrose, lactated Ringer’s, or 0.9% sodium chloride injection recommended by manufacturer.
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.
Importance of swallowing capsule intact, without crushing or chewing.
For orally disintegrating tablets, importance of allowing tablet to dissolve on tongue with or without water, then swallowing particles without chewing.
Importance of not crushing or chewing granules in prepared suspension.
Importance of not administering suspension through an enteral administration tube.
If capsule contents are mixed with food or juice, importance of immediately swallowing mixture without crushing or chewing.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs. Antacids may be used concomitantly as needed for pain relief.
Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients with phenylketonuria that orally disintegrating tablets contain aspartame.
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.
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. 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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