|
This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
Special Alerts
Possible Increased Risk of Fractures (Hip, Wrist, and Spine) with Proton Pump Inhibitor (PPI) Use (Update)
March 2011
The U.S. Food and Drug Administration (FDA) has announced that over-the-counter (OTC) labeling for proton pump inhibitors (PPI) will not be required to carry an osteoporosis or fracture warning at this time. In May 2010, the FDA had revised all prescription and OTC labels for PPIs with information regarding an increase in the risk of fractures (hip, wrist, and spine) based on several epidemiologic studies. The greatest risk for these fractures was in patients who received high doses or used them for ≥1 year. The majority of the patients in the epidemiologic studies were ≥50 years of age with the risk of fractures being limited to this age group. The FDA has now concluded that short-term, low dose PPI use is unlikely to increase fracture risk.
The FDA has recommended that healthcare providers continue to prescribe, and patients continue to use these products as described within their labeling. In addition, healthcare providers should consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition. Patients who continue to receive PPIs and who are at risk for osteoporosis, should receive vitamin D and calcium supplementation and have their bone status monitored and managed according to current practice standards. Patients should not stop taking their proton pump inhibitor unless told to do so by their healthcare provider.
For more information, U.S. healthcare professionals may refer to the following websites:
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm213321.htm
Proton Pump Inhibitors (PPIs): Long-term Use May be Associated With Hypomagnesemia
March 2011
The U.S. Food and Drug Administration (FDA) is notifying healthcare providers and patients that long-term use of proton pump inhibitors (PPIs) may be associated with hypomagnesemia. Some of the reported cases of hypomagnesemia occurred after 3 months of use, but most occurred in patients using PPIs for longer than 1 year. The mechanism for this adverse effect is not clearly defined.
Healthcare providers should consider obtaining serum magnesium levels prior to beginning long-term PPI therapy, especially in patients taking concomitant digoxin, diuretics, or other drugs known to cause hypomagnesemia; and periodically thereafter. Although magnesium supplementation may correct hypomagnesemia, discontinuation of the PPI may be necessary to correct and maintain normal magnesium levels. Typically, according to the case reports, magnesium levels returned to normal within 1 week of stopping the PPI. Hypomagnesemia can cause serious adverse events including tetany, tremors, seizures, QT prolongation, and cardiac arrhythmias. Patients should not stop PPI therapy without first discussing with a healthcare professional.
The FDA is requiring all manufacturers of prescription PPI products to update the package labeling to include the potential risk of hypomagnesemia. Since OTC PPIs are only approved for short-term use, the package labeling for these products will not be updated. However, healthcare professionals should be aware of the risk of hypomagnesemia if OTC PPIs are used longer than the approved use.
For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm245011.htm.
Statement Released Regarding Clopidogrel-Proton Pump Inhibitor (PPI) Interaction
November 2010
The American College of Cardiology Foundation, in conjunction with the American College of Gastroenterology and the American Heart Association, has issued a consensus document regarding the concomitant use of PPIs and thienopyridines, specifically clopidogrel.
The following highlighted recommendations are discussed within this consensus statement:
- Clopidogrel alone, aspirin alone, and their combination are associated with an increased risk of GI bleeding.
- Risk of GI bleeding increases as the number of risk factors increase (eg, prior GI bleeding, advanced age, concurrent use of anticoagulants).
- PPIs are appropriate in patients with multiple risk factors for GI bleeding who are also receiving antiplatelet therapy (eg, clopidogrel).
- Although pharmacokinetic and pharmacodynamic studies have demonstrated varying effects of PPIs on the extent of clopidogrel metabolic conversion to the active metabolite, no evidence has established clinically meaningful differences in outcomes.
- A clinically-significant interaction cannot be excluded in subgroups who are poor metabolizers of clopidogrel.
- Until solid evidence exists to support staggering PPIs with clopidogrel, the dosing of PPIs should not be altered.
Healthcare professionals must evaluate the risks and benefits of concomitant use of PPIs and thienopyridines, considering both the cardiovascular and GI complications. For more information, healthcare professionals may refer to the following website: http://content.onlinejacc.org/cgi/reprint/j.jacc.2010.09.010v1.pdf
Pronunciation
(ra BEP ra zole)
Generic Available (U.S.)
No
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Short-term (4-8 weeks) treatment and maintenance of erosive or ulcerative gastroesophageal reflux disease (GERD); symptomatic GERD; short-term (up to 4 weeks) treatment of duodenal ulcers; long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome; H. pylori eradication (in combination therapy)
Canadian labeling: Additional uses (not in U.S. labeling): Treatment of nonerosive reflux disease (NERD); treatment of gastric ulcers
Use: Unlabeled/Investigational
Maintenance of duodenal ulcer
Pregnancy Risk Factor
B
Pregnancy Considerations
Not shown to be teratogenic in animal studies, however, adequate and well-controlled studies have not been done in humans; use during pregnancy only if clearly needed
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to rabeprazole, substituted benzimidazoles (ie, esomeprazole, lansoprazole, omeprazole, pantoprazole), or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• Atrophic gastritis: Long-term omeprazole therapy has caused atrophic gastritis (by biopsy); this may also occur with rabeprazole.
• Carcinoma: No reports of enterochromaffin-like (ECL) cell carcinoids, dysplasia, or neoplasia has occurred.
• Fractures: Increased incidence of osteoporosis-related bone fractures of the hip, spine, or wrist may occur with proton pump inhibitor therapy. Patients on high-dose (multiple daily doses) or long-term therapy (≥1 year) should be monitored. Use the lowest effective dose for the shortest duration of time, use vitamin D and calcium supplementation, and follow appropriate guidelines to reduce risk of fractures in patients at risk.
Disease-related concerns:
• Gastric malignancy: Relief of symptoms does not preclude the presence of a gastric malignancy.
• Gastrointestinal infection (eg, Salmonella, Campylobacter): Use of proton pump inhibitors may increase risk of these infections.
• Hepatic impairment: Use caution in patients with severe hepatic impairment.
Concurrent drug therapy issues:
• Clopidogrel: Proton pump inhibitors may diminish the therapeutic effect of clopidogrel, thought to be due to reduced formation of the active metabolite of clopidogrel; an increase in the risk of cardiovascular events may occur. The manufacturer of clopidogrel recommends avoidance of concomitant administration of another PPI (ie, omeprazole); given the potency of CYP2C19 inhibitory activity, similar recommendations with rabeprazole would appear prudent.
Other warnings/precautions:
• Appropriate use: Helicobacter pylori eradication: Short-term combination therapy (≤7 days) has been associated with a higher incidence of treatment failure. The American College of Gastroenterology recommends 10-14 days of therapy (triple or quadruple) for eradication of H. pylori (Chey, 2007).
Adverse Reactions
1% to 10%:
Central nervous system: Pain (3%), headache (2% to 5%)
Gastrointestinal: Diarrhea (3%), flatulence (3%), constipation (2%), nausea (2%)
Respiratory: Pharyngitis (3%)
Miscellaneous: Infection (2%)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Abdomen enlarged, abdominal pain, abnormal stools, abnormal vision, agitation, agranulocytosis, albuminuria, allergic reaction, alopecia, amblyopia, anaphylaxis, anemia, angina pectoris, angioedema, anorexia, apnea, arrhythmia, arthralgia, arthritis, ascites, asthma, bloody diarrhea, bone pain, bradycardia, breast enlargement, bullous and other drug eruptions of skin, bundle branch block, bursitis, cataract, cellulitis, cerebral hemorrhage, chest pain substernal, cholangitis, cholecystitis, cholelithiasis, colitis, coma, contact dermatitis, convulsions, corneal opacity, CPK increased, cystitis, deafness, delirium, depression, diaphoresis, diabetes mellitus, diplopia, disorientation, dizziness, duodenitis, dysmenorrhea, dyspepsia, dysphagia, dyspnea, dysuria, edema, electrocardiogram abnormal, embolus, epistaxis, erythema multiforme, esophageal stenosis, esophagitis, extrapyramidal syndrome, eye hemorrhage, facial edema, fever, fracture, fungal dermatitis, gastritis, gastroenteritis, gastrointestinal hemorrhage, gingivitis, glaucoma, glossitis, gout, gynecomastia, hematuria, hemolytic anemia, hepatic encephalopathy, hepatic cirrhosis, hepatic enzymes increased, hepatitis, hepatoma, hernia, hyperammonemia, hypercholesteremia, hyperglycemia, hyperkinesia, hyperlipemia, hypertension, hyper-/hypothyroidism, hypertonia, hypokalemia, hyponatremia, hypoxia, impotence, injection site hemorrhage/pain/reaction, insomnia, interstitial nephritis, interstitial pneumonia, jaundice, kidney calculus, leukocytosis, leukopenia, leukorrhea, liver fatty deposit, lymphadenopathy, malaise, melena, menorrhagia, metrorrhagia, MI, migraine, myalgia, neck rigidity, nervousness, neuralgia, neuropathy, neutropenia, orchitis, osteoporosis-related fracture, palpitation, pancreatitis, pancytopenia, paresthesia, peripheral edema, photosensitivity, polycystic kidney, polyuria, proctitis, pruritus, PSA increased, psoriasis, pulmonary embolus, QTc prolongation, rash, rectal hemorrhage, retinal degeneration, rhabdomyolysis, salivary gland enlargement, sinus bradycardia, skin discoloration, somnolence, Stevens-Johnson syndrome, stomatitis, strabismus, sudden death, supraventricular tachycardia, syncope, tachycardia, taste abnormal, thrombocytopenia, thrombophlebitis, thrombosis, thirst (rare) tinnitus, toxic epidermal necrolysis, tremor, TSH increased, ulcerative colitis, urinary incontinence, urticaria, vasodilation, ventricular arrhythmias, vertigo, vomiting, weakness, weight gain/loss, xerostomia
Metabolism/Transport Effects
Substrate (major) of CYP2C19, 3A4; Inhibits CYP2C8 (moderate), 2C19 (moderate), 2D6 (weak), 3A4 (weak)
Drug Interactions
Amphetamines: Proton Pump Inhibitors may increase the serum concentration of Amphetamines. Specifically, data indicate that Proton Pump Inhibitors may increase the rate at which Amphetamines are absorbed. Total exposure to Amphetamines is not significantly changed. Risk C: Monitor therapy
Atazanavir: Proton Pump Inhibitors may decrease the serum concentration of Atazanavir. Management: Avoid concurrent PPI in HIV treatment-experienced patients. For treatment-naive patients, atazanavir/ritonavir dose should be given approximately 12 hours after the PPI, and the PPI should not exceed the equivalent of 20 mg omeprazole. Risk D: Consider therapy modification
Bisphosphonate Derivatives: Proton Pump Inhibitors may diminish the therapeutic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy
Cefditoren: Proton Pump Inhibitors may decrease the serum concentration of Cefditoren. Management: If possible, avoid use of cefditoren with proton pump inhibitors (PPIs). Consider alternative methods to minimize/control acid reflux (eg, diet modification) or alternative antimicrobial therapy if use of PPIs can not be avoided. Risk D: Consider therapy modification
Clopidogrel: RABEprazole may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Risk D: Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Management: Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates. Risk D: Consider therapy modification
CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C8 Substrates (High risk): CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates (High risk). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Dabigatran Etexilate: Proton Pump Inhibitors may decrease serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Risk C: Monitor therapy
Dasatinib: Proton Pump Inhibitors may decrease the absorption of Dasatinib. Risk D: Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Delavirdine: Proton Pump Inhibitors may decrease the serum concentration of Delavirdine. Management: Chronic therapy with proton pump inhibitors (PPIs) should be avoided in patients treated with delavirdine. The clinical significance of short-term PPI therapy with delavirdine is uncertain, but such therapy should be undertaken with caution. Risk X: Avoid combination
Dexmethylphenidate: Proton Pump Inhibitors may increase the absorption of Dexmethylphenidate. Specifically, proton pump inhibitors may interfere with the normal release of drug from the extended-release capsules (Focalin XR brand), which could result in both increased absorption (early) and decreased delayed absorption. Risk C: Monitor therapy
Erlotinib: Proton Pump Inhibitors may decrease the serum concentration of Erlotinib. Risk X: Avoid combination
Fluconazole: May increase the serum concentration of Proton Pump Inhibitors. Risk C: Monitor therapy
Gefitinib: Proton Pump Inhibitors may decrease the serum concentration of Gefitinib. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Indinavir: Proton Pump Inhibitors may decrease the serum concentration of Indinavir. Risk C: Monitor therapy
Iron Salts: Proton Pump Inhibitors may decrease the absorption of Iron Salts. Exceptions: Ferric Gluconate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk C: Monitor therapy
Itraconazole: Proton Pump Inhibitors may decrease the serum concentration of Itraconazole. Risk D: Consider therapy modification
Ketoconazole: Proton Pump Inhibitors may decrease the serum concentration of Ketoconazole. Ketoconazole may increase the serum concentration of Proton Pump Inhibitors. Risk D: Consider therapy modification
Ketoconazole (Systemic): Proton Pump Inhibitors may decrease the serum concentration of Ketoconazole (Systemic). Ketoconazole (Systemic) may increase the serum concentration of Proton Pump Inhibitors. Risk D: Consider therapy modification
Mesalamine: Proton Pump Inhibitors may diminish the therapeutic effect of Mesalamine. Proton pump inhibitor-mediated increases in gastrointestinal pH may cause the premature release of mesalamine from specific sustained-release mesalamine products. Management: Consider avoiding concurrent administration of high-dose proton pump inhibitors (PPIs) with sustained-release mesalamine products. Risk D: Consider therapy modification
Methotrexate: Proton Pump Inhibitors may decrease the excretion of Methotrexate. Antirheumatic doses of methotrexate probably hold minimal risk. Risk C: Monitor therapy
Methylphenidate: Proton Pump Inhibitors may increase the absorption of Methylphenidate. Specifically, proton pump inhibitors may interfere with the normal release of drug from the extended-release capsules (Ritalin LA brand), which could result in both increased absorption (early) and decreased delayed absorption. Risk C: Monitor therapy
Mycophenolate: Proton Pump Inhibitors may decrease the serum concentration of Mycophenolate. Specifically, concentrations of the active mycophenolic acid may be reduced. Risk C: Monitor therapy
Nelfinavir: Proton Pump Inhibitors may decrease serum concentrations of the active metabolite(s) of Nelfinavir. Proton Pump Inhibitors may decrease the serum concentration of Nelfinavir. Risk X: Avoid combination
Posaconazole: Proton Pump Inhibitors may decrease the serum concentration of Posaconazole. Risk X: Avoid combination
Raltegravir: Proton Pump Inhibitors may increase the serum concentration of Raltegravir. Risk C: Monitor therapy
Saquinavir: Proton Pump Inhibitors may increase the serum concentration of Saquinavir. Risk C: Monitor therapy
Tacrolimus: Proton Pump Inhibitors may increase the serum concentration of Tacrolimus. Management: Tacrolimus dose adjustment may be required. Rabeprazole, pantoprazole, or selected H2-receptor antagonists (i.e., ranitidine or famotidine) may be less likely to interact. Genetic testing may predict patients at highest risk. Risk D: Consider therapy modification
Tacrolimus (Systemic): Proton Pump Inhibitors may increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose adjustment may be required. Rabeprazole, pantoprazole, or selected H2-receptor antagonists (i.e., ranitidine or famotidine) may be less likely to interact. Genetic testing may predict patients at highest risk. Risk D: Consider therapy modification
Tipranavir: May decrease the serum concentration of Proton Pump Inhibitors. These data are derived from studies with Ritonavir-boosted Tipranavir. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Voriconazole: Proton Pump Inhibitors may increase the serum concentration of Voriconazole. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may cause gastric mucosal irritation).
Food: High-fat meals may delay absorption, but Cmax and AUC are not altered.
Herb/Nutraceutical: St John's wort may increase the metabolism and thus decrease the levels/effects of rabeprazole.
Storage
Store at 25°C (77°F). Protect from moisture.
Mechanism of Action
Potent proton pump inhibitor; suppresses gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump
Pharmacodynamics/Kinetics
Onset of action: Within 1 hour
Duration: 24 hours
Absorption: Oral: Well absorbed within 1 hour
Protein binding, serum: ~96%
Metabolism: Hepatic via CYP3A and 2C19 to inactive metabolites
Bioavailability: Oral: ~52%
Half-life elimination (dose dependent): 1-2 hours
Time to peak, plasma: 2-5 hours
Excretion: Urine (90% primarily as thioether carboxylic acid metabolites); remainder in feces
Dosage
Oral:
Children ≥12 years: U.S. labeling: Short-term treatment of GERD: 20 mg once daily for ≤8 weeks
Adults >18 years and Elderly:
Erosive/ulcerative GERD: Treatment: 20 mg once daily for 4-8 weeks; if inadequate response, may repeat up to an additional 8 weeks; maintenance: 20 mg once daily
Canadian labeling: 20 mg once daily for 4 weeks; if inadequate response, may repeat for an additional 4 weeks (lack of symptom control after 4 weeks warrants further evaluation); maintenance: 10 mg once daily (maximum: 20 mg once daily)
Symptomatic GERD: Treatment: 20 mg once daily for 4 weeks; if inadequate response, may repeat for an additional 4 weeks
Canadian labeling: 10 mg once daily (maximum: 20 mg once daily) for 4 weeks; lack of symptom control after 4 weeks warrants further evaluation
Duodenal ulcer: 20 mg/day before breakfast for 4 weeks; additional therapy may be required for some patients
Gastric ulcers (Canadian labeling): 20 mg once daily up to 6 weeks; additional therapy may be required for some patients
Helicobacter pylori eradication:
Manufacturer labeling: 20 mg twice daily administered with amoxicillin 1000 mg and clarithromycin 500 mg twice daily for 7 days
American College of Gastroenterology guidelines (Chey, 2007):
Nonpenicillin allergy: 20 mg twice daily administered with amoxicillin 1000 mg and clarithromycin 500 mg twice daily for 10-14 days
Penicillin allergy: 20 mg twice daily administered with clarithromycin 500 mg and metronidazole 500 mg twice daily for 10-14 days or 20 mg once or twice daily administered with bismuth subsalicylate 525 mg and metronidazole 250 mg plus tetracycline 500 mg 4 times/day for 10-14 days
Hypersecretory conditions: 60 mg once daily; dose may need to be adjusted as necessary. Doses as high as 100 mg once daily and 60 mg twice daily have been used, and continued as long as necessary (up to 1 year in some patients).
NERD (Canadian labeling): Treatment: 10 mg (maximum: 20 mg once daily) for 4 weeks; lack of symptom control after 4 weeks warrants further evaluation
Dosage adjustment in renal impairment: No dosage adjustment required
Dosage adjustment in hepatic impairment:
Mild-to-moderate: Elimination decreased; no dosage adjustment required
Severe: Use caution
Administration: Oral
May be administered without regard to meals; best if taken before breakfast. Do not crush, split, or chew tablet. May be administered with an antacid.
Dietary Considerations
May be taken without regard to meals; best if taken before breakfast.
Patient Education
Swallow whole; do not crush, split, or chew. Follow recommended diet and activity instructions. Avoid alcohol. You may experience headache, diarrhea, or gas. Report persistent abdominal pain or headaches.
Geriatric Considerations
No difference in efficacy or safety was noted in elderly subjects as compared to younger subjects. No dosage adjustment is necessary in the elderly.
An increased risk of fractures of the hip, spine, or wrist has been observed in epidemiologic studies with proton pump inhibitor (PPI) use, primarily in older adults ≥50 years of age. The greatest risk was seen in patients receiving high doses or on long-term therapy (≥1 year). Calcium and vitamin D supplementation and close monitoring are recommended to reduce the risk of fracture in high-risk patients.
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 insomnia, anxiety, dizziness, depression, nervousness, somnolence, vertigo, convulsions, abnormal dreams; may rarely cause agitation, amnesia, confusion, extrapyramidal syndrome
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Assess those medications requiring acid environment for absorption. Monitor reduction in symptoms.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, delayed release, enteric coated, oral, as sodium:
AcipHex®: 20 mg
Pricing: U.S. (www.drugstore.com)
Tablet, EC (Aciphex)
20 mg (30): $219.99
References
Chey WD, Wong BC, et al, “American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection,” Am J Gastroent, 2007, 102(8):1808-25.
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.
Kahrilas PJ, Shaheen NJ, Vaezi MF, et al, “American Gastroenterological Association Medical Position Statement on the Management of Gastroesophageal Reflux Disease,” Gastroenterology, 2008, 135(4):1383-91.
Natsch S, Vinks MH, Voogt AK, et al, “Anaphylactic Reactions to Proton-Pump Inhibitors,” Ann Pharmacother, 2000, 34(4):474-6.
Paoluzi P, Iacopini F, Crispino P, et al, “2-Week Triple Therapy for Helicobacter pylori Infection is Better Than 1-Week in Clinical Practice: a Large Prospective Single-Center Randomized Study,” Helicobacter, 2006, 11(6):562-8.
Talley NJ and Vakil N, “Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the Management of Dyspepsia,” Am J Gastroenterol, 2005, 100(10):2324-37.
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
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
| 
