Bosentan: A review of its use in the management of mildly symptomatic pulmonary arterial hypertension

American Journal of Cardiovascular Drugs

Volumn 9, Issue 5, 2009, Pages 331-350

  Dhillon, Sohita ^a   Keating, Gillian M ^a  

^a ADIS INTERNATIONAL LIMITED   (New Zealand)

Author keywords

[No Author keywords available]

Indexed keywords

AMBRISENTAN; AMINOTRANSFERASE; BOSENTAN; CYCLOSPORIN; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; DIGOXIN; DIURETIC AGENT; ENDOTHELIN 1; ENDOTHELIN A RECEPTOR; ENDOTHELIN B RECEPTOR; ETHINYLESTRADIOL PLUS NORETHISTERONE; FLUCONAZOLE; GLIBENCLAMIDE; HEMOGLOBIN; ITRACONAZOLE; KETOCONAZOLE; LOPINAVIR PLUS RITONAVIR; NEVIRAPINE; PROSTACYCLIN; RIFAMPICIN; RITONAVIR; SILDENAFIL; SIMVASTATIN; TACROLIMUS; TADALAFIL; UNINDEXED DRUG; UNIPROST; VORICONAZOLE; WARFARIN;

ABDOMINAL DISCOMFORT; ABDOMINAL PAIN; ALANINE AMINOTRANSFERASE BLOOD LEVEL; AMINOTRANSFERASE BLOOD LEVEL; ANEMIA; CLINICAL TRIAL; DOSE RESPONSE; DOSE TIME EFFECT RELATION; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG DOSE TITRATION; DRUG ELIMINATION; DRUG EXPOSURE; DRUG FATALITY; DRUG HALF LIFE; DRUG METABOLISM; DRUG TOLERABILITY; DRUG TOLERANCE; DRUG WITHDRAWAL; ERYTHROCYTE TRANSFUSION; EXERCISE; FLUID THERAPY; FLUSHING; HEADACHE; HEART FAILURE; HOSPITALIZATION; HUMAN; HYPERTENSION; INFECTION; LEG EDEMA; LIVER FUNCTION; LIVER FUNCTION TEST; LIVER TOXICITY; LUNG VASCULAR RESISTANCE; PATIENT MONITORING; PLASMA CONCENTRATION-TIME CURVE; PRACTICE GUIDELINE; PRIORITY JOURNAL; PULMONARY HYPERTENSION; REVIEW; SIDE EFFECT; TACHYCARDIA; TREMOR; VASCULAR RESISTANCE; WORLD HEALTH ORGANIZATION;

ADOLESCENT; ADULT; ANTIHYPERTENSIVE AGENTS; DRUG INTERACTIONS; HUMANS; HYPERTENSION, PULMONARY; MULTICENTER STUDIES AS TOPIC; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RECEPTOR, ENDOTHELIN A; SULFONAMIDES;

EID: 70349947253     PISSN: 11753277     EISSN: 1179187X     Source Type: Journal    
DOI: 10.2165/11202270-000000000-00000     Document Type: Review

References (93)

1. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. Epub 2009 Aug 27
2. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009 Jun 30; 54 (1 Suppl.): S55-66
3. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004 Sep 30; 351 (14): 1425-1436
4. Highland KB. Pulmonary arterial hypertension. Am J Med Sci 2008 Jan; 335 (1): 40-45
5. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991 Sep 1; 115 (5): 343-349
6. Thenappan T, Shah SJ, Rich S, et al. A USA-based registry for pulmonary arterial hypertension: 1982-2006. Eur Respir J 2007 Dec; 30 (6): 1103-1110
7. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006 May 1; 173 (9): 1023-1030
8. Peacock AJ, Murphy NF, McMurray JJ, et al. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007 Jul; 30 (1): 104-109
9. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004 Oct 14; 351 (16): 1655-1665
10. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987 Aug; 107 (2): 216-223
11. Ghamra ZW, Dweik RA. Primary pulmonary hypertension: an overview of epidemiology and pathogenesis. Cleve Clin J Med 2003; 70 Suppl. 1: S2-8
12. Galie N, Manes A, Palazzini M, et al. Management of pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger's syndrome. Drugs 2008; 68 (8): 1049-1066 (Pubitemid 351693675)
13. Kahler CM, Colleselli D. Pulmonary arterial hypertension (PAH) in connective tissue diseases. Rheumatology (Oxford) 2006 Oct; 45 Suppl. 3: iii11-3 (Pubitemid 44446767)
14. Proudman SM, Stevens WM, Sahhar J, et al. Pulmonary arterial hypertension in systemic sclerosis: the need for early detection and treatment. Intern Med J 2007; 37 (7): 485-494 (Pubitemid 46855082)
15. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009 Jun 30; 54 (1 Suppl.): S43-54
16. Distler O, Pignone A. Pulmonary arterial hypertension and rheumatic diseases: from diagnosis to treatment. Rheumatology (Oxford) 2006; 45 Suppl. 4: iv22-5
17. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997 Jan 9; 336 (2): 111-117
18. Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009 Jun 30; 54 (1 Suppl.): S20-31
19. Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009 Jun 30; 54 (1 Suppl.): S10-9
20. Traiger GL. Pulmonary arterial hypertension. Crit Care Nurs Q 2007 Jan 31; 30 (1): 20-43
21. Murali S. Pulmonary arterial hypertension. Curr Opin Crit Care 2006 Jun; 12 (3): 228-234
22. Braun-Moscovici Y, Nahir AM, Balbir-Gurman A. Endothelin and pulmonary arterial hypertension. Semin Arthritis Rheum 2004; 34 (1): 442-453
23. European Medicines Agency. Tracleer (bosentan) 62.5mg film-coated tablets: summary of product characteristics [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/tracleer/H-401-PI-en.pdf [Accessed 2009 Aug 6]
24. Actelion Pharmaceuticals US Inc. Tracleer (bosentan) tablets: US prescribing information [online]. Available from URL: http://www.accessdata.fda. gov/drugsatfda-docs/label/2009/021290s012lbl.pdf [Accessed 2009 Aug 19]
25. Oldfield V, Lyseng-Williamson KA. Bosentan: a review of its use in pulmonary arterial hypertension and systemic sclerosis. Am J Cardiovasc Drugs 2006; 6 (3): 189-208
26. Prakash A, Perry CM. Bosentan. Am J Cardiovasc Drugs 2002; 2 (5): 335-43; discussion 343
27. Dingemanse J, van Giersbergen PLM. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet 2004; 43 (15): 1089-1115 (Pubitemid 40013178)
28. Barst RJ. A review of pulmonary arterial hypertension: role of ambrisentan. Vasc Health Risk Manag 2007; 3 (1): 11-22 (Pubitemid 46860713)
29. Clozel M, Breu V, Gray GA, et al. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther 1994 Jul; 270 (1): 228-235 (Pubitemid 24229632)
30. Dupuis J, Hoeper MM. Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J 2008 Feb; 31 (2): 407-415
31. Price LC, Howard LS. Endothelin receptor antagonists for pulmonary arterial hypertension: rationale and place in therapy. Am J Cardiovasc Drugs 2008; 8 (3): 171-185 (Pubitemid 351812270)
32. Opitz CF, Ewert R, Kirch W, et al. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur Heart J 2008 Jun 17; 29: 1936-1948
33. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993 Jun 17; 328 (24): 1732-1739 (Pubitemid 23170122)
34. Dupuis J, Cernacek P, Tardif JC, et al. Reduced pulmonary clearance of endothelin-1 in pulmonary hypertension. Am Heart J 1998 Apr; 135 (4): 614-620 (Pubitemid 28164896)
35. Dupuis J, Goresky CA, Fournier A. Pulmonary clearance of circulating endothelin-1 in dogs in vivo: exclusive role of ETB receptors. J Appl Physiol 1996 Oct; 81 (4): 1510-1515 (Pubitemid 26349600)
36. Hiramoto Y, Shioyama W, Kuroda T, et al. Effect of bosentan on plasma endothelin-1 concentration in patients with pulmonary arterial hypertension. Circ J 2007 Mar; 71 (3): 367-369 (Pubitemid 46409540)
37. Barst RJ, Ivy D, Dingemanse J, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003 Apr; 73 (4): 372-382
38. Galie N, Rubin LJ, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008 Jun 21; 371 (9630): 2093-2100
39. Sfikakis PP, Papamichael C, Stamatelopoulos KS, et al. Improvement of vascular endothelial function using the oral endothelin receptor antagonist bosentan in patients with systemic sclerosis. Arthritis Rheum 2007 Jun; 56 (6): 1985-1993
40. Sauvageau S, Thorin E, Villeneuve L, et al. Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: role of ETB-receptor expression levels. Pulm Pharmacol Ther 2009 Aug; 22 (4): 311-317
41. Mouchaers KT, Schalij I, Versteilen AM, et al. Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 2009 Jul; 297 (1): H200-7
42. Williams MH, Handler CE, Akram R, et al. Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. Eur Heart J 2006; 27 (12): 1485-1494 (Pubitemid 43998084)
43. European Medicines Agency. Tracleer: updated scientific discussion (tracleer-H-401-II-37-AR ) [online]. Available from URL: http://www.emea.europa. eu/humandocs/Humans/EPAR/tracleer/tracleerM2.htm [Accessed 2009 Aug 6]
44. Cella G, Vianello F, Cozzi F, et al. Effect of bosentan on plasma markers of endothelial cell activity in patients with secondary pulmonary hypertension related to connective tissue diseases. J Rheumatol 2009 Apr; 36 (4): 760-767
45. Iannone F, Riccardi MT, Guiducci S, et al. Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension. Ann Rheum Dis 2008 Aug; 67 (8): 1121-1126
46. Hamaguchi Y, Fujimoto M, Hasegawa M, et al. Bosentan increases serum IL-12 levels in systemic sclerosis patients with pulmonary arterial hypertension [letter]. J Dermatol Sci 2009 Mar 31; 55 (1): 66-67
47. Giannelli G, Iannone F, Marinosci F, et al. Clinical outcomes of bosentan in pulmonary arterial hypertension do not correlate with levels of TIMPs. Eur J Clin Invest 2006 Sep; 36 Suppl. 3: 73-77 (Pubitemid 44179787)
48. Giannelli G, Iannone F, Marinosci F, et al. The effect of bosentan on matrix metalloproteinase-9 levels in patients with systemic sclerosis-induced pulmonary hypertension. Curr Med Res Opin 2005 Mar; 21 (3): 327-332 (Pubitemid 40490670)
49. Yuyama H, Noguchi Y, Fujimori A, et al. Superiority of YM598 over atrasentan as a selective endothelin ETA receptor antagonist. Eur J Pharmacol 2004 Sep 13; 498 (1-3): 171-177 (Pubitemid 39208077)
50. Wu-Wong JR, Dixon DB, Chiou WJ, et al. Endothelin receptor antagonists: effect of serum albumin on potency and comparison of pharmacological characteristics. J Pharmacol Exp Ther 1997 May; 281 (2): 791-798
51. Yang Z, Krasnici N, Lüscher TF. Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade. Circulation 1999 Jul 6; 100 (1): 5-8
52. Kunichika N, Landsberg JW, Yu Y, et al. Bosentan inhibits transient receptor potential channel expression in pulmonary vascular myocytes. Am J Respir Crit Care Med 2004 Nov 15; 170 (10): 1101-1107
53. European Medicines Agency. Tracleer (bosentan) scientific discusssion [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/ tracleer/100002en6.pdf [Accessed 2009 Aug 6]
54. Weber C, Gasser R, Hopfgartner G. Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects. Drug Metab Dispos 1999 Jul; 27 (7): 810-815
55. Dingemanse J, Schaarschmidt D, van Giersbergen PLM. Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin Pharmacokinet 2003; 42 (3): 293-301 (Pubitemid 36308067)
56. Dingemanse J, Bodin F, Weidekamm E, et al. Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. J Clin Pharmacol 2002 Mar; 42: 283-289 (Pubitemid 34163474)
57. Weber C, Schmitt R, Birnboeck H, et al. Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an endothelin receptor antagonist, in healthy male volunteers. J Clin Pharmacol 1999; 39: 703-714 (Pubitemid 29297779)
58. Weber C, Schmitt R, Birnboeck H, et al. Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther 1996 Aug; 60 (2): 124-137
59. van Giersbergen PL, Popescu G, Bodin F, et al. Influence of mild liver impairment on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. J Clin Pharmacol 2003 Jan; 43 (1): 15-22
60. Dingemanse J, van Giersbergen PLM. Influence of severe renal dysfunction on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. Int J Clin Pharmacol Ther 2002 Jul; 40 (7): 310-316 (Pubitemid 34732808)
61. Binet I, Wallnöfer A, Weber C, et al. Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A. Kidney Int 2000 Jan; 57 (1): 224-231
62. van Giersbergen PLM, Treiber A, Clozel M, et al. In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide. Clin Pharmacol Ther 2002; 71: 253-262
63. van Giersbergen PLM, Halabi A, Dingemanse J. Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole. Br J Clin Pharmacol 2002; 53: 589-595 (Pubitemid 34621784)
64. Weber C, Banken L, Birnboeck H, et al. Effect of endothelin-receptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1999 Aug; 39 (8): 847-854 (Pubitemid 30629445)
65. Weber C, Banken L, Birnboeck H, et al. The effect of bosentan on the pharmacokinetics of digoxin in healthymale subjects. Br J Clin Pharmacol 1999 Jun; 47: 701-706 (Pubitemid 29257670)
66. Paul GA, Gibbs JS, Boobis AR, et al. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol 2005; 60 (1): 107-112
67. van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006 Mar; 44 (3): 113-118 (Pubitemid 43338011)
68. Treiber A, Schneiter R, Häusler S, et al. Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab Dispos 2007 Aug; 35 (8): 1400-1407
69. van Giersbergen PL, Treiber A, Schneiter R, et al. Inhibitory and inductive effects of rifampin on the pharmacokinetics of bosentan in healthy subjects. Clin Pharmacol Ther 2007 Mar; 81 (3): 414-419
70. Burgess G, Hoogkamer H, Collings L, et al. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol 2008 Jan; 64 (1): 43-50
71. Humbert M, Segal ES, Kiely DG, et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007 Aug; 30 (2): 338-344
72. Beghetti M, Hoeper MM, Kiely DG, et al. Safety experience with bosentan in 146 children 2-11 years old with pulmonary arterial hypertension: results from the European Postmarketing Surveillance program. Pediatr Res 2008 Aug; 64 (2): 200-204
73. Taichman DB. Therapy for pulmonary arterial hypertension: the more, the merrier? Ann Intern Med 2008 Oct 21; 149 (8): 583-585
74. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association [published erratum appears in Circulation 2009 Jul 14; 120 (2): e13]. Circulation 2009 Apr 28; 119 (16): 2250-2294
75. Lee SH, Rubin LJ. Current treatment strategies for pulmonary arterial hypertension. J Intern Med 2005 Sep; 258 (3): 199-215 (Pubitemid 41243051)
76. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009 Jun 30; 54 (1 Suppl.): S78-84
77. Galie N, Manes A, Negro L, et al. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009 Feb; 30 (4): 394-403
78. Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001-2006. Heart 2009 Feb; 95 (4): 312-317
79. Juergens UR, Racke K, Uen S, et al. Inflammatory responses after endothelin B (ETB) receptor activation in human monocytes: new evidence for beneficial anti-inflammatory potency of ETB-receptor antagonism. Pulm Pharmacol Ther 2008; 21 (3): 533-539 (Pubitemid 351625935)
80. McLaughlin VV, Shillington A, Rich S, et al. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002; 106 (12):1477-1482 (Pubitemid 35050873)
81. Beghetti M. Bosentan in pediatric patients with pulmonary arterial hypertension. Curr Vasc Pharmacol 2009 Apr; 7 (2): 225-233
82. Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008 Jun 10; 117 (23): 3010-3019
83. Simonneau G, Barst RJ, Galie N, et al., on behalf of the Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002 Mar 15; 165 (6): 800-804
84. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension [published erratum appears in N Engl J Med 2006 Jun 1; 354 (22): 2400-1]. N Engl J Med 2005 Nov 17; 353 (20): 2148-2157
85. Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009 Jun 9; 119 (22): 2894-2903
86. Steiner MK, Preston IR. Optimizing endothelin receptor antagonist use in the management of pulmonary arterial hypertension. Vasc Health Risk Manag 2008; 4 (5): 943-952
87. Gilead Sciences Inc. Letairis (ambrisentan) tablets: US prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/ drugsatfda-docs/label/2009/022081s010lbl.pdf [Accessed 2009 Aug 19]
88. European Medicines Agency. Volibris (ambrisentan) 5mg film-coated tablets: summary of product characteristics [online]. Available from URL: http://www.emea.europa.eu/humandocs/Humans/EPAR/volibris/volibris.htm [Accessed 2009 Aug 6]
89. Trow TK, Taichman DB. Endothelin receptor blockade in the management of pulmonary arterial hypertension: selective and dual antagonism. Respir Med 2009 Jul; 103 (7): 951-962
90. European Medicines Agency. Revatio (sildenafil) tablets: summary of product characteristics [online]. Available from URL: http://www.emea.europa.eu/ humandocs/PDFs/EPAR/Revatio/emea-combined-h638en.pdf [Accessed 2009 Aug 19]
91. Pfizer Labs. Revatio (slidenafil) tablets: US prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda-docs/ label/2009/021845s006lbl.pdf [Accessed 2009 Sep 8]
92. Eli Lilly and Company. Adcirca (tadalafil) tablets: US prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/ drugsatfda-docs/label/2009/022332lbl.pdf [Accessed 2009 Sep 8]
93. Baxter Pharmaceutical Solutions LLC. Remodulin (treprostinil sodium) injection: US prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda-docs/label/2008/021272s008lbl.pdf [Accessed 2009 Aug 19]