Advertisement

Drug Safety

, Volume 40, Issue 10, pp 895–909 | Cite as

Muscular Adverse Drug Reactions Associated with Proton Pump Inhibitors: A Disproportionality Analysis Using the Italian National Network of Pharmacovigilance Database

  • Alice Capogrosso Sansone
  • Irma Convertino
  • Maria Teresa Galiulo
  • Stefano Salvadori
  • Stefania Pieroni
  • Tamara Knezevic
  • Stefania Mantarro
  • Alessandra Marino
  • Manfred Hauben
  • Corrado Blandizzi
  • Marco Tuccori
Original Research Article

Abstract

Introduction

Proton pump inhibitors (PPIs) have been implicated in the occurrence of moderate to severe myopathies in several case reports.

Aim

This study was performed to assess the reporting risk of muscular adverse drug reactions (ADRs) associated with PPIs in the Italian National Network of Pharmacovigilance database.

Methods

A disproportionality analysis (case/non-case) was performed using spontaneous reports collected in the database between July 1983 and May 2016. Reporting odds ratio (ROR) and 95% confidence intervals (CIs) were calculated as a measure of disproportionality. In a secondary and tertiary analysis, we explored the association of PPIs with muscular ADRs after taking into account the masking effect of statins. Moreover, the possibility of an interaction between PPIs and statins, leading to the occurrence of muscular ADRs, was also tested.

Results

The study was carried out on 274,108 reports. The ROR of muscular ADRs for PPIs, adjusted for age and gender, was 1.484 (95% CI 1.204–1.829; p < 0.001), whereas the ROR for rhabdomyolysis was 0.621 (95% CI 0.258–1.499). Similar results were obtained in the secondary analysis. The tertiary analysis, where PPIs were considered regardless of whether their role was suspected or concomitant, showed a potential disproportionate reporting for the combination PPIs–rhabdomyolysis (ROR 1.667, 95% CI 1.173–2.369; p < 0.01). The PPIs–statins combination was not associated with an enhanced ROR of muscular ADRs/rhabdomyolysis compared with statins alone.

Conclusions

This explorative study suggests that the class of PPIs could be involved in reports of muscular ADRs, rather than any other ADR, more frequently than any non-statin drug. Our results must be corroborated by further studies.

Notes

Compliance with Ethical Standards

Funding

No funding was used for the preparation of this manuscript.

Conflicts of interest

Manfred Hauben is a full-time employed of Pfizer Inc. and receives part of his compensation in the form of stock options and restricted stock units. He has also declared he owns stocks in other pharmaceutical companies that, like Pfizer Inc., manufacture and/or market statins and PPIs. Marco Tuccori, Alice Capogrosso Sansone, Irma Convertino, Maria Teresa Galiulo, Stefano Salvadori, Stefania Pieroni, Tamara Knezevic, Stefania Mantarro, Alessandra Marino and Corrado Blandizzi have no conflicts of interest that are directly relevant to the content of this study.

Ethical Approval and Patient Consent

Ethical approval and patient consent are not required for this kind of study.

Supplementary material

40264_2017_564_MOESM1_ESM.pdf (358 kb)
Supplementary material 1 (PDF 357 kb)

References

  1. 1.
    Dalakas MC. Toxic and drug-induced myopathies. J Neurol Neurosurg Psychiatry. 2009;80(8):832–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40(3):567–72.CrossRefPubMedGoogle Scholar
  3. 3.
    Alis R, Sanchis-Gomar F, Risso-Ballester J, et al. Inhibition of xanthine oxidase to prevent statin-induced myalgia and rhabdomiolysis. Atherosclerosis. 2015;239(1):38–42.CrossRefPubMedGoogle Scholar
  4. 4.
    Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346(7):539–40.CrossRefPubMedGoogle Scholar
  5. 5.
    Motola D, Vargiu A, Leone R, et al. Influence of regulatory measures on the rate of spontaneous adverse drug reaction reporting in Italy. Drug Saf. 2008;31(7):609–16.CrossRefPubMedGoogle Scholar
  6. 6.
    McAdams M, Staffa J, Dal Pan G. Estimating the extent of reporting to FDA: a case study of statin-associated rhabdomyolysis. Pharmacoepidemiol Drug Saf. 2008;17(3):229–39.CrossRefPubMedGoogle Scholar
  7. 7.
    Conforti A, Chiamulera C, Moretti U, et al. Musculoskeletal adverse drug reactions: a review of literature and data from ADR spontaneous reporting databases. Curr Drug Saf. 2007;2(1):47–63.CrossRefPubMedGoogle Scholar
  8. 8.
    Bebarta VS, King JA, McDonough M. Proton pump inhibitor-induced rhabdomyolysis and hyponatremic delirium. Am J Emerg Med 2008;26(4):519 e1–2.Google Scholar
  9. 9.
    Tanaka K, Nakada TA, Abe R, et al. Omeprazole-associated rhabdomyolysis. Crit Care. 2014;18(4):462.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Troger U, Reiche I, Jepsen MS, et al. Esomeprazole-induced rhabdomyolysis in a patient with heart failure. Intensive Care Med. 2010;36(7):1278–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Di Grande A, Giustolisi V, Tabita V, et al. Hypokalemic rhabdomyolysis in a patient with a laparoscopic adjustable gastric banding. Clin Ter. 2008;159(3):169–72.PubMedGoogle Scholar
  12. 12.
    Garrote FJ, Lacambra C, del Ser T, et al. Subacute myopathy during omeprazole therapy. Lancet. 1992;340(8820):672.CrossRefPubMedGoogle Scholar
  13. 13.
    Tuccori M, Giovannoni S, Giustini SE, et al. Acute severe myopathy following a single infusion of omeprazole. Ann Pharmacother. 2006;40(2):352–3.CrossRefPubMedGoogle Scholar
  14. 14.
    Nozaki M, Suzuki T, Hirano M. Rhabdomyolysis associated with omeprazole. J Gastroenterol. 2004;39(1):86.CrossRefPubMedGoogle Scholar
  15. 15.
    Grattagliano I, Portincasa P, Mastronardi M, et al. Esomeprazole-induced central fever with severe myalgia. Ann Pharmacother. 2005;39(4):757–60.CrossRefPubMedGoogle Scholar
  16. 16.
    Visruthan NK, Boo PK, Kader A, et al. Omeprazole-induced myositis in a child receiving triple therapy for Helicobacter pylori infection. J Pediatr Gastroenterol Nutr. 2012;55(3):338–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Sivakumar K, Dalakas MC. Autoimmune syndrome induced by omeprazole. Lancet. 1994;344(8922):619–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Villa A, Martinoli E, Nucera G, et al. Proton pump inhibitor-induced hypomagnesemia. Italian J Med. 2014;8(s2):134.Google Scholar
  19. 19.
    Bilbao JM, Moddel G. Autophagic myopathy induced by omeprazole therapy. Can J Neurol Sci. 1998;25(4):339.Google Scholar
  20. 20.
    Colmenares EW, Pappas AL. Proton pump inhibitors: risk for myopathy? Ann Pharmacother 2016. doi: 10.1177/1060028016665641.
  21. 21.
    Jeon DH, Kim Y, Kim MJ, et al. Rhabdomyolysis associated with single-dose intravenous esomeprazole administration: a case report. Med (Baltimore). 2016;95(29):e4313.CrossRefGoogle Scholar
  22. 22.
    Wang AK, Sharma S, Kim P, et al. Hypomagnesemia in the intensive care unit: choosing your gastrointestinal prophylaxis, a case report and review of the literature. Indian J Crit Care Med. 2014;18(7):456–60.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Clark DW, Strandell J. Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors? Eur J Clin Pharmacol. 2006;62(6):473–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Ruiter R, Visser LE, van Herk-Sukel MP, et al. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia. 2012;55(1):51–62.CrossRefPubMedGoogle Scholar
  25. 25.
    Colmers IN, Bowker SL, Tjosvold LA, et al. Insulin use and cancer risk in patients with type 2 diabetes: a systematic review and meta-analysis of observational studies. Diabetes Metab. 2012;38(6):485–506.CrossRefPubMedGoogle Scholar
  26. 26.
    Bronsveld HK, ter Braak B, Karlstad O, et al. Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence. Br Cancer Res BCR. 2015;17:100.CrossRefGoogle Scholar
  27. 27.
    Grimaldi-Bensouda L, Cameron D, Marty M, et al. Risk of breast cancer by individual insulin use: an international multicenter study. Diabetes Care. 2014;37(1):134–43.CrossRefPubMedGoogle Scholar
  28. 28.
    Elazzazy S, Eziada SS, Zaidan M. Rhabdomyolysis secondary to drug interaction between atorvastatin, omeprazole, and dexamethasone. Int Med Case Rep J. 2012;5:59–61.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sipe BE, Jones RJ, Bokhart GH. Rhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interaction. Ann Pharmacother. 2003;37(6):808–11.CrossRefPubMedGoogle Scholar
  30. 30.
    Kanth R, Shah MS, Flores RM. Statin-associated polymyositis following omeprazole treatment. Clin Med Res. 2013;11(2):91–5.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Marusic S, Lisicic A, Horvatic I, et al. Atorvastatin-related rhabdomyolysis and acute renal failure in a genetically predisposed patient with potential drug–drug interaction. Int J Clin Pharm. 2012;34(6):825–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Hylton AC, Ezekiel TO. Rhabdomyolysis in a patient receiving ranolazine and simvastatin. Am J Health Syst Pharm. 2010;67(21):1829–31.CrossRefPubMedGoogle Scholar
  33. 33.
    Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities (MedDRA). Drug Saf. 1999;20(2):109–17.CrossRefPubMedGoogle Scholar
  34. 34.
    Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45.CrossRefPubMedGoogle Scholar
  35. 35.
    Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ (Clin Res Ed). 2005;330(7503):1304–5.CrossRefGoogle Scholar
  36. 36.
    Yue Z, Shi J, Jiang P, et al. Acute kidney injury during concomitant use of valacyclovir and loxoprofen: detecting drug–drug interactions in a spontaneous reporting system. Pharmacoepidemiol Drug Saf. 2014;23(11):1154–9.CrossRefPubMedGoogle Scholar
  37. 37.
    de Langen JJ, van Puijenbroek EP. HMG-CoA-reductase inhibitors and neuropathy: reports to the Netherlands Pharmacovigilance Centre. Neth J Med. 2006;64(9):334–8.PubMedGoogle Scholar
  38. 38.
    Cakir M, Samanci N, Balci N, et al. Musculoskeletal manifestations in patients with thyroid disease. Clin Endocrinol (Oxf). 2003;59(2):162–7.CrossRefGoogle Scholar
  39. 39.
    Lindner LS, Emkey GR. Exertion-related rhabdomyolysis observed with hyperthyroidism. Am J Med. 2015;128(6):e7–8.CrossRefPubMedGoogle Scholar
  40. 40.
    van Puijenbroek EP, Egberts AC, Heerdink ER, et al. Detecting drug–drug interactions using a database for spontaneous adverse drug reactions: an example with diuretics and non-steroidal anti-inflammatory drugs. Eur J Clin Pharmacol. 2000;56(9–10):733–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Van Puijenbroek EP, Egberts AC, Meyboom RH, et al. Signalling possible drug–drug interactions in a spontaneous reporting system: delay of withdrawal bleeding during concomitant use of oral contraceptives and itraconazole. Br J Clin Pharmacol. 1999;47(6):689–93.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Egberts AC, Meyboom RH, van Puijenbroek EP. Use of measures of disproportionality in pharmacovigilance: three Dutch examples. Drug Saf. 2002;25(6):453–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Piccinni C, Gissi DB, Gabusi A, et al. Paraesthesia after local anaesthetics: an analysis of reports to the FDA Adverse Event Reporting System. Basic Clin Pharmacol Toxicol. 2015;117(1):52–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Hauben M, Reich L. Communication of findings in pharmacovigilance: use of the term “signal” and the need for precision in its use. Eur J Clin Pharmacol. 2005;61(5–6):479–80.CrossRefPubMedGoogle Scholar
  45. 45.
    Hauben M, Hung EY. Revisiting the reported signal of acute pancreatitis with rasburicase: an object lesson in pharmacovigilance. Ther Adv Drug Saf. 2016;7(3):94–101.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Maignen F, Hauben M, Hung E, et al. Assessing the extent and impact of the masking effect of disproportionality analyses on two spontaneous reporting systems databases. Pharmacoepidemiol Drug Saf. 2014;23(2):195–207.CrossRefPubMedGoogle Scholar
  47. 47.
    Wang HW, Hochberg AM, Pearson RK, et al. An experimental investigation of masking in the US FDA adverse event reporting system database. Drug Saf. 2010;33(12):1117–33.CrossRefPubMedGoogle Scholar
  48. 48.
    Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case–control study. BMC Nephrol. 2013;14:150.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Harper CR, Jacobson TA. Evidence-based management of statin myopathy. Curr Atheroscler Rep. 2010;12(5):322–30.CrossRefPubMedGoogle Scholar
  50. 50.
    Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother. 2001;35(9):1096–107.CrossRefPubMedGoogle Scholar
  51. 51.
    Sathasivam S, Lecky B. Statin induced myopathy. BMJ. 2008;337:a2286.CrossRefPubMedGoogle Scholar
  52. 52.
    Juhlin K, Ye X, Star K, et al. Outlier removal to uncover patterns in adverse drug reaction surveillance—a simple unmasking strategy. Pharmacoepidemiol Drug Saf. 2013;22(10):1119–29.PubMedGoogle Scholar
  53. 53.
    van Puijenbroek EP, Bate A, Leufkens HG, et al. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol Drug Saf. 2002;11(1):3–10.CrossRefPubMedGoogle Scholar
  54. 54.
    Coulter D. Does omeprazole cause polymyositis? Proceedings of the Royal Australasian College of Physicians, Annual Clinical and Scientific meeting, 1996:81 (abstract).Google Scholar
  55. 55.
    Coulter DM. Signal generation in the New Zealand Intensive Medicines Monitoring Programme: a combined clinical and statistical approach. Drug Saf. 2002;25(6):433–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Gould AL. Practical pharmacovigilance analysis strategies. Pharmacoepidemiol Drug Saf. 2003;12(7):559–74.CrossRefPubMedGoogle Scholar
  57. 57.
    Pariente A, Avillach P, Salvo F, et al. Effect of competition bias in safety signal generation: analysis of a research database of spontaneous reports in France. Drug Saf. 2012;35(10):855–64.CrossRefPubMedGoogle Scholar
  58. 58.
    Hauben M, Hochberg A. The importance of reporting negative findings in data mining. Pharm Med. 2008;22(4):215–9.CrossRefGoogle Scholar
  59. 59.
    Salvo F, Leborgne F, Thiessard F, et al. A potential event-competition bias in safety signal detection: results from a spontaneous reporting research database in France. Drug Saf. 2013;36(7):565–72.CrossRefPubMedGoogle Scholar
  60. 60.
    Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev Clin Pharmacol. 2013;6(4):443–51.CrossRefPubMedGoogle Scholar
  61. 61.
    Wolfe-Wylie M, Mouzaki M, Sochett E, et al. chronic high dose proton-pump inhibitors as a cause of hypophosphatemic rickets. Endocr Rev 2016. doi: 10.1210/endo-meetings.2016.BCHVD.16.FRI-348.
  62. 62.
    Su SS, Yu KH, Woung PS. Comment: esomeprazole-induced central fever with severe myalgia. Ann Pharmacother 2005;39(10):1764; author reply 65.Google Scholar
  63. 63.
    Schonhofer PS, Werner B, Troger U. Ocular damage associated with proton pump inhibitors. BMJ. 1997;314(7097):1805.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Burlinson B, Morriss SH, Gatehouse DG, et al. Genotoxicity studies of gastric acid inhibiting drugs. Lancet. 1990;335(8686):419–20.CrossRefPubMedGoogle Scholar
  65. 65.
    National Report on Medicines use in Italy. 2015. The Medicines Utilisation Monitoring Centre. Available from: http://www.agenziafarmaco.gov.it/sites/default/files/Rapporto_OsMed_2015__AIFA.pdf. Last accessed on 23 Sept 2016.
  66. 66.
    Li XQ, Andersson TB, Ahlstrom M, et al. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos. 2004;32(8):821–7.CrossRefPubMedGoogle Scholar
  67. 67.
    Zvyaga T, Chang SY, Chen C, et al. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos. 2012;40(9):1698–711.CrossRefPubMedGoogle Scholar
  68. 68.
    Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002;41(12):913–58.CrossRefPubMedGoogle Scholar
  69. 69.
    Pauli-Magnus C, Rekersbrink S, Klotz U, et al. Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol. 2001;364(6):551–7.CrossRefPubMedGoogle Scholar
  70. 70.
    Holtzman CW, Wiggins BS, Spinler SA. Role of P-glycoprotein in statin drug interactions. Pharmacotherapy. 2006;26(11):1601–7.CrossRefPubMedGoogle Scholar
  71. 71.
    Barkas F, Elisaf M, Rizos CV, et al. Proton pump inhibitors and statins: a possible interaction that favors low-density lipoprotein cholesterol reduction? Hippokratia. 2015;19(4):332–7.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80(6):565–81.CrossRefPubMedGoogle Scholar
  73. 73.
    Cronican AA, Fitz NF, Pham T, et al. Proton pump inhibitor lansoprazole is a nuclear liver X receptor agonist. Biochem Pharmacol. 2010;79(9):1310–6.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Namazi MR, Sharifian M. The potential anti-xanthoma and anti-atherosclerotic effects of proton pump inhibitors. J Clin Pharm Ther. 2008;33(6):579–80.CrossRefPubMedGoogle Scholar
  75. 75.
    Bergvall T, Noren GN, Lindquist M. vigiGrade: a tool to identify well-documented individual case reports and highlight systematic data quality issues. Drug Saf. 2014;37(1):65–77.CrossRefPubMedGoogle Scholar
  76. 76.
    Sundstrom A, Hallberg P. Data mining in pharmacovigilance–detecting the unexpected: the role of index of suspicion of the reporter. Drug Saf. 2009;32(5):419–27.CrossRefPubMedGoogle Scholar
  77. 77.
    Ferrajolo C, Capuano A, Trifiro G, et al. Pediatric drug safety surveillance in Italian pharmacovigilance network: an overview of adverse drug reactions in the years 2001–2012. Expert Opin Drug Saf. 2014;13(Suppl 1):S9–20.CrossRefPubMedGoogle Scholar
  78. 78.
    O’Leary C, McCarthy J, Humphries M, et al. The prophylactic use of a proton pump inhibitor before food and alcohol. Aliment Pharmacol Ther. 2003;17(5):683–6.CrossRefPubMedGoogle Scholar
  79. 79.
    Sutherland D, Stanley AJ. Editorial: proton pump inhibitors in cirrhosis. Aliment Pharmacol Ther. 2015;41(6):592.CrossRefPubMedGoogle Scholar
  80. 80.
    Lodato F, Azzaroli F, Di Girolamo M, et al. Proton pump inhibitors in cirrhosis: tradition or evidence based practice? World J Gastroenterol. 2008;14(19):2980–5.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Munson JC, Wahl PM, Daniel G, et al. Factors associated with the initiation of proton pump inhibitors in corticosteroid users. Pharmacoepidemiol Drug Saf. 2012;21(4):366–74.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Bate A, Lindquist M, Edwards IR, et al. A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol. 1998;54(4):315–21.CrossRefPubMedGoogle Scholar
  83. 83.
    Noren GN, Bate A, Orre R, et al. Extending the methods used to screen the WHO drug safety database towards analysis of complex associations and improved accuracy for rare events. Stat Med. 2006;25(21):3740–57.CrossRefPubMedGoogle Scholar
  84. 84.
    Noren GN, Sundberg R, Bate A, et al. A statistical methodology for drug–drug interaction surveillance. Stat Med. 2008;27(16):3057–70.CrossRefPubMedGoogle Scholar
  85. 85.
    Strandell J, Bate A, Hagg S, et al. Rhabdomyolysis a result of azithromycin and statins: an unrecognized interaction. Br J Clin Pharmacol. 2009;68(3):427–34.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Strandell J, Caster O, Bate A, et al. Reporting patterns indicative of adverse drug interactions: a systematic evaluation in VigiBase. Drug Saf. 2011;34(3):253–66.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Alice Capogrosso Sansone
    • 1
  • Irma Convertino
    • 1
  • Maria Teresa Galiulo
    • 1
  • Stefano Salvadori
    • 2
  • Stefania Pieroni
    • 2
  • Tamara Knezevic
    • 2
  • Stefania Mantarro
    • 1
  • Alessandra Marino
    • 1
  • Manfred Hauben
    • 3
    • 5
  • Corrado Blandizzi
    • 1
    • 4
  • Marco Tuccori
    • 4
  1. 1.Division of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  2. 2.Institute of Clinical PhysiologyNational Research CouncilPisaItaly
  3. 3.Pfizer Inc.New YorkUSA
  4. 4.Unit of Adverse Drug Reactions Monitoring, Tuscan Regional Centre of PharmacovigilanceUniversity Hospital of PisaPisaItaly
  5. 5.Department of MedicineNew York University School of MedicineNew YorkUSA

Personalised recommendations