Martindale: The Complete Drug Reference Omeprazole

تعليق: مرجع محترم مثل مارتندل يذكر الأعراض الجانبية للأوميبراز ويلاحظ أن أكثر عرض جانبي له مراجع هو مشاكل الإبصار رغم أن كل مراجعه من التسعينيات فقط. ويعتبر الأوميبراز تأثيره على البصر نادر وهذا ربما يحتاج لمراجعة. وأيضاً الإسهال يحدث بكثرة في المسنين وأيضاً عيوب دراسات الأعراض الجانبية يذكرها مارتندل ولهذا تقارير الحالات قد تقدم قيمة مضافة لدراسات الأعراض الجانبية. --احمد شوقي محمدين 19:16، 21 أكتوبر 2016 (ت ع م)

Adverse Effects (Latest modification: 12-Oct-2009)

Proton pump inhibitors are generally well tolerated, and adverse effects are relatively infrequent. The adverse effects reported most often with omeprazole and other proton pump inhibitors have been headache, diarrhoea, and skin rashes; they have sometimes been severe enough to require stopping treatment. Other effects include pruritus, dizziness, fatigue, constipation, nausea and vomiting, flatulence, abdominal pain, arthralgia and myalgia, urticaria, and dry mouth. Isolated cases of photosensitivity, bullous eruption, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred. Hypersensitivity reactions, including fever, bronchospasm, angioedema, and anaphylaxis have been reported. Effects on the CNS include occasional insomnia, somnolence, and vertigo; reversible confusional states, agitation, depression, and hallucinations have occurred in severely ill patients. Raised liver enzymes, and isolated cases of hepatitis, jaundice, hepatic failure, and hepatic encephalopathy, have been reported. Other adverse effects reported rarely include paraesthesia, blurred vision, alopecia, stomatitis, increased sweating, taste disturbances, peripheral oedema, malaise, hyponatraemia, blood disorders (including agranulocytosis, leucopenia, and thrombocytopenia), gynaecomastia, impotence, and interstitial nephritis.

Proton pump inhibitors may increase the risk of gastrointestinal infections because of their acid suppressive effects. Early toxicological studies identified carcinoid-like tumours of the gastric mucosa in rats given very high doses of omeprazole over long periods (see under Gastrointestinal Tumours, ).

Incidence of adverse effects

Prescription-event monitoring for 16 205 patients prescribed omeprazole, 17 329 prescribed lansoprazole, and 11 541 prescribed pantoprazole indicated that adverse events were reported infrequently, with the most common being gastrointestinal disturbances and headache. The incidences of diarrhoea, the most commonly reported event, per 1000 days of exposure, were 0.18 for omeprazole, 0.39 for lansoprazole, and 0.23 for pantoprazole. Despite the inherent biases of such a cohort study, there did seem to be some evidence that lansoprazole might be associated with a somewhat greater risk of diarrhoea, particularly in the elderly.1

Effects on the blood

There have been rare cases of leucopenia, agranulocytosis, thrombocytopenia, and pancytopenia, with omeprazole and other proton pump inhibitors such as lansoprazole and pantoprazole.1-4 Auto-immune haemolytic anaemia has also been reported with omeprazole.5

1. 1. Holt TL, et al. Neutropenia associated with omeprazole. Med J Aust 1999; 170: 141–2. PubMed

2. 2. Zlabek JA, Anderson CG. Lansoprazole-induced thrombocytopenia. Ann Pharmacother 2002; 36: 809–11. PubMed

3. 3. Watson TD, et al. Pantoprazole-induced thrombocytopenia. Ann Pharmacother 2006; 40: 758–61. PubMed

4. 4. Thakor AS, et al. Toxic epidermal necrolysis and neutropaenia: complications of omeprazole. Australas J Dermatol 2009; 50: 207–10. PubMed

5. 5. Butt MI, et al. Autoimmune haemolytic anaemia associated with use of omeprazole. Br J Hosp Med 2007; 68: 108. PubMed

Effects on the cardiovascular system

Results and preliminary analyses from 2 studies raised concerns about a possible increased risk of myocardial infarction, cardiac failure, and cardiacrelated sudden death in patients taking omeprazole or esomeprazole compared with patients who had surgery for gastro-oesophageal reflux disease.1,2 However, an FDA safety review found that patients who had surgery tended to be younger and less likely to have a history of cardiac problems or cardiac risk factors than those given such drugs.2 The FDA concluded that long-term use of these drugs is not likely to be associated with an increased risk of cardiac problems.3 However, while Health Canada4 considered that there was no evidence to support such an increased risk with long-term use of esomeprazole they were unable to make such a definitive conclusion for omeprazole.

1. 1. FDA. Early communication about an ongoing safety review: omeprazole (Prilosec) esomeprazole (Nexium) (issued 9th August 2007). Available at: online (accessed 15/07/10)

2. 2. FDA. Follow-up to the August 9, 2007, communication about the ongoing safety review of omeprazole and esomeprazole (issued 10th December 2007). Available at: online (accessed 15/07/10)

3. 3. FDA. FDA's safety reviews of Prilosec and Nexium find no evidence of increased rates of cardiac events (issued 10th December 2007). Available at: online (accessed 15/07/10)

4. 4. Health Canada. Health Canada completes safety review of Losec (omeprazole) and Nexium (esomeprazole) (issued 27 February 2008). Available at: online (accessed 09/07/08)

Effects on electrolytes

Refractory hypomagnesaemia with hypocalcaemia and hypokalaemia has been reported in 2 patients given omeprazole. Both patients were also taking other medicines that can affect electrolyte balance; however all abnormalities resolved when omeprazole was stopped.1

In another case, severe hypomagnesaemia with hypocalcaemia and hypokalaemia occurred after prolonged treatment with omeprazole; electrolytes recovered when treatment with ranitidine was substituted, but fell again when pantoprazole and then lansoprazole therapy were tried.2

1. 1. Shabajee N, et al. Omeprazole and refractory hypomagnesaemia. Abridged version: BMJ 2008; 337: 173–5. PubMed Full version: online (accessed 17/06/09)

2. 2. Broeren MAC, et al. Hypomagnesemia induced by several proton-pump inhibitors. Ann Intern Med 2009; 151: 755–6. PubMed Correction. ibid. 2010; 152: 268.

Effects on the endocrine system

Up to December 1991, WHO had received 30 reports of impotence or gynaecomastia which might have been due to omeprazole;1 of these reports 15 were of impotence, 13 of gynaecomastia in men, and 2 of breast enlargement in women. The Spanish Pharmacovigilance System reported 24 cases of gynaecomastia associated with the use of proton pump inhibitors, including lansoprazole and rabeprazole, between January 1982 and July 2006. In most of the cases, gynaecomastia improved after stopping the drug.2 For reference to a case-control study showing no statistical link between gynaecomastia and omeprazole, see under Cimetidine, .

1. 1. Lindquist M, Edwards IR. Endocrine adverse effects of omeprazole. BMJ 1992; 305: 451–2. PubMed

2. 2. Carvajal A, et al. Gynaecomastia associated with proton pump inhibitors: a case series from the Spanish Pharmacovigilance System. Drug Safety 2007; 30: 527–31. PubMed

Effects on the eyes

Visual disturbances associated with the use of omeprazole have included 6 cases of irreversible blindness or visual impairment in severely ill patients given the drug intravenously, and 13 cases of visual disturbances associated with oral use.1 As a result of concern about these effects the availability of intravenous omeprazole was restricted in Germany; however, the consensus appears to be that a causal link has not been established ممكن تكون مضخة البروتون في الشبكة

. Suggestions that visual (and also auditory2 ) impairment could follow drug-induced vasculitis2-4 appear to be contentious.1,5-7 A cohort study involving 140 128 patients given antisecretory therapy, 33 988 of whom received omeprazole, found no evidence that any of the drugs used was associated with a major increase in risk of vascular or inflammatory disorders of the eye;8 however, the statistical power of this study was not high.9

1. 1. Creutzfeldt WC, Blum AL. Safety of omeprazole. Lancet 1994; 343: 1098. PubMed

2. 2. Schönhöfer PS. Intravenous omeprazole and blindness. Lancet 1994; 343: 665.

3. 3. Schönhöfer PS. Safety of omeprazole and lansoprazole. Lancet 1994; 343: 1369–70. PubMed

4. 4. Schönhöfer PS, et al. Ocular damage associated with proton pump inhibitors. BMJ 1997; 314: 1805. PubMed

5. 5. Colin-Jones D. Safety of omeprazole and lansoprazole. Lancet 1994; 343: 1369. PubMed

6. 6. Lessell S. Omeprazole and ocular damage. BMJ 1998; 316: 67. PubMed

7. 7. Sachs G. Omeprazole and ocular damage. BMJ 1998; 316: 67–8. PubMed

8. 8. García Rodríguez LA, et al. A cohort study of the ocular safety of antiulcer drugs. Br J Clin Pharmacol 1996; 42: 213–16. PubMed

9. 9. Merlo J, Ranstam J. Ocular safety of anti-ulcer drugs. Br J Clin Pharmacol 1997; 43: 449. PubMed

يلاحظ أن مشاكل الإبصار هي صاحبة أعلى عدد من المراجع في العراض الجانبية وأن كل المراجع كانت من فترة التسعينيات وهذا ربما يؤكد ظاهرة ويبر Weber عن تلاشي الإبلاغ عن الأعراض الجانبية.

Effects on the kidneys

A systematic review of proton pump inhibitor-associated interstitial nephritis included 47 cases with omeprazole, 6 with pantoprazole, 3 with esomeprazole, 2 with lansoprazole, and 2 with rabeprazole. Although there was insufficient evidence to conclude that proton pump inhibitors caused this reaction, there was a low-prevalence association between their use and the development of interstitial nephritis.1

The Australian Adverse Drug Reactions Advisory Committee (ADRAC)2 stated in April 2003 that it had received 18 biopsy-confirmed reports of interstitial nephritis associated with the use of omeprazole. These patients had presented with symptoms including weight loss, malaise, fever, and nausea; polyuria and polydipsia occurred in one case. Most patients had raised plasma-urea and/or plasma-creatinine concentrations. ADRAC had also received 2 reports of interstitial nephritis associated with rabeprazole.2 Over an 8-year period the Netherlands Pharmacovigilance Centre (Lareb) received 7 reports of acute interstitial nephritis with the use of proton pump inhibitors, 3 with omeprazole, 3 with pantoprazole, and 1 with rabeprazole. In all but one case the patients recovered without treatment once the drug was stopped; the other patient recovered after treatment with a corticosteroid.3 Another case of acute interstitial nephritis associated with pantoprazole has also been reported.4 A case report (in March 2005) of 2 cases of interstitial nephritis associated with the omeprazole isomer esomeprazole noted that, by October 2004, the manufacturer had reported being aware of some 15 cases worldwide possibly associated with the drug, and at least 200 associated with omeprazole.5

In some reports6,7 of interstitial nephritis with omeprazole the condition was associated with rash and eosinophilia, and an allergic mechanism has been postulated.7

1. 1. Sierra F, et al. Systematic review: proton pump inhibitor-associated acute interstitial nephritis. Aliment Pharmacol Ther 2007; 26: 545–53. PubMed 2. 2. Adverse Drug Reactions Advisory Committee (ADRAC). Interstitial nephritis with the proton pump inhibitors. Aust Adverse Drug React Bull 2003; 22: 3. Also available at: online (accessed 07/05/04) 3. 3. Härmark L, et al. proton pump inhibitor-induced acute interstitial nephritis. Br J Clin Pharmacol 2007; 64: 819–23. PubMed Martindale: The Complete Drug Reference 4. 4. Ra A, Tobe SW. Acute interstitial nephritis due to pantoprazole. Ann Pharmacother 2004; 38: 41–5. PubMed 5. 5. Geevasinga N, et al. Acute interstitial nephritis secondary to esomeprazole. Med J Aust 2005; 182: 235–6. PubMed 6. 6. Ruffenach SJ, et al. Acute interstitial nephritis due to omeprazole. Am J Med 1992; 93: 472–3. PubMed 7. 7. Christensen PB, et al. Renal failure after omeprazole. Lancet 1993; 341: 55. PubMed

Effects on the liver

Raised liver enzymes have occurred with omeprazole and other proton pump inhibitors, and there have been isolated cases of hepatotoxicity. For a study comparing the incidence of acute liver injury in patients receiving omeprazole or histamine H2-antagonists, see Cimetidine, .

References. 1. 1. Jochem V, et al. Fulminant hepatic failure related to omeprazole. Am J Gastroenterol 1992; 87: 523–5. PubMed 2. 2. Kourg SI, et al. Omeprazole and the development of acute hepatitis. Eur J Emerg Med 1998; 5: 467–9. PubMed

Effects on the musculoskeletal system

Progressive muscular weakness suggestive of myopathy developed in a 78- year-old patient given oral omeprazole.1 After 4 weeks of treatment the patient required assistance in walking and rising from squatting. Weakness resolved on withdrawal of the drug, but returned on rechallenge. Acute myopathy has also been reported after a single infusion of omeprazole.2 Analysis of the WHO adverse drug reaction database in March 2005 revealed 868 reports associating proton pump inhibitors with myalgia, of which 292 cases had symptoms indicative of muscle disorders including polymyositis and rhabdomyolysis.

3 Reports implicated omeprazole, pantoprazole, lansoprazole, esomeprazole, and rabeprazole, and it was suggested that myopathy was probably a class effect. The mechanism might involve induction of auto-immune antibodies.

A report of 5 cases of arthralgia, sometimes associated with swelling of the affected joints, in patients receiving omeprazole,4 also noted that some reported cases of omeprazole-associated headache were accompanied by arthralgia or myalgia. In another case5 arthralgia in a patient with a hereditary myopathy receiving omeprazole appeared to represent one aspect of a drug-induced lupus syndrome, being accompanied by malaise, fever, Raynaud's phenomenon, raised antinuclear antibody titres, and anticardiolipin and antihistone antibodies. Symptoms resolved on withdrawal of the drug.

A case of eosinophilia and myalgia related to lansoprazole treatment has been reported.6 There has also been a report of 2 cases of acute gout associated with omeprazole;7 in one patient symptoms, which resolved on withdrawal, recurred on rechallenge. However, case control studies have failed to show an increased risk of polyarthralgia8 or gout9 associated with omeprazole use. A large case-control study found an increased risk of hip fracture with more than 1 year of proton pump inhibitor therapy, especially with those patients on high doses.10 The authors theorised that calcium malabsorption secondary to acid suppression may explain this association. Another such study11 also found that use of proton pump inhibitors was associated with an increased risk of osteoporosis-related fracture, but only after at least 7 years of continuous exposure; such patients were almost twice as likely as controls (odds ratio 1.92) to suffer a fracture. However, a review12 noted that while evidence tended to suggest an association, some studies had failed to find one, and the low magnitude of the association, the lack of experimental evidence for the proposed mechanism, and the inability to assess confounding factors limited any possible conclusions about causality. The FDA subsequently reviewed 7 epidemiological studies (including those cited above)13 in which patients took proton pump inhibitors for 1 to 12 years and found that 6 reported an increased risk of fractures of the hip, wrist, or spine, and the one that did not find an association limited the study population to those without major risk factors for fracture. Patients in most studies were 50 years of age or older, and the increased risk was mainly in this age group, with treatment for one year or more. Two studies reported an increase in fractures with higher doses, and 2 reported an increase with longer duration of use. These data suggest patients taking proton pump inhibitors may be at an increased risk of fractures. However, factors that might influence this conclusion such as history of osteoporosis, smoking status, alcohol use, and BMI cannot be accounted for in epidemiological studies and 3 studies found no consistent association between chronic proton pump inhibitor use and bone mineral density; it is therefore unclear if proton pump inhibitor use causes an increased risk of fractures.

1. 1. Garrote FJ, et al. Subacute myopathy during omeprazole therapy. Lancet 1992; 340: 672. PubMed 2. 2. Tuccori M, et al. Acute severe myopathy following a single infusion of omeprazole. Ann Pharmacother 2006; 40: 352–3. PubMed 3. 3. Clark DWJ, Strandell J. Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors? Eur J Clin Pharmacol 2006; 62: 473–9. PubMed 4. 4. Beutler M, et al. Arthralgias and omeprazole. BMJ 1994; 309: 1620. PubMed 5. 5. Sivakumar K, Dalakas MC. Autoimmune syndrome induced by omeprazole. Lancet 1994; 344: 619–20. PubMed 6. 6. Smith JD, et al. Possible lansoprazole-induced eosinophilic syndrome. Ann Pharmacother 1998; 32: 196–200. PubMed Martindale: The Complete Drug Reference 7. 7. Kraus A, Flores-Suárez LF. Acute gout associated with omeprazole. Lancet 1995; 345: 461–2. PubMed 8. 8. Meier CR, Jick H. Omeprazole, H2 blockers, and polyarthralgia: casecontrol study. BMJ 1997; 315: 1283. PubMed 9. 9. Meier CR, Jick H. Omeprazole, other antiulcer drugs and newly diagnosed gout. Br J Clin Pharmacol 1997; 44: 175–8. PubMed 10.10. Yang Y-X, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006; 296: 2947–53. PubMed Correction. ibid. 2007; 297: 470. 11.11. Targownik LE, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008; 179: 319–26. PubMed 12.12. Laine L. Proton pump inhibitors and bone fractures? Am J Gastroenterol 2009; 104 (Suppl): S21–S26. PubMed 13.13. FDA. FDA drug safety communication: possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors (issued 25th May, 2010). Available at: online (accessed 25/05/10)

Effects on the nervous system

Ataxia has been reported in a patient given omeprazole;1 symptoms resolved on stopping the drug. A patient given rabeprazole developed marked anxiety with panic attacks, episodic night terrors, confusion, and attention deficit.2 Her symptoms resolved 2 days after stopping therapy. A month later, she was given esomeprazole, with no adverse neuropsychiatric symptoms. The authors hypothesised that rabeprazole use had resulted in significantly greater plasma gastrin concentrations than esomeprazole, which may have affected gastrin receptors in the brain.

1. 1. Varona L, et al. Gait ataxia during omeprazole therapy. Ann Pharmacother 1996; 30: 192. PubMed 2. 2. Polimeni G, et al. Rabeprazole and psychiatric symptoms. Ann Pharmacother 2007; 41: 1315–17. PubMed Martindale: The Complete Drug Reference

يلاحظ قلة مراجع الإبلاغ عن الهذيان الإختلاط رغم تواجدها بكثرة.

Effects on the respiratory system

An intractable, dry, non-productive cough started abruptly in a 42-year-old non-smoker given omeprazole for gastro-oesophageal reflux disease (GORD). The cough was initially thought to be related to the GORD and treatment was continued for 4 months, without any cessation in the cough. Omeprazole was stopped, and the cough ceased abruptly, with no recurrence during a 2-year follow-up.1

For discussion of a possible increased risk of respiratory infection and pneumonia in patients taking proton pump inhibitors see Infection, .

1. 1. Howaizi M, Delafosse C. Omeprazole-induced intractable cough. Ann Pharmacother 2003; 37: 1607–9. PubMed

Effects on the skin

An extensive blistering erythematous skin rash in an elderly woman given omeprazole1 was characteristic of acute disseminated epidermal necrosis. The UK CSM had received 223 reports of cutaneous reactions to omeprazole up to August 1992, including 6 of erythema multiforme, but none of this severity. Other severe reactions that have subsequently been reported include a toxic bullous skin reaction,2 exfoliative dermatitis,3,4 erythema multiforme,4 toxic erythema,4 and dermatomyositis.5 One patient developed exfoliative dermatitis with both omeprazole and lansoprazole.4 The authors of this report noted that by January 1998 a total of 1296 skin reactions to omeprazole, 500 to lansoprazole, and 44 to pantoprazole, had been reported to the CSM. Most were non-specific rashes, pruritus, urticaria, erythematous rashes, and photosensitive eruptions. A lichenoid reaction that occurred in a patient taking omeprazole cleared after ceasing the drug, but recurred during treatment with both lansoprazole and pantoprazole.6 Proton pump inhibitors, including esomeprazole, have been reported to worsen vitiligo.7

For a report of urticaria and angioedema possibly associated with the formulation of omeprazole see Hypersensitivity, . For the association of rash with interstitial nephritis, see Effects on the Kidneys, .

1. 1. Cox NH. Acute disseminated epidermal necrosis due to omeprazole. Lancet 1992; 340: 857. PubMed 2. 2. Stenier C, et al. Bullous skin reaction induced by omeprazole. Br J Dermatol 1995; 133: 343–4. PubMed 3. 3. Epelde Gonzalo FD, et al. Exfoliative dermatitis related to omeprazole. Ann Pharmacother 1995; 29: 82–3. PubMed 4. 4. Cockayne SE, et al. Severe erythrodermic reactions to the proton pump inhibitors omeprazole and lansoprazole. Br J Dermatol 1999; 141: 173–5. PubMed 5. 5. Pan Y, et al. Omeprazole-induced dermatomyositis. Br J Dermatol 2006; 154: 557–8. PubMed 6. 6. Bong JL, et al. Lichenoid drug eruption with proton pump inhibitors. BMJ 2000; 320: 283. PubMed 7. 7. Schallreuter KU, Rokos H. From the bench to the bedside: proton pump inhibitors can worsen vitiligo. Br J Dermatol 2007; 156: 1371–3. PubMed

Fever

Fever, associated with severe myalgia and headache, was seen in a 64-yearold man on 2 occasions, several hours after taking a dose of esomeprazole.1 Although it was suggested2 that the patient's hyperpyrexia was due to a hypersensitivity reaction, the authors argued3 that esomeprazole may have interfered with the hypothalamic regulatory centres of body temperature.1,3

1. 1. Grattagliano I, et al. Esomeprazole-induced central fever with severe myalgia. Ann Pharmacother 2005; 39: 757–60. PubMed 2. 2. Su SS, et al. Comment: esomeprazole-induced central fever with severe myalgia. Ann Pharmacother 2005; 39: 1764. PubMed Martindale: The Complete Drug Reference 3. 3. Grattagliano I. Comment: esomeprazole-induced central fever with severe myalgia. Ann Pharmacother 2005; 39: 1765. PubMed

Gastrointestinal tumours

Early toxicological studies in rats given high doses of omeprazole over 2 years identified carcinoid tumours of the gastric mucosa associated with complete block of gastric acid secretion leading to hypergastrinaemia and hyperplasia of enterochromaffin-like cells.

1 This has been the main issue concerning the safety of omeprazole and other proton pump inhibitors and initially led to restrictions in use and duration of treatment. A drug manufacturer, Glaxo, developed a new test to detect genotoxicity of antisecretory drugs which indicated that a genotoxic effect of omeprazole could not be discounted.2 This study was heavily criticised; more established genotoxicity tests have been reported to be negative for omeprazole,3-5 and other groups have not been able to replicate the findings with the new test.6 The lowest doses at which Glaxo found2 a genotoxic effect of omeprazole were 10 to 20 mg/kg and the clinical significance of their results was questioned.3 Long-term studies of omeprazole in patients with ZollingerEllison syndrome have found no increase in fasting serum-gastrin concentrations and no evidence of gastric carcinoid tumours.7,8 For mention of the risk of proton pump inhibitors delaying the diagnosis of gastric carcinoma, see under Precautions, . Hypergastrinaemia can occur with both short- and long-term omeprazole therapy,9 and may be higher in patients with Helicobacter pylori infection.10,11 Patients who had H. pylori eradicated before long-term omeprazole treatment had lower gastrin concentrations than those who did not, since H. pylori eradication reduced the pretreatment gastrin concentrations.12

H. pylori is also a cause of atrophic gastritis, another risk factor for stomach cancer, and one study found that omeprazole increased the risk of atrophic gastritis in H. pylori-positive patients with gastro-oesophageal reflux disease.13 However, the results of this study require confirmation since it was nonrandomised and retrospective. Nevertheless, some have suggested that it may be appropriate to eradicate H. pylori before long-term treatment with a proton pump inhibitor.12,13 Conversely, there is some evidence that H. pylori may be protective in gastro-oesophageal reflux disease.14 There has been a report of gastric polyps developing in 3 of 8 patients after receiving omeprazole 20 or 40 mg daily for one year.15 In a subsequent report it was noted that these omeprazole-induced fundic gland polyps had remained asymptomatic and non-malignant for up to five years after their onset.16

The possible association between acid suppressing drugs and risk of gastric cancer has been studied (see also Cimetidine, under Carcinogenicity, ). A small increase in the risk of gastric cancer has been reported with the use of proton pump inhibitors, although the authors of this case control study suggested that confounding by indication was the most likely explanation.17 Further long-term studies of omeprazole may be needed before a realistic risk assessment can be made.

1. 1. Ekman L, et al. Toxicological studies on omeprazole. Scand J Gastroenterol 1985; 20 (suppl 108): 53–69. PubMed 2. 2. Burlinson B, et al. Genotoxicity studies of gastric acid inhibiting drugs. Lancet 1990; 335: 419. PubMed 3. 3. Ekman L, et al. Genotoxicity studies of gastric acid inhibiting drugs. Lancet 1990; 335: 419–20. PubMed 4. 4. Wright NA, Goodlad RA. Omeprazole and genotoxicity. Lancet 1990; 335: 909–10. PubMed 5. 5. Helander HF, et al. Omeprazole and genotoxicity. Lancet 1990; 335: 910–11. Martindale: The Complete Drug Reference 6. 6. Goodlad RA. Acid suppression and claims of genotoxicity: what have we learned? Drug Safety 1994; 10: 413–19. PubMed 7. 7. Lloyd-Davies KA, et al. Omeprazole in the treatment of Zollinger-Ellison syndrome: a 4-year international study. Aliment Pharmacol Ther 1988; 2: 13–32. PubMed 8. 8. Maton PN, et al. Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: a prospective study. Gastroenterology 1989; 97: 827–36. PubMed 9. 9. Koop H, et al. Serum gastrin levels during long-term omeprazole treatment. Aliment Pharmacol Ther 1990; 4: 131–8. PubMed 10.10. Sanduleanu S, et al. Serum gastrin and chromogranin A during medium- and long-term acid suppressive therapy: a case-control study. Aliment Pharmacol Ther 1999; 13: 145–53. PubMed 11.11. Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut 2006; 55: 1217–21. PubMed 12.12. El-Nujumi A, et al. Eradicating Helicobacter pylori reduces hypergastrinaemia during long term omeprazole treatment. Gut 1998; 42: 159–65. PubMed 13.13. Kuipers EJ, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med 1996; 334: 1018–22. PubMed 14.14. Labenz J, Malfertheiner P. Helicobacter pylori in gastro-oesophageal reflux disease: causal agent, independent or protective factor? Gut 1997; 41: 277–80. PubMed 15.15. Graham JR. Gastric polyposis: onset during long-term therapy with omeprazole. Med J Aust 1992; 157: 287–8. PubMed 16.16. Graham JR. Gastric acne: omeprazole-induced fundic gland polyposis. Med J Aust 1998; 168: 93. PubMed 17.17. Tamim H, et al. Association between use of acid-suppressive drugs and risk of gastric cancer: a nested case-control study. Drug Safety 2008; 31: 675–84. PubMed

Hypersensitivity

Cases of anaphylactic reactions after treatment with omeprazole, lansoprazole, and pantoprazole, have been reported in the literature and to WHO.1 Cross-sensitivity to pantoprazole was reported2 on skin-testing in 4 of 9 patients sensitive to omeprazole; oral challenge tests with pantoprazole in 3 patients, 2 of whom were negative on skin testing, produced pruritus and urticaria in all 3. However, none of the patients had a reaction to skin tests with lansoprazole, and 8 of the 9 tolerated oral challenge with lansoprazole without problems; the other developed widespread urticaria one hour after a therapeutic dose was reached.

Urticaria, facial angioedema, and bronchospasm in a patient given omeprazole capsules did not recur when the patient was given omeprazole granules and the reaction might have been precipitated by the ingredients of the capsule shell.3 See also under Effects on the Kidney, , and Effects on the Musculoskeletal System, .

1. 1. Natsch S, et al. Anaphylactic reactions to proton-pump inhibitors. Ann Pharmacother 2000; 34: 474–6. PubMed 2. 2. Lobera T, et al. Nine cases of omeprazole allergy: cross-reactivity between proton pump inhibitors. J Investig Allergol Clin Immunol 2009; 19: 57–60. PubMed 3. 3. Haeney MR. Angio-oedema and urticaria associated with omeprazole. BMJ 1992; 305: 870. PubMed

Infection

Gastric-acid suppressing drugs such as proton pump inhibitors and H2- antagonists have been linked to an increased risk of infection. A systematic review1 found an increased risk of enteric infections such as Salmonella, Campylobacter, Shigella, or Clostridium difficile in patients taking acid Martindale: The Complete Drug Reference suppressing drugs, although there was considerable heterogeneity between studies. Increased rates of sepsis2 and necrotising enterocolitis3 have also been reported in infants given H2-antagonists. It has been suggested that the increased rate of infection could be due to the rise in gastric pH after acid suppressive treatment, resulting in increased microbial colonisation of the upper gastrointestinal tract.1-3 Results from studies into the risk of developing community-acquired pneumonia with the use of acid suppressants have been inconsistent. Increased rates of pneumonia have been reported with current use of acid suppressants in case-control and cohort studies,4-7 whereas an industrysponsored analysis of pooled adverse effect data on esomeprazole did not support an association between its use and respiratory-tract infections, including pneumonia.8 A case control study found no overall increase in the risk of community-acquired pneumonia with current use of proton pump inhibitors, although unexpectedly, an increased risk was noted when proton pump inhibitors had been started in the previous month.9 A systematic review also failed to find an association between use of proton pump inhibitors (esomeprazole, rabeprazole, pantoprazole and omeprazole) and respiratory infections, although it noted a trend towards an association.10

1. 1. Leonard J, et al. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007; 102: 2047–56. PubMed 2. 2. Bianconi S, et al. Ranitidine and late-onset sepsis in the neonatal intensive care unit. J Perinat Med 2007; 35: 147–50. PubMed 3. 3. Guillet R, et al. National Institute of Child Health and Human Development Neonatal Research Network. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2006; 117: e137–e142. PubMed Also available at: online (accessed 09/04/08) 4. 4. Laheij RJF, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004; 292: 1955–60. PubMed 5. 5. Canani RB, et al. Working Group on Intestinal Infections of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP). Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics 2006; 117: e817–e820. PubMed Available at: online (accessed 01/04/09) 6. 6. Herzig SJ, et al. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. JAMA 2009; 301: 2120–8. PubMed 7. 7. Eurich DT, et al. Recurrent community-acquired pneumonia in patients starting acid-suppressing drugs. Am J Med 2010; 123: 47–53. PubMed 8. 8. Estborn L, Joelson S. Occurrence of community-acquired respiratory tract infection in patients receiving esomeprazole: retrospective analysis of adverse events in 31 clinical trials. Drug Safety 2008; 31: 627–36. PubMed 9. 9. Sarkar M, et al. Proton-pump inhibitor use and the risk for communityacquired pneumonia. Ann Intern Med 2008; 149: 391–8. PubMed 10.10. Sultan N, et al. Association between proton pump inhibitors and respiratory infections: a systematic review and meta-analysis of clinical trials. Can J Gastroenterol 2008; 22: 761–6. PubMed

Lupus syndrome

For a report of drug-induced lupus syndrome associated with omeprazole therapy, see Effects on the Musculoskeletal System, .

Malabsorption

Omeprazole has been reported to result in a substantial reduction in cyanocobalamin (vitamin B12) absorption,1 probably related to the increase in gastric pH, and indicating a potential risk of vitamin deficiency with longterm therapy.2 UK licensed product information recommends that severely ill children, who may have borderline body stores of cyanocobalamin, should have serum vitamin B12 concentrations monitored if they require long-term therapy. Omeprazole has also been reported to impair the bioavailability of dietary vitamin C. 3 Fat malabsorption, secondary to increased deconjugation of bile acids caused by bacterial overgrowth in the jejunum, has also been reported with omeprazole treatment.4 For the suggestion that proton pump inhibitors can cause calcium malabsorption, see Effects on the Musculoskeletal System, . 1. 1. Marcuard SP, et al. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med 1994; 120: 211–15. PubMed 2. 2. Termanini B, et al. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. Am J Med 1998; 104: 422–30. PubMed 3. 3. Henry EB, et al. Proton pump inhibitors reduce the bioavailability of dietary vitamin C. Aliment Pharmacol Ther 2005; 22: 539–45. PubMed 4. 4. Shindo K, et al. Omeprazole induces altered bile acid metabolism. Gut 1998; 42: 266–71. PubMed

Overdosage

A report of 2 cases of overdosage with omeprazole.1 The major clinical features were drowsiness, headache (possibly due to a metabolite), and tachycardia. Both patients recovered uneventfully without specific treatment. 1. 1. Ferner RE, Allison TR. Omeprazole overdose. Hum Exp Toxicol 1993; 12: 541–2. PubMed

Precautions (Latest modification: 15-Jul-2008)

Before giving omeprazole or other proton pump inhibitors to patients with gastric ulcers the possibility of malignancy should be excluded since these drugs may mask symptoms and delay diagnosis. Omeprazole and other proton pump inhibitors should be used with caution in hepatic impairment and dose adjustment may be required.

Gastric carcinoma

Proton pump inhibitors relieve dyspeptic symptoms associated with gastric carcinoma and can therefore delay its diagnosis. In addition, there is some evidence that they may also endoscopically 'heal' early gastric carcinoma so that the diagnosis is missed.1 Consequently, some commentators recommend that proton pump inhibitors should not be prescribed for symptom control before endoscopy in patients at risk for gastric carcinoma.2 1. 1. Wayman J, et al. The response of early gastric cancer to proton-pump inhibitors. N Engl J Med 1998; 338: 1924–5. PubMed 2. 2. Griffin SM, Raimes SA. Proton pump inhibitors may mask early gastric cancer: dyspeptic patients over 45 should undergo endoscopy before these drugs are started. BMJ 1998; 317: 1606–7. PubMed

Helicobacter infection

Treatment with proton pump inhibitors may cause false-negative results in the urea breath test for Helicobacter pylori infection. In one study in patients with H. pylori infection, lansoprazole 30 mg daily for 4 weeks caused 33% of patients to have negative urea breath tests.1 The breath test became positive again in all patients within 2 weeks of stopping lansoprazole therapy. In a similar study, 52% of patients had negative urea breath tests for H. pylori while receiving omeprazole 20 mg daily, and the breath test became positive again in all patients within 2 to 6 days of stopping treatment.2 The manufacturers of the urea breath test for H. pylori recommend that it should not be performed for at least 2 weeks after stopping treatment with an antisecretory drug.

For a discussion of the link between proton pump inhibitors, H. pylori, and gastritis, see under Gastrointestinal Tumours .

1. 1. Laine L, et al. Effect of proton-pump inhibitor therapy on diagnostic testing for Helicobacter pylori. Ann Intern Med 1998; 129: 547–50. PubMed 2. 2. Connor SJ, et al. The effect of dosing with omeprazole on the accuracy of the 13C-urea breath test in Helicobacter pylori-infected subjects. Aliment Pharmacol Ther 1999; 13: 1287–93. PubMed

Hepatic impairment

In patients with cirrhosis an increase in omeprazole bioavailability, and elimination half-life has been reported.1 For dosage adjustment in hepatic impairment see Administration in Hepatic Impairment, .

1. 1. Andersson T, et al. Pharmacokinetics of [14C]omeprazole in patients with liver cirrhosis. Clin Pharmacokinet 1993; 24: 71–8. PubMed

Interactions (Latest modification: 29-Sep-2009)

أدوية كثيرة تتفاعل معه ويتفاعل معها ويلاحظ إستخدام كثير منها في المسنين والرعايات المركزة وهذا ينفي أنه دواء آمن. له تداخلات لا نعرفها. Omeprazole and other proton pump inhibitors are metabolised by the cytochrome P450 system, primarily by isoenzyme CYP2C19, and to a smaller extent by CYP3A4. Inhibitors or inducers of these isoenzymes may affect exposure to omeprazole and other proton pump inhibitors. In turn, proton pump inhibitors may alter the metabolism of some drugs metabolised by these enzymes. Omeprazole may prolong the elimination of diazepam, phenytoin, and warfarin (but see ). Omeprazole and other proton pump inhibitors can reduce the absorption of drugs such as dasatinib, ketoconazole, and itraconazole, whose absorption is dependent on an acid gastric pH. With voriconazole, the plasma concentration of both drugs may be increased (for further information, see ). Other proton pump inhibitors may be similarly affected by voriconazole. Omeprazole and other proton pump inhibitors should not be used with atazanavir, as it substantially reduces exposure to atazanavir. Omeprazole is metabolised primarily by the cytochrome P450 isoenzyme CYP2C19 (see Metabolism, ) and therefore may interact with diazepam (see under Gastrointestinal Drugs, ). Some metabolism of phenytoin (see ), tolbutamide, and the R-enantiomer of warfarin (see ) also takes place by CYP2C19, but the effects seen have been minor.1 Although some induction of CYP1A2, which metabolises caffeine and theophylline ( ), has been reported this does not appear to be clinically significant.2 While some consider the effect of omeprazole on CYP3A4 activity to be insignificant,3 others have noted increasing evidence that competitive inhibition of intestinal CYP3A4 by omeprazole may affect the first-pass metabolism of several drugs.4 A review concluded that, while omeprazole and possibly esomeprazole have a considerable potential for drug interactions, lansoprazole, pantoprazole and rabeprazole are associated with a lower incidence of drug interactions.4 For a study in vitro suggesting that omeprazole affected CYP3A4 metabolism of tacrolimus, see under Interactions of Tacrolimus, . For more on the effect of proton pump inhibitors on tacrolimus, see Gastrointestinal Drugs, . For reference to the possibility of enhanced digoxin absorption with omeprazole, see . For a study suggesting that omeprazole reduces the absorption of cyanocobalamin and vitamin C, see Malabsorption, , and for its effect on calcium absorption see . For reference to possible interactions between methotrexate and omeprazole, see .

1. 1. Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors: focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet 1996; 31: 9–28. PubMed 2. 2. Rizzo N, et al. Omeprazole and lansoprazole are not inducers of cytochrome P4501A2 under conventional therapeutic conditions. Eur J Clin Pharmacol 1996; 49: 491–5. PubMed 3. 3. Tateishi T, et al. Omeprazole does not affect measured CYP3A4 activity using the erythromycin breath test. Br J Clin Pharmacol 1995; 40: 411–12. PubMed 4. 4. Blume H, et al. Pharmacokinetic drug interaction profiles of proton pump inhibitors. Drug Safety 2006; 29: 769–84. PubMed

Clarithromycin

وهو مضاد حيوي مشهور في المسنين لسهولته جرعته. Studies in healthy subjects have indicated that use of omeprazole with clarithromycin results in an approximate 30% increase in peak plasma concentrations of omeprazole, and an increase in its mean half-life from 1.2 to 1.6 hours.1 At the same time, plasma concentrations of clarithromycin were also modestly increased, as were local concentrations in gastric tissue and mucus.1 Clarithromycin inhibits2 the metabolism of omeprazole mediated by the cytochrome P450 isoenzyme CYP3A4. The interaction may contribute to the benefits of combined therapy for Helicobacter pylori infection.

1. 1. Gustavson LE, et al. Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state. Antimicrob Agents Chemother 1995; 39: 2078–83. PubMed 2. 2. Furuta T, et al. Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans. Clin Pharmacol Ther 1999; 66: 265–74. PubMed

Clopidogrel

For recommendations that the use of proton pump inhibitors such as omeprazole with clopidogrel should be discouraged, see . يوجد مرجع يشير له مارتندل. ومارتندل ينصح بعدم إستخدام الأوميبراز مع البلافكس.

Fluvoxamine

Omeprazole and other proton pump inhibitors are metabolised mainly by cytochrome P450 isoenzyme CYP2C19, which shows genetically determined polymorphism, yielding extensive metabolisers and poor metabolisers. Fluvoxamine increased exposure to omeprazole, lansoprazole, and rabeprazole in patients who were extensive metabolisers, but had no effect on pharmacokinetic parameters in poor metabolisers.1-3 Dose reductions may need to be considered in patients treated with fluvoxamine and proton pump inhibitors.

1. 1. Yasui-Furukori N, et al. Different inhibitory effect of fluvoxamine on omeprazole metabolism between CYP2C19 genotypes. Br J Clin Pharmacol 2004; 57: 487–94. PubMed 2. 2. Yasui-Furukori N, et al. Effects of fluvoxamine on lansoprazole pharmacokinetics in relation to CYP2C19 genotypes. J Clin Pharmacol 2004; 44: 1223–9. PubMed 3. 3. Uno T, et al. Different effects of fluvoxamine on rabeprazole pharmacokinetics in relation to CYP2C19 genotype status. Br J Clin Pharmacol 2006; 61: 309–14. PubMed

Voriconazole

When omeprazole is given with voriconazole, exposure to both drugs is increased. UK licensed product information for omeprazole states that a dose adjustment of omeprazole is not routinely indicated, unless patients have severe hepatic impairment and long-term therapy is indicated. However, UK licensed product information for voriconazole states that, while no dosage adjustment is considered necessary for voriconazole, when patients already receiving omeprazole are started on voriconazole, the dose of omeprazole should be halved. Other proton pump inhibitors may be similarly affected by voriconazole.

ب

Bioavailability of omeprazole may be increased in elderly patients, in some ethnic groups such as Chinese, and in patients with hepatic impairment, but is not markedly affected in patients with renal impairment.

Uses and Administration (Latest modification: 29-Jul-2010)

Omeprazole is a proton pump inhibitor. It suppresses secretion of gastric acid by inhibiting the enzyme system of hydrogen/potassium adenosine triphosphatase (H+ /K+ ATPase), the 'proton pump' of the gastric parietal cell.

It is used in conditions where inhibition of gastric acid secretion may be beneficial, including aspiration syndromes ( ), dyspepsia ( ), gastrooesophageal reflux disease ( ), peptic ulcer disease ( ), and the Zollinger-Ellison syndrome ( ).

Esomeprazole ( ), an isomer of omeprazole, is also used.

Omeprazole may be given orally as the base or magnesium salt, or intravenously as the sodium salt. Doses are expressed in terms of the base. Omeprazole magnesium 10.32 mg and omeprazole sodium 10.64 mg are each equivalent to about 10 mg of omeprazole.

For the relief of acid-related dyspepsia omeprazole is given in usual doses of 10 or 20 mg daily orally for 2 to 4 weeks. فقط عسر الهضم ذو الصلة بالحامض وليس أي عسر هضم كما يجهل الناس

The usual dose for the treatment of gastro-oesophageal reflux disease is 20 mg orally once daily for 4 weeks, followed by a further 4 to 8 weeks if not fully healed. In refractory oesophagitis, a dose of 40 mg daily may be used. Maintenance therapy after healing of oesophagitis is 20 mg once daily, and for acid reflux is 10 mg daily. For dosage in children see . وليس 40 ملليجم

In the management of peptic ulcer disease a single daily dose of 20 mg orally, or 40 mg in severe cases, is given. Treatment is continued for 4 weeks for duodenal ulcer and 8 weeks for gastric ulcer. Where appropriate, a dose of 10 to 20 mg once daily may be given for maintenance. لهذا جرعة 40 ممللي جم بتاعت الPolypill asprin omepraz تعتبر كفتة.

For the eradication of Helicobacter pylori in peptic ulceration omeprazole may be combined with antibacterials in dual or triple therapy. Effective triple therapy regimens include omeprazole 20 mg twice daily or 40 mg once daily combined with: amoxicillin 500 mg and metronidazole 400 mg, both three times daily; clarithromycin 250 mg and metronidazole 400 mg (or tinidazole 500 mg) both twice daily; or with amoxicillin 1 g and clarithromycin 500 mg, both twice daily. These regimens are given for 1 week. Dual therapy regimens such as omeprazole 20 mg twice daily or 40 mg daily with either amoxicillin 750 mg to 1 g twice daily or clarithromycin 500 mg three times daily, are licensed but are much less effective and must be given for 2 weeks. Omeprazole alone may be continued for a further 4 to 8 weeks.

Doses of 20 mg daily orally are used in the treatment of NSAID-associated ulceration; a dose of 20 mg daily may also be used for prophylaxis in patients with a history of gastroduodenal lesions who require continued NSAID treatment.

The initial recommended dosage for patients with the Zollinger-Ellison syndrome is 60 mg orally once daily, adjusted as required. The majority of patients are effectively controlled by doses in the range 20 to 120 mg daily, but doses up to 120 mg three times daily have been used. Daily doses above 80 mg should be given as divided doses (usually 2). Omeprazole is also used for the prophylaxis of acid aspiration during general anaesthesia, in a dose of 40 mg the evening before surgery and a further 40 mg two to six hours before the procedure. The dose of omeprazole may need to be reduced in patients with hepatic impairment (see ).

===PARENTERAL DOSAGE=== In patients who are unsuited to receive oral therapy omeprazole sodium may be given on a short-term basis by intravenous infusion, in a usual dose equivalent to 40 mg of the base over a period of 20 to 30 minutes in 100 mL of sodium chloride 0.9% or glucose 5%. It may also be given by slow intravenous injection. Higher intravenous doses have been given to patients with Zollinger-Ellison syndrome.

Although unlicensed in the UK for major peptic bleeding after endoscopy, the BNF 59 suggests that omeprazole 80 mg can be infused intravenously over 40 to 60 minutes, followed by a continuous infusion of 8 mg/hour for 72 hours; treatment can then be continued orally. General reviews.

1. 1. Langtry HD, Wilde MI. Omeprazole: a review of its use in Helicobacter pylori infection, gastro-oesophageal reflux disease and peptic ulcers induced by nonsteroidal anti-inflammatory drugs. Drugs 1998; 56: 447– 86. PubMed 2. 2. Berardi RR, Welage LS. Proton-pump inhibitors in acid-related diseases. Am J Health-Syst Pharm 1998; 55: 2289–98. PubMed 3. 3. Erstad BL. Proton-pump inhibitors for acute peptic ulcer bleeding. Ann Pharmacother 2001; 35: 730–40. PubMed 4. 4. Robinson M, Horn J. Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. Drugs 2003; 63: 2739–54. PubMed 5. 5. Dekel R, et al. The role of proton pump inhibitors in gastro-oesophageal reflux disease. Drugs 2004; 64: 277–95. PubMed 6. 6. Anonymous. Proton pump inhibitors for GERD in children. Med Lett Drugs Ther 2007; 49: 17–18. PubMed 7. 7. Boparai V, et al. Guide to the use of proton pump inhibitors in adult patients. Drugs 2008; 68: 925–47. PubMed 8. 8. Lazzaroni M, Porro GB. Management of NSAID-induced gastrointestinal toxicity: focus on proton pump inhibitors. Drugs 2009; 69: 51–69. PubMed 9. 9. Bardou M, et al. Intravenous proton pump inhibitors: an evidence-based review of their use in gastrointestinal disorders. Drugs 2009; 69: 435–48. PubMed

Dyspepsia

تصريح مهم يجب مراجعته لأن الدواء ليس آمن كما ظنوا من قبل. Although earlier UK guidelines on the use of proton pump inhibitors in dyspepsia ( ) suggested that they should not be used routinely in nonulcer dyspepsia,1 subsequent guidelines on its general management in both the UK2 and the USA3 consider that a 1-month empirical trial in patients aged under 55 without symptoms suggestive of more serious disease is a valid first-line treatment.

فقط شهر واحد ولا يكون مسن

1. 1. NICE. Guidance on the use of proton pump inhibitors in the treatment of dyspepsia (issued July 2000). Available at: online (accessed 11/02/08)

2. 2. NICE. Dyspepsia: management of dyspepsia in adults in primary care (Clinical Guideline 17: issued August 2004, updated June 2005). Available at: online (accessed 11/02/08)

3. 3. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology 2005; 129: 1753–5. PubMed Also available at: online (accessed 11/02/08)

غزارة الأسماء وغزارة الإنتاج

Preparations (Latest modification: 07-Feb-2011)

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The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

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Multi-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Danlox Rapido; Gastec Rapido; Australia: Klacid HP 7; Losec Helicopak¤; Losec Hp 7¤; Brazil: Erradic; Helicocid Triplice¤; Omepramix; Canada: Losec 1-2-3 A¤; Losec 1-2-3 M¤; Finland: Losec Helira¤; India: Helipac; Nogacid D; Okacid D; OTC HP Kit; Malaysia: Pylobact Combi; Mexico: Pridamiral Pack; New Zealand: Helicosec¤; Klacid HP 7¤; Losec Hp7; Philippines: OAC Hp7¤; Russia: Pylobact (Пилобакт); South Africa: Losec 20 Triple¤; Ukraine: Limzer (Лімзер); Omez-D (Омез-Д); Pylobact Neo (Пилобакт Нео); United States: Zegerid;

Adjuvant to Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Dioxaflex Protect; United Kingdom: Axorid;

لإجراء تعداد لعدد الأسماء التجارية الأفضل الرجوع للملف اللأصلي لأنه ملون وواضح فيكون سهل بإذن الله

رابط

http://www.valeant.com.mx/cif/repositorio/archivos/detalles/20121113_100426_115_4.pdf