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Generic Name: Latanoprost
Class: Prostaglandin Analogs
VA Class: OP109
Molecular Formula: C26H40O5
CAS Number: 130209-82-4
Ocular hypotensive agent; a synthetic analog of prostaglandin F2α (PGF2α).1 2 3 32 33
Reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.1 3 10 11 12 13 15 30 31 32 33 48 55 60 One of several first-line agents to reduce elevated IOP.75
Safety and efficacy not established for the treatment of angle-closure, inflammatory, or neovascular glaucoma.1
Appears to be more effective than unoprostone, as effective as travoprost, and slightly less effective than bimatoprost in reducing IOP in patients with open-angle glaucoma or ocular hypertension.76 77 78 79 80 81
May be more effective or at least as effective as twice daily administration of timolol 0.5% in reducing IOP in patients with open-angle glaucoma or ocular hypertension.1 3 10 11 12 30 31 32 33 Appears to be more effective than thrice-daily administration of dorzolamide 2%.86 87
May be used in conjunction with a topical β-adrenergic blocking agent (e.g., betaxolol, carteolol, levobunolol, metipranolol, timolol),3 28 29 32 33 36 topical dipivefrin,33 59 topical epinephrine, an oral carbonic anhydrase inhibitor (e.g., acetazolamide), 33 or a topical carbonic anhydrase inhibitor (e.g., dorzolamide).1 44 56
Tolerance does not occur, and reduction in mean IOP is maintained for up to at least 24 months of therapy after initial stabilization.1 3 10 11 12 15 36 44 48
Apply topically to the affected eye(s).1 10 11 12 32 33 36
Avoid contamination of the solution container.1
If more than one topical ophthalmic drug is used, administer the drugs at least 5 minutes apart.1 (See Interactions.)
One drop of a 0.005% solution (1.5 mcg) in the affected eye(s) once daily in the evening.1 10 11 12 32 33 36 More frequent dosing may paradoxically diminish the IOP-lowering effect of the drug.1 15 29 39 If a dose is missed, omit the dose and apply the next dose the following evening.15
Known hypersensitivity to latanoprost, benzalkonium chloride, or any ingredient in the formulation.1
Increases in brown pigmentation of the iris and periorbital tissue (eyelid) or increases in length, thickness, and pigmentation of eyelashes or vellus hair in the treated eye reported;1 3 10 11 12 15 31 32 33 36 misdirected growth of eyelashes also may occur.1 Pigmentation is expected to increase throughout the treatment period.1 Increased pigmentation of the iris may be permanent, while pigmentation of the periorbital tissue and eyelash changes reportedly are reversible in some patients.1 Long-term effects (i.e., beyond 5 years) of increased pigmentation are unknown.1
Increased pigmentation of iris develops slowly; may not be evident until after several months to years of latanoprost therapy.1 In clinical studies, noticeable increased pigmentation of the iris generally occurred within the first year of therapy.1 Therapy generally may be continued in the presence of increased iris pigmentation;1 patients should be examined regularly.1 33 36
Macular edema, including cystoid macular edema, reported in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema; use with caution in such patients.1 51 52 53 54 58 61 62 63 64 65
Use with caution in patients with a history of intraocular inflammation (e.g., iritis, uveitis); use generally not recommended in patients with active intraocular inflammation.1
Category C.1
Not known if distributed into milk; use with caution.1
Safety and efficacy not established in pediatric patients.1 15
No substantial differences in safety and efficacy relative to younger adults.1 10 11 12
Blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, pruritus, increased pigmentation of the iris, punctate epithelial keratopathy.1
Potential for additive IOP-lowering effects when used concomitantly with another ocular hypotensive agent (e.g., topical β-adrenergic blocking agent, oral or topical carbonic anhydrase inhibitor).1 3 19 28 29 32 33 36 56 59 Additive effect may be used to therapeutic advantage.1 3 19 28 29 32 33 36
Precipitation occurs when ophthalmic solutions containing thimerosal are admixed with latanoprost ophthalmic solution.1 If more than one topical ophthalmic drug is used, administer the drugs at least 5 minutes apart.1
Approximately 1% of a topically applied dose penetrates the human eye;15 remaining portion is absorbed into systemic circulation through blood vessels in the conjunctiva and mucous membranes of the nose, pharynx, esophagus, and GI tract.6 15
Prodrug; absorbed through the cornea following ocular instillation and rapidly hydrolyzed to active form (latanoprost acid).1 6 14 15 16 18 Peak plasma concentrations of latanoprost acid occur within 2 hours.1 15
Reduction in IOP generally occurs within 3–4 hours after topical application and peaks within 8–12 hours.
Effects on IOP generally persist for up to 24 hours or longer.1 10 11 12 13 15 17
Following long-term therapy (i.e., 6 months), pharmacologic effects may persist for at least 14 days after the drug is discontinued.15
The volume of distribution of latanoprost acid in humans following ocular or IV administration is 0.36 or 0.16 L/kg, respectively.1 15 Latanoprost acid can be measured in aqueous humor during the first 4 hours, and in plasma only during the first hour after ocular instillation.1
Not known whether the drug or its metabolites distribute into milk in humans.1
Rapidly hydrolyzed by esterases in the cornea and plasma to biologically active form (latanoprost acid).1 15 16 33
Systemically absorbed latanoprost acid is metabolized in the liver.1 15
Metabolites are excreted principally in urine; however, biliary excretion also may occur.1 6 15 Unchanged latanoprost or latanoprost acid generally are not recovered in urine or feces.15 Following topical administration of radiolabeled latanoprost to the eye, 88% of the dose was eliminated in urine.15
The elimination half-life of latanoprost acid from aqueous humor is approximately 3 hours.15
Following topical application to the eye, the plasma elimination half-life of latanoprost acid is approximately 17 minutes.15
Unopened bottles: refrigerate at 2–8°C and protect from light.1 15
Opened bottles: room temperature (not exceeding 25°C) for up to 6 weeks.1
Selective prostanoid agonist.1 2 3 5 6 7 8 9 33 40
Appears to reduce IOP by increasing uveoscleral outflow of aqueous humor.1 2 3 5 6 7 9 31 32 33
Risk of changes in eyelashes and permanent darkening of iris, eyelashes, or skin around the eyes associated with therapy.1 Potential for disparity between eyes if only one eye is treated.1 36
Importance of learning and adhering to proper administration techniques to avoid contamination of the solution with common bacteria that can cause ocular infections.1 Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic solutions.1
Importance of informing clinicians if intercurrent ocular condition (e.g., trauma, infection) develops or ocular surgery is planned.1 Importance of immediately reporting ocular reactions, particularly conjunctivitis and eyelid reactions.1
Importance of delaying insertion of contact lenses for at least 15 minutes after latanoprost instillation, since benzalkonium chloride preservative may be absorbed by soft lenses.1
Importance of administering different topical ophthalmic preparations at least 5 minutes apart.1
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.1
Importance of women informing clinicians if they are or intend to become pregnant or plan to breast-feed.1
Importance of informing patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Ophthalmic | Solution | 0.005% | Xalatan (with benzalkonium chloride) | Pharmacia |
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Xalatan 0.005% Solution (PFIZER U.S.): 2/$104.99 or 7/$295.97
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
1. Pharmacia & Upjohn Inc. Xalatan (latanoprost) sterile ophthalmic solution 0.005% (50 mcg/mL) prescribing information. Kalamazoo, MI; 2003 Sep.
2. Stjernschantz J, Resul B. Phenyl substituted prostaglandin analogs for glaucoma treatment. Drugs Future. 1992; 17:691-704.
3. Camras CB. Prostaglandins. In: Ritch R, Shields MB, Krupin T eds. The glaucomas. 2nd ed. St. Louis: Mosby-Year Book, Inc; 1996:1449-61.
4. Campbell WB, Halushka PV. Lipid-derived autacoids: eicosanoids and platelet-activating factor. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996:601-16.
5. Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a new prostaglandin F2α analog, on aqueous humor dynamics in human eyes. Ophthalmology. 1993; 100:1297-304. [PubMed 8371915]
6. Stjernschantz J, Selén G, Sjöquist B et al. Preclinical pharmacology of latanoprost, a phenyl-substituted PGF2α analogue. Adv Prostaglandin Thromboxane Leukotriene Res. 1995; 23:513-8.
7. True Gabelt B, Kaufman PL. Prostaglandin F2α increases uveoscleral outflow in the cynomolgus monkey. Exp Eye Res. 1989; 49:389-402. [PubMed 2792235]
8. Nilsson SFE, Samuelsson M, Bill A et al. Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2α-1-isopropylester in the cynomolgus monkey. Exp Eye Res. 1989; 48:707-16. [PubMed 2737263]
9. Ziai N, Dolan JW, Kacere RD et al. The effects on aqueous dynamics of PhXA41, a new prostaglandin F2α analogue, after topical application in normal and ocular hypertensive human eyes. Arch Ophthalmol. 1993; 111:1351-8. [IDIS 320631] [PubMed 8216015]
10. Alm A, Stjernschantz J, and the Scandinavian Latanoprost Study Group. Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning: a comparison with timolol. Ophthalmology. 1995; 102:1743-52. [IDIS 358006] [PubMed 9098273]
11. Camras CB, and the United States Latanoprost Study Group. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month, masked, multicenter trial in the United States. Ophthalmology. 1996; 103:138-47. [IDIS 359594] [PubMed 8628544]
12. Watson P, Stjernschantz J, and the Latanoprost Study Group. A six-month, randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. Ophthalmology. 1996; 103:126-37. [IDIS 359593] [PubMed 8628543]
13. Rácz P, Ruzsonyi MR, Nagy ZT et al. Around-the-clock intraocular pressure reduction with once-daily application of latanoprost by itself or in combination with timolol. Arch Ophthalmol. 1996; 114:268-73. [IDIS 364525] [PubMed 8600885]
14. Bito LZ, Baroody RA. The ocular pharmacokinetics of eicosanoids and their derivatives. 1. Comparison of ocular eicosanoid penetration and distribution following the topical application of PGF2α, PGF2α-1-methyl ester, and PGF2α-1-isopropyl ester. Exp Eye Res. 1987; 44:217-26. [PubMed 3472899]
15. Pharmacia & Upjohn Inc, Kalamazoo, MI: Personal communication.
16. Basu S, Sjöquist B, Stjernschantz J et al. Corneal permeability to and ocular metabolism of phenyl substituted prostaglandin esters in vitro. Prostaglandins Leukotrienes Essent Fatty Acids. 1994; 50:161-8.
17. Rácz P, Ruzsonyi MR, Nagy ZT et al. Maintained intraocular pressure reduction with once-a-day application of a new prostaglandin F2α analogue (PhXA41): an in-hospital, placebo-controlled study. Arch Ophthalmol. 1993; 111:657-61. [IDIS 313809] [PubMed 8489449]
18. Bito LZ, Stjernschantz J, Resul B et al. The ocular effects of prostaglandins and the therapeutic potential of a new PGF2α analog, PhXA41 (latanoprost), for glaucoma management. J Lipid Mediators. 1993; 6:535-43.
19. Friström B, Nilsson SEG. Interaction of PhXA41, a new prostaglandin analogue, with pilocarpine: a study on patients with elevated intraocular pressure. Arch Ophthalmol. 1993; 111:662-5. [IDIS 313810] [PubMed 8489450]
20. Alm A, Villumsen J, Törnquist P et al. Intraocular pressure-reducing effect of PhXA41 in patients with increased eye pressure: a one-month study. Ophthalmology. 1993; 100:1312-7. [PubMed 8371917]
21. Lichter PR. Another blockbuster glaucoma drug? Ophthalmology. 1993; 100:1281-2. Editorial.
22. Serle JB. Pharmacological advances in the treatment of glaucoma. Drugs Aging. 1994; 5:156-70. [PubMed 7803944]
23. Bienfang DC, Kelly LD, Nicholson DH et al. Ophthalmology. N Engl J Med. 1990; 323:956-67. [IDIS 271813] [PubMed 2205800]
24. Cotton P. Glaucoma: detection before damage, fewer side effects may be possible. JAMA. 1990; 264:1793. [PubMed 2402030]
25. Rosenberg LF. Glaucoma: early detection and therapy for prevention of vision loss. Am Fam Physician. 1995; 52:2289-98. [IDIS 359410] [PubMed 7484722]
26. Chaudhry I, Wong S. Recognizing glaucoma. A guide for the primary care physician. Postgrad Med. 1996; 99:247-8,251-2,257-9. [IDIS 367760] [PubMed 8650090]
27. Hayreh SS, Zimmerman MB, Podhajsky P et al. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol. 1994; 117: 603-24.
28. Rulo AH, Greve EL, Hoyng PF. Additive effect of latanoprost, a prostaglandin F2α analogue, and timolol in patients with elevated intraocular pressure. Br J Ophthalmol. 1994; 78:899-902. [PubMed 7819171]
29. Alm A, Widengard I, Kjellgren D et al. Latanoprost administered once daily caused a maintained reduction of intraocular pressure in glaucoma patients treated concomitantly with timolol. Br J Ophthalmol. 1995; 79:12-6. [PubMed 7880782]
30. Mishima HK, Masuda K, Kitazawa Y et al. A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension. Arch Ophthalmol. 1996; 114: 929-932. [IDIS 370988] [PubMed 8694726]
31. Higginbotham EJ. Will latanoprost be the “wonder” drug of the ’90s for the treatment of glaucoma? Arch Ophthalmol. 1996; 114:998-999.
32. Anon. A topical prostaglandin for glaucoma. Med Lett Drugs Ther. 1996; 38:100-1. [PubMed 8914508]
33. Patel SS, Spencer CM. Latanoprost: a review of its pharmacological properties, clinical efficacy and tolerability in the management of primary open-angle glaucoma and ocular hypertension. Drugs Aging. 1996; 9:363-78. [PubMed 8922563]
34. The eye: I. Optics of vision. In: Guyton AC ed. Textbook of medical physiology. 8th ed. Philadelphia: WB Saunders Company; 1991:542-4.
35. Prostaglandin. Dorland’s illustrated medical dictionary. 28th ed. Philadelphia: WB Saunders Company; 1994:1366.
36. Camras CB, Alm A, Watson P et al et al. Latanoprost, a prostaglandin analog, for glaucoma therapy. Ophthalmology. 1996; 103:1916-24. [IDIS 377481] [PubMed 8942890]
37. Rulo AH, Greve EL, Geijssen HC et al. Reduction of intraocular pressure with treatment of latanoprost once daily in patients with normal-pressure glaucoma. Ophthalmology. 1996; 103:1276-82. [IDIS 372462] [PubMed 8764799]
38. Nicolela MT, Buckley AR, Walman BE et al. A comparative study of the effects of timolol and latanoprost on blood flow velocity of the retrobulbar vessels. Am J Ophthalmol. 1996; 122:784-9. [IDIS 376778] [PubMed 8956632]
39. Nagasubramanian S, Sheth GP, Hitchings RA et al. Intraocular pressure-reducing effect of PhXA41 in ocular hypertension: comparison of dose regimens. Ophthalmology. 1993; 100:1305-11. [PubMed 8371916]
40. Coleman RA, Smith WL, Narumiya S. International union of pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev. 1994; 46:205-29. [PubMed 7938166]
41. Johnstone MA. Hypertrichosis and increased pigmentation of lashes and adjacent hair in the region of the eye in patients treated with unilateral topical latanoprost. Am J Ophthalmol. (in press)
42. Lindsey JD, Kashiwagi K, Boyle D et al. Prostaglandins increase proMMP-1 and proMMP-3 secretion by human ciliary smooth muscle cells. Curr Eye Res. 1996; 15: 869-75.
43. Lindsey JD, Kashiwagi K, Kashiwagi F et al. Prostaglandin action on ciliary smooth muscle extracellular matrix metabolism: implications for uveoscleral outflow. Surv Ophthalmol. 1997; 42(Suppl 2):S53-9.
44. Reviewers’ comments (personal observations).
46. Alward WLM. Medical management of glaucoma. N Engl J Med. 1998; 339:1298-307. [IDIS 414110] [PubMed 9791148]
47. Crawford K, Kaufman PL. Pilocarpine antagonizes prostaglandin F2 alpha-induced ocular hypotension in monkeys. Evidence for enhancement of uveoscleral outflow by prostaglandin F2 alpha. Arch Ophthalmol. 1987; 105:1112-6. [PubMed 3477218]
48. Watson PG, and the Latanoprost Study Group. Latanoprost: two years’ experience of its use in the United Kingdom. Ophthalmology. 1998; 105:82-7. [IDIS 399628] [PubMed 9442782]
49. Peak AS, Sutton BM. Systmic adverse effects associated with topically applied latanoprost. Ann Pharmacother. 1998; 32:504-5. [IDIS 403361] [PubMed 9562149]
50. Reynolds A, Murray PI, Colloby PS. Darkening of eyelashes in a patient treated with latanoprost. Eye. 1998; 12:741-3. [PubMed 9850277]
51. Ayyala RS, Cruz DA, Margo CE et al. Cystoid macular edema associated with latanoprost in aphakic and pseudophakic eyes. Am J Ophthalmol. 1998; 126:602-4. [PubMed 9780112]
52. Thorne JE, Maguire AM, Lanciano R. CME and anterior uveitis with latanoprost use. Ophthalmology. 1998; 105:1981-3. [IDIS 423347] [PubMed 9818590]
53. Camras CB. CME and anterior uveitis with latanoprost use. Ophthalmology. 1998; 105:1978-81. [IDIS 423345] [PubMed 9818589]
54. Eisenberg D. CME and anterior uveitis with latanoprost use. Ophthalmology. 1998; 105:1978. [IDIS 423344] [PubMed 9818588]
55. Camras CB, Wax MB, Ritch R et al and the United States Latanoprost Study Group. Latanoprost treatment for glaucoma: effects of treating for 1 year and of switching from timolol. Am J Ophthalmol. 1998; 126:390-9. [IDIS 414482] [PubMed 9744372]
56. Vanlandigham BD, Brubaker RF. Combined effect of dorzolamide and latanoprost on the rate of aqueous humor flow. Am J Ophthalmol. 1998; 126:191-6. [IDIS 418945] [PubMed 9727512]
57. Fechtner RD, Khouri AS, Zimmerman TJ et al. Anterior uveitis associated with latanoprost. Am J Ophthalmol. 1998; 126:37-41. [IDIS 410266] [PubMed 9683147]
58. Callanan D, Fellman RL, Savage JA. Latanoprost-associated cystoid macular edema. Am J Ophthalmol. 1998; 126:134-5. [PubMed 9683162]
59. Widengard I, Maepea O, Alm A. Effects of latanoprost and dipivefrin, alone or combined, on intraocular pressure and on blood-aqueous barrier permeability. Br J Ophthalmol. 1998; 82:404-6. [PubMed 9640189]
60. Drance SM, Crichton A, Mills RP. Comparison of the effect of latanoprost 0.005% and timolol 0.5% on the calculated ocular perfusion pressure in patients with normal-tension glaucoma. Am J Ophthalmol. 1998; 125:585-92. [IDIS 408145] [PubMed 9625541]
61. Heier JS, Steinert RF, Frederick AR Jr. Cystoid macular edema associated with latanoprost use. Arch Ophthalmol. 1998; 116:680-2. [IDIS 406366] [PubMed 9596510]
62. Avakian A, Renier SA, Butler PJ. Adverse effects of latanaprost on patients with medically resistant glaucoma. Arch Ophthalmol. 1998; 116:679-80. [IDIS 406365] [PubMed 9596509]
63. Gaddie IB, Bennett DW. Cystoid macular edema associated with the use of latanoprost. J Am Optom Assoc. 1998; 69:122-8. [PubMed 9549261]
64. Warwar RE, Bullock JD, Ballal D. Cystoid macular edema and anterior uveitis associated with latanoprost use: experience and incidence in a retrospective review of 94 patients. Ophthalmology. 1998; 105:263-8. [IDIS 401387] [PubMed 9479285]
65. Rowe JA, Hattenhauer MG, Herman DC. Adverse side effects associated with latanoprost. Am J Ophthalmol. 1997; 124:683-5. [IDIS 396198] [PubMed 9372723]
66. Wand M. Latanoprost and hyperpigmentation of eyelashes. Arch Ophthalmol. 1997; 115:1206-8. [IDIS 392336] [PubMed 9298071]
67. Hedner J, Everts B, Moller CS. Latanoprost and respiratory function in asthmatic patients: randomized, double-masked, placebo-controlled crossover evaluation. Arch Ophthalmol. 1999; 117:1305-9. [IDIS 436687] [PubMed 10532438]
68. Kent AR, Vroman DT, Thomas TJ et al. Interaction of pilocarpine with latanoprost in patients with glaucoma and ocular hypertension. J Glaucoma. 1999; 8:257-62. [PubMed 10464735]
69. Moroi SE, Gottfredsdottir MS, Schteingart MT et al. Cystoid macular edema associated with latanoprost therapy in a case series of patients with glaucoma and ocular hypertension. Ophthalmology. 1999; 106:1024-9. [IDIS 427941] [PubMed 10328408]
70. Wand M, Gilbert CM, Liesegang TJ. Latanoprost and herpes simplex keratitis. Am J Ophthalmol. 1999; 127:602-4. [IDIS 428960] [PubMed 10334356]
71. Weston BC. Migraine headache associated with latanoprost. Arch Ophthalmol. 2001; 119:300-1. [IDIS 459054] [PubMed 11176999]
72. Wand M, Ritch R, Isbey EK et al. Latanoprost and periocular skin color changes. Arch Ophthalmol. 2001; 119:614-5. [IDIS 462463] [PubMed 11296032]
73. Demitsu T, Manabe M, Harima N et al. Hypertrichosis induced by latanoprost. J Am Acad Dermatol. 2001; 44:721-3. [IDIS 461970] [PubMed 11260563]
74. Johnstone MA, Albert DM. Prostaglandin-induced hair growth. Surv Ophthalmol. 2002; 47(suppl 1):S185-202.
75. Distelhorst JS and Hughes GM. Open-angle glaucoma. Am Fam Physician. 2003; 67: 1937-44.
76. Noecker RS, Dirks MS, Choplin NT et al. A six-month randomized clinical trial comparing the intraocular pressure-lowering efficacy of bimatoprost and latanoprost in patients with ocular hypertension or glaucoma. Am J Ophthalmol. 2003; 135:55-63. [IDIS 491912] [PubMed 12504698]
77. Choplin N, Bernstein P, Batoosingh AL et al. A randomized, investigator-masked comparison of diurnal responder rates with bimatoprost and latanoprost in the lowering of intraocular pressure. Surv Ophthalmol. 2004; 49(suppl 1):S19-25. [PubMed 15016558]
78. Gandolfi S, Simmons ST, Sturm R et al. Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and ocular hypertension. Adv Ther. 2001; 18:110-21. [PubMed 11571823]
79. Dubiner H, Cooke D, Dirks M et al. Efficacy and safety of bimatoprost in patients with elevated intraocular pressure: a 30-day comparison with latanoprost. Surv Ophthalmol. 2001; 45(suppl 4):S353-60. [PubMed 11434938]
80. Dubiner HB, Sircy MD, Landry T et al. Comparison of the diurnal ocular hypotensive efficacy of travoprost and latanoprost over a 44-hour period in patients with elevated intraocular pressure. Clin Ther. 2004; 26:84-91. [PubMed 14996520]
81. Perry CM, McGavin JK,, Culy CR et al. Latanoprost: an update of its use in glaucoma and ocular hypertension. Drugs Aging. 2003; 20:597-630. [PubMed 12795627]
82. Jampel HD, Bacharach J, Sheu WP et al. Randomized clinical trial of latanoprost and unoprostone in patients with elevated intraocular pressure. Am J Ophthalmol. 2002; 134:863-71. [IDIS 491312] [PubMed 12470755]
83. Sponsel WE, Paris G, Trigo Y et al. Comparative effects of latanoprost (Xalatan) and unoprostone (Rescula) in patients with open-angle glaucoma and suspected glaucoma. Am J Ophthalmol. 2002; 134:552-9. [IDIS 487694] [PubMed 12383812]
84. Aung T, Chew PT, Yip CC et al. A randomized double-masked crossover study comparing latanoprost 0.005% with unoprostone 0.12% in patients with primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol. 2001; 131:636-42. [IDIS 465245] [PubMed 11336940]
85. Susanna R Jr, Giampani J Jr, Borges AS et al. A double-masked, randomized clinical trial comparing latanoprost with unoprostone in patients with open-angle glaucoma or ocular hypertension. Ophthalmology. 2001; 108:259-63. [IDIS 459094] [PubMed 11158796]
86. Niazi MK and Raja N. Comparison of latanoprost and dorzolamide in the treatment of patients with open angle glaucoma. J Ayub Med Coll Abbottabad. 2004; 16:50-3.
87. O’Donoghue EP for the Ireland Latanoprost Study Group. A comparison of latanoprost and dorzolamide in patients with glaucoma and ocular hypertension: a 3 month, randomised study. Br J Ophthalmol. 2000; 84:579-82. [PubMed 10837379]
88. Shin DH, McCracken MS, Bendel RE et al. The additive effect of latanoprost to maximum-tolerated medications with low-dose, high-dose, or no pilocarpine therapy. Ophthalmology. 1999; 106:386-90. [IDIS 422864] [PubMed 9951495]
89. Toris CB, Zhan GL, Zhao J et al. Potential mechanism for the additivity of pilocarpine and latanoprost. Am J Ophthalmol. 2001; 131:722-8. [IDIS 464258] [PubMed 11384567]
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Onsenal®
Each capsule contains 400 mg of celecoxib.
Excipients: Lactose Monohydrate 99.6 mg For a full list of excipients, see section 6.1.
Hard capsule.
White, opaque capsules with two green bands marked 7767 and 400.
Onsenal is indicated for the reduction of the number of adenomatous intestinal polyps in familial adenomatous polyposis (FAP), as an adjunct to surgery and further endoscopic surveillance (see section 4.4).
The effect of Onsenal-induced reduction of polyp burden on the risk of intestinal cancer has not been demonstrated (see sections 4.4 and 5.1)
The recommended oral dose is one 400 mg capsule twice per day, taken with food (see section 5.2).
Usual medical care for FAP patients should be continued while on celecoxib. The maximum recommended daily dose is 800 mg.
Hepatic impairment
In patients with moderate hepatic impairment (serum albumin of 25-35 g/l), the daily recommended dose of celecoxib should be reduced by 50% (see sections 4.3 and 5.2). Caution should be used as there is no experience in such patients at doses higher than 400 mg.
Renal impairment
Experience with celecoxib in patients with mild or moderate renal impairment is limited, therefore such patients should be treated with caution (see sections 4.3, 4.4 and 5.2).
Paediatric patients
Experience with celecoxib in FAP patients below the age of 18 years is limited to a single pilot study in a very small population, in which patients were treated with celecoxib at doses up to 16 mg/kg daily, which corresponds to the recommended adult FAP dose of 800 mg daily (see section 5.1).
CYP2C9 Poor Metabolizers
Patients who are known or suspected to be CYP2C9 poor metabolizers based on genotyping or previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution, as the risk of dose-dependent adverse effects is increased.
Patients with the CYP2C9*3 allele, and, in particular those with CYP2C9*3*3 homozygous genotype, may be exposed to celecoxib levels that are higher than those for which safety has been studied in clinical trials. Therefore, the risk for high celecoxib exposure in poor metabolizers should be considered carefully when treating FAP patients. Consider starting treatment at a reduced dose (see section 5.2).
Elderly
The dose for elderly FAP patients has not been established. Special care should be used in such patients (see section 5.2).
• Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
• Known hypersensitivity to sulphonamides.
• Active peptic ulceration or gastrointestinal (GI) bleeding.
• Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid or non steroidal anti-inflammatory drugs (NSAIDs) including COX-2 (cyclooxigenase-2) selective inhibitors.
• In pregnancy and in women who can become pregnant unless using an effective method of contraception (see sections 4.5, 4.6 and 5.3)
• Breast feeding (see sections 4.6 and 5.3)
• Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score >10) (Class C).
• Patients with renal insufficiency with estimated creatinine clearance <30 ml/ min.
• Inflammatory bowel disease.
• Congestive heart failure (NYHA II-IV).
• Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
Treatment with celecoxib in FAP has been studied for up to 6 months and has not been shown to reduce the risk of gastrointestinal or other form of cancer or the need for surgery. Therefore, the usual care of FAP patients should not be altered because of the concurrent administration of celecoxib. In particular, the frequency of routine endoscopic surveillance should not be decreased and FAP-related surgery should not be delayed.
Gastro-intestinal disorder
Upper gastrointestinal complications [perforations, ulcers or bleeds (PUBs)], some of them resulting in fatal outcome, have occurred in patients treated with celecoxib. Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs: the elderly, patients using any other NSAID or acetylsalicylic acid concomitantly or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding.
There is further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) when celecoxib is taken concomitantly with acetylsalicylic acid (even at low doses). A significant difference in GI safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term clinical trials (see 5.1).
The concomitant use of celecoxib and a non-aspirin NSAID should be avoided.
FAP patients carrying an ileorectal anastomosis or ileo pouch-anal anastomosis can develop anastomotic ulcerations. If an anastomotic ulcer is present, patients should not receive concomitant treatment with anticoagulants or acetyl salicylic acid.
Blood and lymphatic system disorder / Cardio-vascular disorder
Increased number of serious cardiovascular events, mainly myocardial infarction, has been found in a long-term placebo-controlled study in subjects with sporadic adenomatous polyps treated with celecoxib at doses of 200 mg BID and 400 mg BID compared to placebo (see section 5.1).
As the cardiovascular risks of celecoxib were increased with the 400 mg twice daily dose in the APC trial (section 5.1), the response of the FAP patient to celecoxib should be re-examined periodically in order to avoid unnecessary exposure in FAP patients for whom celecoxib is not effective (sections 4.2, 4.3, 4.8 and 5.1).
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with celecoxib after careful consideration (see section 5.1).
COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thrombo-embolic diseases because of their lack of antiplatelet effect. Therefore, antiplatelet therapies should not be discontinued (see section 5.1).
As with other medicinal products known to inhibit prostaglandin synthesis, fluid retention and oedema have been observed in patients taking celecoxib. Therefore, celecoxib should be used with caution in patients with history of cardiac failure, left ventricular dysfunction or hypertension, and in patients with pre-existing oedema from any other reason, since prostaglandin inhibition may result in deterioration of renal function and fluid retention. Caution is also required in patients taking diuretic treatment or otherwise at risk of hypovolaemia.
As with all NSAIDS, celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. Therefore, blood pressure should be monitored closely during the initiation of therapy with celecoxib and throughout the course of therapy.
In the event of elderly patients with mild to moderate cardiac dysfunction requiring therapy, special care and follow up is warranted. Compromised renal or hepatic function and especially cardiac dysfunction are more likely in the elderly and therefore medically appropriate supervision should be maintained.
Renal and hepatic disorders
NSAIDs, including celecoxib, may cause renal toxicity. Clinical trials with celecoxib have shown renal effects similar to those observed with comparator NSAIDs. Patients at greatest risk for renal toxicity are those with impaired renal function, heart failure, liver dysfunction, and the elderly. Such patients should be carefully monitored while receiving treatment with celecoxib.
Experience with celecoxib in patients with mild or moderate renal or hepatic impairment is limited, therefore such patients should be treated with caution (see sections 4.2 and 5.2).
If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of celecoxib therapy should be considered.
Skin Reactions
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of celecoxib (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy; the onset of the reaction occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (anaphylaxis and angioedema) have been reported in patients receiving celecoxib (see section 4.8). Patients with a history of sulphonamide allergy or any drug allergy may be at greater risk of serious skin reactions or hypersensitivity reactions (see section 4.3). Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Other
Patients known to be CYP2C9 poor metabolisers should be treated with caution (see section 5.2).
Celecoxib may mask fever and other signs of inflammation.
In patients on concurrent therapy with warfarin, serious bleeding events have been reported. Caution should be exercised when combining celecoxib with warfarin and other oral anticoagulants (see section 4.5).
Onsenal 400 mg capsules contain lactose (99.6 mg). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pharmacodynamic interactions
The majority of the interaction studies have been performed with celecoxib doses of 200 mg BID (i.e. those used for osteoarthritis/rheumatoid arthritis). A more pronounced effect at 400 mg BID therefore cannot be excluded.
Anticoagulant activity should be monitored in patients taking warfarin or other anticoagulants, particularly in the first few days after initiating or changing the dose of celecoxib, since these patients have an increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR. Bleeding events in association with increases in prothrombin time have been reported in arthritis patients (mainly elderly) receiving celecoxib concurrently with warfarin, some of them fatal (see section 4.4).
NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products. As for NSAIDs, the risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g. dehydrated patients or elderly patients) when ACE inhibitors or angiotensin II receptor antagonists are combined with NSAIDs, including celecoxib. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.
In a 28-day clinical study in patients with lisinopril-controlled Stage I and II hypertension, administration of celecoxib 200 mg BID resulted in no clinically significant increases, when compared to placebo treatment, in mean daily systolic or diastolic blood pressure as determined using 24-hour ambulatory blood pressure monitoring. Among patients treated with celecoxib 200 mg BID, 48% were considered unresponsive to lisinopril at the final clinic visit (defined as either cuff diastolic blood pressure>90 mmHg or cuff diastolic blood pressure increased>10% compared to baseline), compared to 27% of patients treated with placebo; this difference was statistically significant.
Co-administration of NSAIDs and cyclosporine D derivatives or tacrolimus have been suggested to increase the nephrotoxic effect of cyclosporin and tacrolimus. Renal function should be monitored when celecoxib and any of these medicinal products are combined.
Celecoxib can be used with low dose acetylsalicylic acid, however it cannot be considered a substitute for acetylsalicylic acid for cardiovascular prophylaxis. As with other NSAIDs, an increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of celecoxib alone was shown for concomitant administration of low-dose acetylsalicylic acid (see section 5.1).
Pharmacokinetic interactions
Effects of celecoxib on other medicinal products
Celecoxib is a weak inhibitor of CYP2D6. During celecoxib treatment, the mean plasma concentrations of the CYP2D6 substrate dextromethorphan were increased by 136%. The plasma concentrations of medicinal products that are substrates of this enzyme may be increased when celecoxib is used concomitantly. Examples of medicines which are metabolised by CYP2D6 are antidepressants (tricyclics and SSRIs), neuroleptics, anti-arrhythmics, etc. The dose of individually dose-titrated CYP2D6 substrates may need to be reduced when treatment with celecoxib is initiated or increased if treatment with celecoxib is terminated.
In vitro studies have shown some potential for celecoxib to inhibit CYP2C19 catalysed metabolism. The clinical significance of this in vitro finding is unknown. Examples of medicinal products which are metabolised by CYP2C19 are diazepam, citalopram and imipramine.
In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of oral contraceptives (1 mg norethistherone /35 microg ethinylestradiol).
Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate), or glibenclamide to a clinically relevant extent.
In patients with rheumatoid arthritis celecoxib had no statistically significant effect on the pharmacokinetics (plasma or renal clearance) of methotrexate (in rheumatologic doses). However, adequate monitoring for methotrexate-related toxicity should be considered when combining these two drugs.
In healthy subjects, co-administration of celecoxib 200 mg twice daily with 450 mg twice daily of lithium resulted in a mean increase in Cmax of 16% and in AUC of 18% of lithium. Therefore, patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.
Effects of other medicinal products on celecoxib
In individuals who are CYP2C9 poor metabolisers and demonstrate increased systemic exposure to celecoxib, concomitant treatment with CYP2C9 inhibitors (eg. fluconazole, amiodarone) could result in further increases in celecoxib exposure. Such combinations should be avoided in known CYP2C9 poor metabolisers (see sections 4.2 and 5.2).
Since celecoxib is predominantly metabolised by CYP2C9 it should be used at half the recommended dose in patients receiving fluconazole. Concomitant use of 200 mg single dose of celecoxib and 200 mg once daily of fluconazole, a potent CYP2C9 inhibitor, resulted in a mean increase in celecoxib Cmax of 60% and in AUC of 130% (analogous studies have not been performed with amiodarone or other known CYP2C9 inhibitors). Concomitant use of inducers of CYP2C9 such as rifampicin, carbamazepine and barbiturates may reduce plasma concentrations of celecoxib.
For celecoxib no clinical data on exposed pregnancies are available.. Studies in animals (rats and rabbits) have shown reproductive toxicity (see sections 4.3 and 5.3). The potential risk for humans is unknown. Celecoxib, as with other medicinal products inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Celecoxib is contraindicated in pregnancy and in women who can become pregnant unless using an effective method of contraception (see section 4.3). If a woman becomes pregnant during treatment, celecoxib should be discontinued.
Celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. Administration of celecoxib to a limited number of lactating women has shown a very low transfer of celecoxib into breast milk. Women who take celecoxib should not breastfeed.
No studies on the effect on the ability to drive and use machines have been performed. However, patients who experience dizziness, vertigo or somnolence while taking celecoxib should refrain from driving or operating machinery.
Adverse reactions are listed by system organ class and ranked by frequency in Table 1, reflecting data from the following sources:
- Adverse reactions reported in osteoarthritis patients and rheumatoid arthritis patients at incidence rates greater than 0.01% and greater than those reported for placebo during 12 placebo- and/or active-controlled clinical trials of duration up to 12 weeks at celecoxib daily doses from 100 mg up to 800 mg. In additional studies using non-selective NSAID comparators, approximately 7400 arthritis patients have been treated with celecoxib at daily doses up to 800 mg, including approximately 2300 patients treated for 1 year or longer. The adverse reactions observed with celecoxib in these additional studies were consistent with those for osteoarthritis and rheumatoid arthritis patients listed in Table 1.
- Adverse drug reactions from post-marketing surveillance as spontaneously reported during a period in which an estimated>70 million patients were treated with celecoxib (various doses, durations, and indications). Because not all adverse drug reactions are reported to the MAH and included in the safety database, the frequencies of these reactions cannot be reliably determined.
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The additional adverse reactions listed by system organ class and ranked by frequency in Table 2 were reported at incidence rates greater than placebo for subjects treated with celecoxib 400 mg to 800 mg daily in long-term polyp prevention trials of duration up to 3 years (the APC and PreSAP trials; see Section 5.1, Pharmacodynamic properties: Cardiovascular Safety – Long
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In final data (adjudicated) from the APC trial in patients treated with celecoxib 800 mg daily for up to 3 years, the excess rates over placebo were 11 events per 1000 patients for myocardial infarction (common); and 5 events per 1000 patients for stroke (uncommon; types of stroke not differentiated).
There is no clinical experience of overdose in clinical trials. Single doses up to 1400 mg and multiple doses up to 1400 mg twice daily have been administered to healthy subjects for nine days without clinically significant adverse events. In the event of suspected overdose, appropriate supportive medical care should be provided e.g. by eliminating the gastric contents, clinical supervision and, if necessary, the institution of symptomatic treatment. Dialysis is unlikely to be an efficient method of medicinal product removal due to high protein binding.
Pharmacotherapeutic group: Antineoplastic, ATC code: L01XX33
Celecoxib is a diaryl-substituted pyrazole, chemically similar to other non-arylamine sulfonamides (e.g. thiazides, furosemide) but differing from arylamine sulfonamides (e.g. sulfamethoxizole and other sulfonamide antibiotics).
Celecoxib is an oral, selective cyclooxygenase-2 (COX-2) inhibitor. No statistically significant inhibition of COX-1 (assessed as ex vivo inhibition of thromboxane B2 [TxB2] formation) was observed in healthy volunteers at the FAP therapeutic dose of 400 mg BID.
Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation and fever. Elevated levels of COX-2 are found in many pre-malignant lesions (such as adenomatous colorectal polyps) and epithelial cancers. Familial Adenomatous Polyposis (FAP) is a genetic disease resulting from an autosomal dominant genetic alteration of a tumor suppressor gene, the adenomatous polyposis coli (APC) gene. Polyps with the APC mutation overexpress COX-2 and left untreated, these polyps continue to form and enlarge in the colon or rectum resulting in essentially a 100% chance of developing colorectal cancer. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous system functions (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevance to ulcer healing has not been established.
The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thrombo-embolic reactions. COX-2 inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane.
A dose-dependent effect on TxB2 formation has been observed after high doses of celecoxib. However, in small multiple dose studies in healthy subjects with 600 mg BID celecoxib had no effect on platelet aggregation and bleeding time compared to placebo.
Experimental evidence shows that the mechanism(s) of action by which celecoxib leads to tumour death may be related to induction of apoptosis and inhibition of angiogenesis. Inhibition of COX-2 may have consequences on tumour viability that are unrelated to inflammation.
Celecoxib inhibits tumour formation in preclinical models of colon cancer, which overexpress COX-2, whether induced by chemical (rat AOM model) or genetic (MIN mouse model) mutation.
Celecoxib has been shown to reduce the number and size of adenomatous colorectal polyps. A randomized double-blind placebo controlled study was conducted in 83 patients with FAP. The study population included 58 patients with a prior subtotal or total colectomy and 25 patients with an intact colon. Thirteen patients had the attenuated FAP phenotype. The mean reduction in the number of colorectal polyps following six months of treatment was 28% (SD + 24%) for celecoxib 400 mg BID which was statistically superior to placebo (mean 5%, SD +16%). A meaningful reduction in duodenal adenoma area was also observed compared with placebo (14.5% celecoxib 400 mg BID versus 1.4% placebo), which however was not statistically significant.
Pilot Study in Juvenile FAP Patients
A total of 18 children 10 to 14 years of age who had genotype or phenotype positive FAP were treated with celecoxib 4 mg/kg/day (4 patients, compared to 2 patients treated with placebo), celecoxib 8 mg/kg/day (4 patients, compared to 2 patients treated with placebo), or celecoxib 16 mg/kg/day (4 patients, compared to 2 patients treated with placebo). Results demonstrated a statistically significant reduction in polyp burden in all celecoxib treatment groups compared to the corresponding placebo treatment groups. The greatest reduction was observed in patients treated with celecoxib 16 mg/kg/day, which corresponds to the recommended adult FAP dose of 800 mg daily. Safety data were reviewed in detail by a Data Safety Monitoring Committee, which concluded that celecoxib 16 mg/kg/day was a safe dose to recommend for further studies in juvenile FAP patients.
The long-term cardiovascular toxicity in children exposed to celecoxib has not been evaluated and it is unknown if the long-term risk may be similar to that seen in adults exposed to celecoxib or other COX-2 selective and non-selective NSAIDs (see section 4.4; cardiovascular effects).
Cardiovascular Safety – Long-Term Studies Involving Subjects With Sporadic Adenomatous Polyps
Two studies involving subjects with sporadic adenomatous polyps were conducted with celecoxib i.e., the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint of cardiovascular death, myocardial infarction, or stroke (adjudicated) with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint.
In the APC trial, the relative risks compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4
In the PreSAP trial, the relative risk compared to placebo for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6
Data from a third long-term study, ADAPT (The Alzheimer's Disease Anti-inflammatory Prevention Trial), did not show a significantly increased cardiovascular risk with celecoxib 200m
