Naftin

Generic Name: Naftifine Hydrochloride
Class: Allylamines
ATC Class: D01AE22
VA Class: DE102
Chemical Name: (E)-N-Methyl-N-(3-phenyl-2-propenyl)-1-naphthalenemethanamine hydrochloride
Molecular Formula: C₂₁H₂₁N•HCl
CAS Number: 65473-14-5

Introduction

Antifungal; synthetic allylamine structurally and pharmacologically related to terbinafine.^{1 3 4 5 9 11 13 14 16 21 22 23 25 29 31 35 36 37 38 41 42 43 48 63 64 65 66 67 68 69}

Uses for Naftin

Dermatophytoses

Treatment of tinea corporis (body ringworm)^{1 22 39 46 48 49 50 51 54 55 63} and tinea cruris (jock itch)^{1 22 23 39 45 48 49 50 51 54 55 63} caused by Epidermophyton floccosum,^{1 39 45 47 49 50 51 53 63} Microsporum canis†,^{49 50 55} Trichophyton mentagrophytes,^{1 39 47 49 50 51 53 55 63} T. rubrum,¹ T. tonsurans,^a T. verrucosum†,^{50 51 53} or T. violaceum†.⁵⁰

Treatment of tinea pedis (athlete's foot)^{1 15 28 47 48 49 51 54 55 63} or tinea manuum†^{51 54 55} caused by Epidermophyton floccosum,^{1 39 45 47 49 50 51 53 63} Microsporum canis†,^{49 50 55} Trichophyton mentagrophytes,^{1 39 47 49 50 51 53 55 63} T. rubrum,¹ T. tonsurans,^a T. verrucosum†,^{50 51 53} or T. violaceum†.⁵⁰

Topical antifungals usually effective for treatment of uncomplicated tinea corporis and tinea cruris.^{69 70 71 72 73} An oral antifungal may be necessary when tinea corporis or tinea cruris is extensive, dermatophyte folliculitis is present, the infection is chronic or does not respond to topical therapy, or the patient is immunocompromised because of coexisting disease or concomitant therapy.^{69 70 71 72 73}

Topical antifungals usually effective for treatment of uncomplicated tinea pedis.^{69 70 71 72 73} An oral antifungal may be necessary for the treatment of hyperkeratotic areas on the palms and soles,^{70 73} for chronic moccasin-type (dry-type) tinea pedis,^{69 70 72} and for tinea unguium (fingernail or toenail dermatophyte infections, onychomycosis).^{69 70 71 72}

Gel has been used in the treatment of tinea unguium (onychomycosis)†.⁵⁷

Cutaneous Candidiasis†

Treatment of cutaneous candidiasis† caused by Candida albicans.^{47 50 51 53 54 55 56 62} Less active than imidazole derivatives.^{36 37 56}

Naftin Dosage and Administration

Administration

Topical Administration

Apply topically to the skin as a cream or gel.^{1 63}

Do not apply to the eye, nose, mouth, or other mucous membranes.^{1 63}

Do not use with occlusive dressings or wrappings, unless otherwise directed by clinician.^{1 63}

Apply a sufficient amount of topical cream or gel; rub gently into the affected area and surrounding skin.^{1 22 33 39 46 47 49 50 51 53 54 60 63}

Wash hands after applying.^{1 63}

Dosage

Available as naftifine hydrochloride; dosage expressed in terms of naftifine.^a

Adults

Dermatophytoses

Tinea Corporis or Tinea Cruris

Topical

Cream: Apply once daily for 2–4 weeks.^{1 15 22 25 33 39 45 46 49 53 54 60}

Gel: Apply twice daily (morning and evening) for 2–4 weeks.^{22 25 39 45 46 49 a}

Clinical improvement usually occurs within the first week of treatment.^{22 25 39 45} If clinical improvement does not occur after 4 weeks of treatment, reevaluate diagnosis.^{1 63} Severe infections may require prolonged treatment.^{50 60 61}

Tinea Pedis

Topical

Cream: Apply once daily for 4–6 weeks.^{1 15 22 15 25 33 39 45 46 47 49 53 54 60}

Gel: Apply twice daily (morning and evening) for 4–6 weeks.^{15 22 25 39 45 46 47 49 a}

Clinical improvement usually occurs within the first week of treatment.^{22 25 39 45} If clinical improvement does not occur after 4 weeks of treatment, reevaluate diagnosis.^{1 63} Severe infections may require prolonged treatment.^{50 60 61}

Special Populations

No special population dosage recommendations at this time.^a

Cautions for Naftin

Contraindications

• 
  

  Known hypersensitivity to naftifine or any ingredient in the formulation. ^{1 63}

  
  

Warnings/Precautions

Warnings

Administration Precautions

For external use only.^{1 63} Use only for topical application to the skin; not for ophthalmic use.^{1 63}

Avoid contact with eyes, nose, mouth, and other mucous membranes.^{1 63}

Sensitivity Reactions

Contact dermatitis has been reported occasionally.^{20 39 49 54 56}

If irritation or sensitivity occurs, discontinue drug and initiate appropriate therapy.^{1 63}

General Precautions

Selection and Use of Antifungals

Prior to use, confirm diagnosis by direct microscopic examination of scrapings from infected tissue mounted in potassium hydroxide (KOH) or by culture.^{1 63}

Specific Populations

Pregnancy

Category B.^a

Lactation

Not known whether distributed into milk following topical application.^{1 63} Use with caution.^{1 63}

Pediatric Use

Safety and efficacy not established.^a

Common Adverse Effects

Burning, stinging.^{1 22 32 39 46 47 50 51 55 63}

Interactions for Naftin

No formal drug interaction studies to date.

Naftin Pharmacokinetics

Absorption

Bioavailability

Following topical application, approximately 3–6% absorbed.^{1 43 63}

Distribution

Extent

Not known whether naftifine crosses the placenta.⁶⁰

Distributed into milk in rats; not known whether distributed into human milk.^{1 43 60 63}

Elimination

Metabolism

Metabolized by oxidation and by N-dealkylation.¹⁸

Elimination Route

Systemically absorbed drug excreted in urine (40–60%) as unchanged drug and metabolites and in feces.^{1 18 43 63}

Half-life

2–3 days.^{1 60 63}

Stability

Storage

Topical

Cream

<30°C;¹ cream is stable for 24 months after the date of manufacture.⁶⁰

Gel

Room temperature.⁶³

Actions and SpectrumActions

• 
  

  Allylamine antifungal.^{1 3 4 5 9 11 13 14 16 21 22 23 25 29 31 35 36 37 38 41 42 43 48 63}

  
  


• 
  

  Usually fungicidal against susceptible dermatocytes.^{1 9 14 41 42} Usually fungistatic against Candida; may be fungicidal at high concentrations.^{1 3 9 14 41 42}

  
  


• 
  

  Exact mechanism unknown; ^{1 3 11 16 41 43} appears to interfere with sterol biosynthesis by inhibiting the enzyme squalene monooxygenase (squalene 2,3-epoxidase).^{1 11 13 14 16 21 41 43} The resulting accumulation of squalene (the usual substrate of the enzyme) in the cells and decreased amounts of sterols, especially ergosterol,^{1 3 10 11 16 41} may contribute to the antifungal effects.⁴¹

  
  


• 
  

  Spectrum of antifungal activity includes many fungi, including dermatophytes and yeasts.^{1 2 3 4 5 8 9 12 22 23 31 37 42} Also may have in vitro activity against some gram-positive and -negative bacteria,^{58 60 61} and Leishmania.²⁷

  
  


• 
  

  Candida: Active in vitro against Candida albicans,^{1 3 4 12 36} C. krusei,⁴ C. parapsilosis,^{4 12 31 41} and C. tropicalis;¹² however, less active than imidazole derivatives against Candida.^{36 37 56}

  
  


• 
  

  Dermatophytes and other fungi: Active in vitro against Aspergillus flavus,¹² A. fumigatus,¹² Blastomyces dermatitidis,¹² Cryptococcus neoformans,¹² Epidermophyton floccosum,^{1 4 8 12 38 42} Histoplasma capsulatum,¹² Microsporum audouinii,¹ M. canis,^{1 8 38 42} M. gypseum,^{1 8} Petriellidium boydii,¹² Sporothrix schenckii,^{4 12} Trichophyton mentagrophytes,^{1 2 8 38 41 42} T. rubrum,^{1 8 38 42} T. tonsurans,^{1 38} T. verrucosum,⁴² and T. violaceum.^{8 38}

  
  


• 
  

  Also has anti-inflammatory activity when applied topically.^{51 52}

  
  


• 
  

  No reports to date of resistance in organisms originally susceptible to naftifine.^{60 61}

  
  

Advice to Patients

• 
  

  Importance of completing full course of treatment, even if symptoms improve.¹

  
  


• 
  

  Importance of contacting clinician if improvement does not occur within 4 weeks.^{1 63}

  
  


• 
  

  Importance of notifying clinician if condition worsens or treated area shows signs of increased irritation.^a

  
  


• 
  

  Importance of applying to affected areas as directed and avoiding contact with eyes, nose, mouth, or other mucous membranes.^{1 63}

  
  


• 
  

  Advise patients to wash their hands after touching the affected areas.^a

  
  


• 
  

  Importance of not using occlusive dressings, unless otherwise directed by clinician.^{1 63}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^a

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^a

  
  


• 
  

  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Naftifine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Topical	Cream	1%	Naftin (with benzyl alcohol)	Merz
	Gel	1%	Naftin (with alcohol 52% v/v)	Merz

Comparative Pricing

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.

Naftin 1% Cream (MERZ PHARMACEUTICAL): 30/$109.99 or 90/$285.96

Naftin 1% Cream (MERZ PHARMACEUTICAL): 60/$190 or 180/$559.94

Naftin 1% Cream (MERZ PHARMACEUTICAL): 90/$239.98 or 270/$676

Naftin 1% Gel (MERZ PHARMACEUTICAL): 40/$155.99 or 120/$435.96

Naftin 1% Gel (MERZ PHARMACEUTICAL): 90/$269.99 or 270/$769.94

Naftin 1% Gel (MERZ PHARMACEUTICAL): 60/$216 or 180/$589.99

Disclaimer

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 January 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Allergan. Naftin (naftifine hydrochloride) 1% cream prescribing information (dated 1996). In: Physicians’ desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:501-2.

2. Meingassner JG, Sleytr U, Petranyi G. Morphological changes induced by naftifine, a new antifungal agent, in Trichophyton mentagrophytes. J Invest Dermatol. 1981; 77:444-51. [IDIS 141591] [PubMed 7310168]

3. Ryder NS, Seidl G, Troke PF. Effect of the antimycotic drug naftifine on growth of and sterol biosynthesis in Candida albicans. Antimicrob Agents Chemother. 1984; 25:483-7. [IDIS 184282] [PubMed 6375557]

4. Georgopoulos A, Petranyi G, Mieth H et al. In vitro activity of naftifine, a new antifungal agent. Antimicrob Agents Chemother. 1981; 19:386-9. [IDIS 134653] [PubMed 7247366]

5. Kerridge D. Mode of action of clinically important antifungal drugs. Adv Microbiol Physiol. 1986; 27:1-64.

6. Dittmar W, Jovic N. Laboratory techniques alternative to in vivo experiments for studying the liberation, penetration and fungicidal action of topical antimycotic agents in the skin, including ciclopiroxolamine. Mykosen. 1987; 30:326-42. [PubMed 3657856]

7. Gehse M, Kuster S, Gloor M. On the effective dimension of inhibition of ciclopiroxolamine and naftifine in the horny layer with regard to the galenic preparation. Mykosen. 1987; 30:322-5. [PubMed 3657855]

8. Regli P, Ferrari H, Buffard Y et al. In vitro activity of naftifine, a new antifungal agent, against dermatophytes. Path Biol. 1985; 33:614-7.

9. Petranyi G, Georgopoulos A, Mieth H. In vivo antimycotic activity of naftifine. Antimicrob Agents Chemother. 1981; 19:390-2. [PubMed 7247367]

10. Georgopapadakou NH, Dix BA, Smith SA et al. Effect of antifungal agents on lipid biosynthesis and membrane integrity in Candida albicans. Antimicrob Agents Chemother. 1987; 31:46-51. [PubMed 3551826]

11. Ryder NS. Specific inhibition of fungal sterol biosynthesis by SF 86-327, a new allylamine antimycotic agent. Antimicrob Agents Chemother. 1985; 27:252-6. [PubMed 4039119]

12. Shadomy S, Espinel-Ingroff A, Gebhart RJ. In- vitro studies with SF 86-327, a new orally active allylamine derivative. Sabouraudia. 1985; 23:125-32. [PubMed 2990057]

13. Petranyi G, Ryder NS, Stutz A. Allylamine derivatives: new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. Science. 1984; 224:1239-41. [PubMed 6547247]

14. Ryder NS. Effect of allylamine antimycotic agents on fungal sterol biosynthesis measured by sterol side-chain methylation. J Gen Microbiol. 1985; 131:1595-1602. [PubMed 3900280]

15. Bojanovsky VA, Haas P. Antimycotic effect of naftifine in tinea pedis: comparative double-blind study with bifonazole. Fortschr Med. 1985; 103:677-9. [PubMed 3897005]

16. Ryder NS, Dupong MC. Inhibition of squalene epoxidase by allylamine antimycotic compounds. Biochem J. 1985; 230:765-70. [PubMed 3877503]

17. Grimus RC, Schuster I. The role of the lymphatic transport in the enteral absorption of naftifine by the rat. Xenobiotica. 1984; 14:287-94. [PubMed 6464498]

18. Schatz F, Haberl H, Battig F et al. Major routes of naftifine biotransformation in laboratory animals and man. Arzneimittelforschung. 1986; 36:248-55. [PubMed 3964331]

19. Schatz F, Haberl H. Analytical methods for the determination of naftifine and its metabolites in human plasma and urine. Arzneimittelforschung. 1986; 36:1850-3. [PubMed 3566849]

20. Hoting VE, Kuchmeister B, Hausen BM. Allergic contact dermatitis from naftifine. Dermatosen. 1987; 35:124-7.

21. Hay RJ. Recent advances in the management of fungal infections. Quart J Med. 1987; 244:631-9.

22. Millikan LE, Galen WK, Gewirtzman GB et al. Naftifine cream 1% versus econazole cream 1% in the treatment of tinea cruris and tinea corporis. J Am Acad Dermatol. 1988; 18:52-6. [PubMed 3279083]

23. Ganzinger U, Stutz A, Petranyi G et al. Allylamines: topical and oral treatment of dermatomycoses with a new class of antifungal agents. Acta Derm Venerol (Stockh). 1986; 121:155-60.

24. Hira SK, Abraham MS, Mwinga A et al. Naftifine solution (1%) in the treatment of pityriasis versicolor in Zambia. Mykosen. 1986; 29:378-81. [PubMed 3531847]

25. Zaun H, Liszpinski P. Multicentric double-blind contralateral comparision of naftifine- and clotrimazole-cream in patients with dermatophytosis or Candidosis. Z Hautkr. 1984; 59:1209-17. [PubMed 6388169]

26. Bechter R, Schmid B, Mayer FK. Teratogenic potential of antimycotic drugs evaluated in the whole- embryo culture system. Food Chem Toxicol. 1986; 24:641-2.

27. Berman JD, Gallalee JV. In vitro antileishmanial activity of inhibitors of steroid biosynthesis and combinations of antileishmanial agents. J Parasitol. 1987; 73:671-3. [PubMed 3037057]

28. Klaschka F, Gartmann H, Weidinger G. Antimycotic naftifine: placebo-controlled comparison in tinea pedum. Z Hautkr. 1984; 59:1218-25. [PubMed 6388170]

29. Bechter R, Schmid BP. Teratogenicity in vitro: a comparative study of four antimycotic drugs using the whole-embryo culture system. Toxicol in Vitro. 1987; 1:11-5. [PubMed 20702373]

30. Schuster I. The interaction of representative members from two classes of antimycotics—the azoles and the allylamines—with cytochromes P-450 in steroidogenic tissues and liver. Xenobiotica. 1985; 15:529-46. [PubMed 4036174]

31. Meingassner JG, Sleytr UB. The effects of naftifine on the ultrastructure of Candida parapsilosis: a freeze fracture study. Sabouraudia. 1982; 20:199-207. [PubMed 7135143]

32. Hantschke D, Reichenberger M. Double blind, randomized in vivo investigations comparing the antifungals clotrimazole, tolnaftate and naftifine. Mykosen. 1980; 23:657-68. [PubMed 7012610]

33. Meinicke K, Striegel C, Weidinger G. Treatment of dermatomycoses with naftifine: therapeutic efficacy after once-a-day and twice-a-day application. Mykosen. 1984; 27:608-14. [PubMed 6395017]

34. Nolting S, Weidinger G. Naftifine in severe dermatomycosis: econazole-controlled therapeutic comparison. Mykosen. 1983; 28:69-76.

35. Stutz A, Georgopoulos A, Granitzer W et al. Synthesis and structure-activity relationships of naftifine-related allylamine antimycotics. J Med Chem. 1986; 29:112-25. [PubMed 3510297]

36. Schaude M, Ackerbauer H, Mieth H. Inhibitory effect of antifungal agents on germ tube formation in Candida albicans. Mykosen. 1987; 30:281-7. [PubMed 3306370]

37. Cauwenbergh G. New and prospective developments in antifungal drugs. Acta Derm Venereol (Stockh). 1986; 121:147-53.

38. Faruqi AH, Khan KA, Qazi AA et al. In vitro antifungal activity of naftifine: (SN 105-843 GEL) against dermatophytes. J Pakistan Med Assoc. 1981; 31:279-82.

39. Lee CT, Giam YC, Tan T. The use of naftifine (Exoderil) cream in the treatment of dermatophytosis. Singapore Med J. 1987; 28:429-31. [PubMed 3324355]

40. Stuttgen G. Biopharmaceutical aspects of topically applied antifungal treatment. Mykosen. 1987; 30(Suppl 1):7-14.

41. Ivessa E, Daum G, Paltauf F. Mechanism of action of naftifine. Mykosen. 1987; 30(Suppl 1):15-21.

42. Petranyi G. Preclinical evaluation of Exoderil (naftifine). Part I. Results of experimental studies of the antifungal activity profile. Mykosen. 1987; 30(Suppl 1):22-7.

43. Czok R. Preclinical evaluation of Exoderil (naftifine). Part II. Mechanism of action, absorption, metabolism and excretion. Mykosen. 1987; 30(Suppl 1):28-31. [PubMed 3550458]

44. Obenaus H, Schon H. Preclinical evaluation of Exoderil (naftifine). Part III. Summary of results of toxicological studies. Mykosen. 1987; 30(Suppl 1):32-7.

45. Gip L, Brundin G. A double-blind, two group multicentre study, comparing naftifine 1% cream with placebo cream in the treatment of tinea cruris. Mykosen. 1987; 30:(Suppl 1)38-41.

46. Zaun H, Luszpinski P. Antifungal treatment of hospital inpatients: left versus right study to compare naftifine and clotrimazole. Mykosen. 1987; 30(Suppl 1):42-8.

47. Haas PJ, Tronnier H, Weidinger G. Naftifine in tinea pedis: double-blind comparison with clotrimazole. Mykosen. 1987; 30(Suppl 1):50-6.

48. Maibach HI. Naftifine: dermatotoxicology and clinical efficacy. Mykosen. 1987; 30(suppl 1):57-62. [PubMed 3553928]

49. Kagawa S. Comparative clinical trial of naftifine and clotrimazole in tinea pedum, tinea cruris and tinea corporis. Mykosen. 1987; 30(Suppl 1):63-9.

50. Nolting S, Weidinger G. Naftifine in severe dermatomycoses: econazole-controlled therapeutic comparison. Mykosen. 1987; 30(Suppl 1):70-7.

51. Tronnier H. Inflammatory dermatomycoses: comparative study of naftifine and a combination of a corticosteroid and an imidazole derivative. Mykosen. 1987; 30(Suppl 1):78-87.

52. Jung EG. The anti-inflammatory efficacy of naftifine as evaluated from the erythema response to ultraviolet light. Mykosen. 1987; 30(Suppl 1):88-91.

53. Polemann G. Antifungal efficacy of naftifine applied once-daily. Mykosen. 1987; 30(Suppl 1):92-7.

54. Meinicke K, Striegel C, Weidinger G. Treatment of dermatomycoses with naftifine: therapeutic efficacy on application once daily and twice daily. Mykosen. 1987; 30(Suppl 1):98-103.

55. Effendy I, Friederich HC. Double-blind, randomized comparative study of naftifine solution (once daily) and clotrimazole solution (twice daily) in the treatment of dermatomycoses. Mykosen. 1987; 30(Suppl 1):104-11.

56. Paetzold OH, Engst R, Kneist W et al. Yeast infections of the skin: comparative double-blind therapeutic trial with naftifine and clotrimazole. Mykosen. 1987; 30(Suppl 1):112-8.

57. Klaschka F. Treatment of onychomycosis with naftifine gel. Mykosen. 1987; 30(Suppl 1):119-23.

58. Nolting S. Investigation of the antibacterial effect of the antifungal agent naftifine: left versus right clinical comparative study between naftifine and gentamycin in pyoderma. Mykosen. 1987; 30(Suppl 1):124-8.

59. Anon. Topical neomycin. Med Lett Drugs Ther. 1973; 15:101-2. [PubMed 4765413]

60. Houser E (Herbert Laboratories, Irvine, CA): Personal communication; 1988 Dec.

61. Reviewers’ comments (personal observations); 1988 Dec.

62. Zaias N, Astorga E, Cordero CN et al. Naftifine cream in the treatment of cutaneous candidiasis. Cutis. 1988; 42:238-40. [PubMed 3048914]

63. Allergan. Naftin (naftifine hydrochloride) 1% gel prescribing information (dated 1996). In: Physicians’ desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:502.

64. Greer DL, Jolly HW Jr. Treatment of tinea cruris with topical terbinafine. J Am Acad Dermatol. 1990; 23:800-4. [PubMed 2229527]

65. Shear NH, Villars VV, Marsolais C. Terbinafine: an oral and topical antifungal agent. Clin Dermatol. 1992; 9:487-95.

66. Lyman CA, Walsh TJ. Systemically administered antifungal agents: a review of their clinical pharmacology and therapeutic applications. Drugs. 1992; 44:9-35. [PubMed 1379913]

67. Anon. Topical terbinafine for tinea infections. Med Lett Drugs Ther. 1993; 35:76-8. [PubMed 8341207]

68. Smith EB. Topical antifungal drugs in the treatment of tinea pedis, tinea cruris, and tinea corporis. J Am Acad Dermatol. 1993; 28(5 Part 1):S24-8. [PubMed 8496408]

69. Gupta AK, Einarson TR, Summerbell RC et al. An overview of topical antifungal therapy in dermatomycoses: a North American perspective. Drugs. 1998; 55:645-74. [PubMed 9585862]

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73. Drake LA, Dincehart SM, Farmer ER et al. Guidelines of care for superficial mycotic infections of the skin: tinea corporis, tinea cruris, tinea faciei, tinea manuum, and tinea pedis. J Am Acad Dermatol. 1996; 34:282-6. [IDIS 363962] [PubMed 8642094]

74. Reviewers’ comments (personal observations) on Sulconazole 84:04.08.

a. Merz Pharmaceuticals. Naftin (naftifine hydrochloride 1%) gel and cream prescribing information. Greensboro, NC; 2007 May.

More Naftin resources

• Naftin Side Effects (in more detail)
• Naftin Use in Pregnancy & Breastfeeding
• Naftin Support Group
• 0 Reviews for Naftin - Add your own review/rating

• Naftin Prescribing Information (FDA)


• Naftin Concise Consumer Information (Cerner Multum)


• Naftin Topical Advanced Consumer (Micromedex) - Includes Dosage Information


• Naftin Cream MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Naftin with other medications

• Tinea Corporis
• Tinea Cruris
• Tinea Pedis

Ticlopidine

tye-KLOE-pi-deen

Oral route(Tablet)

Can cause life-threatening hematological adverse reactions, including neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura (TTP) and aplastic anemia. Hematological adverse reactions cannot be reliably predicted by any identified demographic or clinical characteristics. During the first 3 months of treatment, patients receiving ticlopidine must, therefore, be hematologically and clinically monitored for evidence of neutropenia or TTP. If any such evidence is seen, ticlopidine should be immediately discontinued .

Commonly used brand name(s)

In the U.S.

• Ticlid

Available Dosage Forms:

• Tablet

Therapeutic Class: Platelet Aggregation Inhibitor

Pharmacologic Class: ADP-Induced Aggregation Inhibitor

Uses For ticlopidine

Ticlopidine is used to lessen the chance of having a stroke. It is given to people who have already had a stroke and to people with certain medical problems that may lead to a stroke. Because ticlopidine can cause serious side effects, especially during the first 3 months of treatment, it is used mostly for people who cannot take aspirin to prevent strokes.

A stroke may occur when blood flow to the brain is interrupted by a blood clot. Ticlopidine reduces the chance that a harmful blood clot will form, by preventing certain cells in the blood from clumping together. This effect of ticlopidine may also increase the chance of serious bleeding in some people.

ticlopidine is available only with a doctor's prescription.

Before Using ticlopidine

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For ticlopidine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to ticlopidine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

There is no specific information comparing use of ticlopidine in children with use in other age groups.

Geriatric

ticlopidine has been tested and has not been shown to cause different side effects or problems in older people than it does in younger adults.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking ticlopidine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using ticlopidine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab


• Acenocoumarol


• Alteplase, Recombinant


• Argatroban


• Aspirin


• Bivalirudin


• Bromfenac


• Celecoxib


• Cilostazol


• Citalopram


• Clopidogrel


• Dabigatran Etexilate


• Dalteparin


• Danaparoid


• Desirudin


• Desvenlafaxine


• Diclofenac


• Diflunisal


• Drotrecogin Alfa


• Duloxetine


• Enoxaparin


• Escitalopram


• Etodolac


• Fluoxetine


• Flurbiprofen


• Fluvoxamine


• Fondaparinux


• Heparin


• Ibuprofen


• Ibuprofen Lysine


• Indomethacin


• Ketoprofen


• Ketorolac


• Lepirudin


• Magnesium Salicylate


• Mefenamic Acid


• Meloxicam


• Milnacipran


• Nabumetone


• Naproxen


• Nefazodone


• Nepafenac


• Oxaprozin


• Paroxetine


• Phenindione


• Phenprocoumon


• Piroxicam


• Protein C, Human


• Rivaroxaban


• Salsalate


• Sertraline


• Sulindac


• Tinzaparin


• Tizanidine


• Tolmetin


• Venlafaxine


• Warfarin

Using ticlopidine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aluminum Carbonate, Basic


• Aluminum Hydroxide


• Aluminum Phosphate


• Calcium


• Carbamazepine


• Dihydroxyaluminum Aminoacetate


• Dihydroxyaluminum Sodium Carbonate


• Fosphenytoin


• Magaldrate


• Magnesium Carbonate


• Magnesium Hydroxide


• Magnesium Oxide


• Magnesium Trisilicate


• Phenytoin


• Theophylline


• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of ticlopidine. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood clotting problems, such as hemophilia and von Willebrand's disease, or


• Liver disease (severe) or


• Stomach ulcers—The chance of serious bleeding may be increased

• Blood disease—The chance of serious side effects may be increased

• Kidney disease (severe)—Ticlopidine is removed from the body more slowly when the kidneys are not working properly. This may increase the chance of side effects

Also, tell your doctor if you have ever had a problem called thrombotic thrombocytopenic purpura (TTP). This problem could reoccur if you take ticlopidine.

Proper Use of ticlopidine

Ticlopidine should be taken with food. This increases the amount of medicine that is absorbed into the body. It may also lessen the chance of stomach upset.

Take ticlopidine only as directed by your doctor. Ticlopidine will not work properly if you take less of it than directed. Taking more ticlopidine than directed may increase the chance of serious side effects without increasing the helpful effects.

Dosing

The dose of ticlopidine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of ticlopidine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  
  • For prevention of strokes:
    
    • Adults—1 tablet (250 mg) two times a day, with food.
    
    
    • Children—It is not likely that ticlopidine would be used to help prevent strokes in children. If a child needs ticlopidine, however, the dose would have to be determined by the doctor.
    
    
  
  
  • For prevention of strokes or heart attack following heart stent procedure:
    
    • Adults—1 tablet (250 mg) two times a day, with food together with your doctor's recommended dose of aspirin for up to 30 days following the procedure
    
    
    • Children—It is not likely that ticlopidine would be used to help prevent strokes or heart attack in children. If a child needs ticlopidine, however, the dose would have to be determined by the doctor
    
    
  
  

Missed Dose

If you miss a dose of ticlopidine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using ticlopidine

It is very important that blood tests be done before treatment is started with ticlopidine, and repeated every 2 weeks for the first 3 months of treatment with ticlopidine. The tests are needed to find out whether certain side effects are occurring. Finding these side effects early helps to prevent them from becoming serious. Your doctor will arrange for the blood tests to be done. Be sure that you do not miss any appointments for these tests. You will probably not need to have your blood tested so often after the first 3 months of treatment, because the side effects are less likely to occur after that time.

Tell all medical doctors, dentists, nurses, and pharmacists you go to that you are taking ticlopidine. Ticlopidine may increase the risk of serious bleeding during an operation or some kinds of dental work. Therefore, treatment may have to be stopped about 10 days to 2 weeks before the operation or dental work is done.

Ticlopidine may cause serious bleeding, especially after an injury. Sometimes, bleeding inside the body can occur without your knowing about it. Ask your doctor whether there are certain activities you should avoid while taking ticlopidine (for example, sports that can cause injuries). Also, check with your doctor immediately if you are injured while being treated with ticlopidine.

Check with your doctor immediately if you notice any of the following side effects:

• Bruising or bleeding, especially bleeding that is hard to stop. Bleeding inside the body sometimes appears as bloody or black, tarry stools, or faintness. Also, bleeding may occur from the gums when brushing or flossing teeth.


• Any sign of infection, such as fever, chills, or sore throat.


• Sores, ulcers, or white spots in the mouth.


• Dark or bloody urine, difficulty in speaking, fever, pale color of skin, pinpoint red spots on skin, convulsions (seizures), weakness, or yellow eyes or skin.

After you stop taking ticlopidine, the chance of bleeding may continue for 1 or 2 weeks. During this period of time, continue to follow the same precautions that you followed while you were taking the medicine.

ticlopidine Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Less common or rare

• Abdominal or stomach pain (severe) or swelling


• back pain


• blistering, peeling, or loosening of the skin or lips or mucous membranes (moist lining of many body cavities, including the mouth, lips, inside of nose, anus, and vagina)


• blood in eyes


• bloody or black tarry stools


• bruising or purple areas on skin


• change in mental status


• convulsions (seizures)


• coughing up blood


• dark or bloody urine


• decreased alertness


• dizziness


• fever, chills, or sore throat


• headache (severe or continuing)


• joint pain or swelling


• nosebleeds


• pale color of skin


• paralysis or problems with coordination


• pinpoint red spots on skin


• red lesions on the skin, often with a purple center


• red, thickened, or scaly skin


• sores, ulcers, or white spots in mouth


• stammering or other difficulty in speaking


• unusually heavy bleeding or oozing from cuts or wounds


• unusual tiredness


• unusually heavy or unexpected menstrual bleeding


• vomiting of blood or material that looks like coffee grounds


• weakness


• yellow eyes or skin

Check with your doctor as soon as possible if any of the following side effects occur:

More common

• Skin rash

Less common or rare

• General feeling of discomfort or illness


• hives or itching of skin


• ringing or buzzing in ears

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Abdominal or stomach pain (mild)


• diarrhea


• indigestion


• nausea

Less common

• Bloating or gas


• dizziness


• vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: ticlopidine side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More ticlopidine resources

• Ticlopidine Side Effects (in more detail)
• Ticlopidine Dosage
• Ticlopidine Use in Pregnancy & Breastfeeding
• Drug Images
• Ticlopidine Drug Interactions
• Ticlopidine Support Group
• 0 Reviews for Ticlopidine - Add your own review/rating

• ticlopidine Concise Consumer Information (Cerner Multum)


• Ticlopidine Prescribing Information (FDA)


• Ticlopidine MedFacts Consumer Leaflet (Wolters Kluwer)


• Ticlid Monograph (AHFS DI)


• Ticlid Prescribing Information (FDA)

Compare ticlopidine with other medications

• Cerebral Thrombosis/Embolism

Sandimmune Solution

Pronunciation: SYE-kloe-SPOR-een
Generic Name: Cyclosporine
Brand Name: Sandimmune

Sandimmune Solution should always be used along with adrenal corticosteroids (eg, hydrocortisone), but not with other medicines that suppress the immune system. The risk of developing an infection or a certain type of cancer (lymphoma) may be increased by suppressing the immune system.

Sandimmune Solution cannot be switched with other forms of cyclosporine (eg, Neoral) without your doctor's approval.

If you are taking Sandimmune Solution for a long period of time, especially for a liver transplant, lab tests should be performed to monitor your progress or to check for side effects, such as toxicity or decreased effectiveness.

Sandimmune Solution is used for:

Preventing the rejection of organ transplants (kidney, liver, and heart). It is used in combination with adrenal corticosteroids. It may also be used to treat chronic rejection in patients previously treated with other immunosuppressive agents. It may also be used for other conditions as determined by your doctor.

Sandimmune Solution is an immunosuppressant. Exactly how Sandimmune Solution works is not known, but it may block certain white blood cells (lymphocytes).

Do NOT use Sandimmune Solution if:

• you are allergic to any ingredient in Sandimmune Solution


• you are taking bosentan, disulfiram, fluorouracil, an immunosuppressant (eg, azathioprine, tacrolimus), metronidazole, orlistat, or a potassium-sparing diuretic (eg, spironolactone)


• you are having radiation therapy for psoriasis


• you are going to be vaccinated with a live vaccine

Contact your doctor or health care provider right away if any of these apply to you.

Before using Sandimmune Solution:

Some medical conditions may interact with Sandimmune Solution. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have liver, kidney, brain, or nerve problems; high blood potassium or uric acid levels; low blood magnesium or cholesterol levels; high blood pressure; cancer; gout; an infection; or problems absorbing food or medicine; or have had a recent vaccination


• if your diet contains high amounts of potassium


• if you have a history of seizures


• if you are having phototherapy for psoriasis, or are having radiation treatment

Some MEDICINES MAY INTERACT with Sandimmune Solution. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Many prescription and nonprescription medicines (eg, used for infections, inflammation, allergic reactions, asthma, aches and pains, high blood pressure, cancer, gout, diabetes, heartburn, high cholesterol, irregular heartbeat or other heart problems, birth control, Parkinson disease, stomach and intestinal problems, endometriosis, HIV, seizures, blood clotting, weight loss, arthritis, psoriasis, depression, sleep, other conditions), multivitamin products, and herbal or dietary supplements (eg, St. John's wort) may interact with Sandimmune Solution. They may increase the risk of side effects or decrease the effectiveness of this or other medicines


• Immunosuppressants (eg, azathioprine, tacrolimus ) because the risk of developing an infection or cancer may be increased


• Potassium-sparing diuretics (eg, spironolactone) because the risk of high blood potassium levels may be increased


• Bosentan because the risk of its side effects and toxic effects may be increased by Sandimmune Solution


• Disulfiram, fluorouracil, or metronidazole because flushing, headache, fast or irregular heartbeat, shortness of breath, nausea, or vomiting may occur


• Orlistat because it may decrease Sandimmune Solution's effectiveness

This may not be a complete list of all interactions that may occur. Ask your health care provider if Sandimmune Solution may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Sandimmune Solution:

Use Sandimmune Solution as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Sandimmune Solution on a regular schedule with regard to food and time of day.


• Do not eat grapefruit or drink grapefruit juice while you use Sandimmune Solution.


• If you also take sirolimus, do not take it within 4 hours after taking Sandimmune Solution. Check with your doctor if you have questions.


• Follow your doctor's instructions on how to dilute Sandimmune Solution. Use a glass container to mix Sandimmune Solution. To improve the flavor, Sandimmune Solution may be mixed with room temperature milk, chocolate milk, or orange juice.


• Avoid frequently switching the liquid in which you mix Sandimmune Solution. Stir well and drink immediately (do not let it stand before drinking). Rinse glass with more liquid and drink again to make sure the entire dose is taken.


• Do not rinse the dosing syringe with water or any other liquid; this will affect the dose. After use, dry the outside of the dosing syringe with a clean towel and replace the protective cover. If the syringe needs to be cleaned, it must be completely dry before it is used again.


• If you miss a dose of Sandimmune Solution, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Sandimmune Solution.

Important safety information:

• Sandimmune Solution may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Sandimmune Solution with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not switch to another doseform or change brands of Sandimmune Solution without talking to your doctor. Products made by other companies may not work as well for you.


• Sandimmune Solution may increase your risk of skin cancer. Avoid the sun, sunlamps, or tanning booths until you know how you react to Sandimmune Solution. Use a sunscreen or wear protective clothing if you must be outside for more than a short time. It may also increase your risk of developing other forms of cancer (eg, lymphoma). Discuss any questions or concerns with your doctor.


• Sandimmune Solution may lower the ability of your body to fight infection and may increase the risk of severe infections. Avoid contact with people who have colds or infections. Tell your doctor right away if you notice signs of infection like fever, sore throat, rash, or chills.


• Some people treated with Sandimmune Solution have developed severe kidney problems associated with the BK virus infection. Tell your doctor right away if you notice symptoms of kidney problems (eg, change in the amount of urine produced, difficult or painful urination, blood in the urine). In kidney transplant patients, BK virus infection may cause loss of the transplanted kidney. Discuss any questions or concerns with your doctor.


• Do not receive a live vaccine (eg, measles, mumps) while you are taking Sandimmune Solution. Talk with your doctor before you receive any vaccine.


• Sandimmune Solution may reduce the number of clot-forming cells (platelets) in your blood. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.


• Check with your doctor before you use a salt substitute or a product that has potassium in it.


• Tell your doctor or dentist that you take Sandimmune Solution before you receive any medical or dental care, emergency care, or surgery.


• Diabetes patients - Sandimmune Solution may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Lab tests, including kidney and liver function; cyclosporine levels; and blood pressure, lipids, and electrolytes, may be performed while you use Sandimmune Solution. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Sandimmune Solution with caution in the ELDERLY; they may be more sensitive to its effects.


• PREGNANCY and BREAST-FEEDING: Sandimmune Solution may cause harm to the fetus. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Sandimmune Solution while you are pregnant. Sandimmune Solution is found in breast milk. Do not breast-feed while taking Sandimmune Solution.

Possible side effects of Sandimmune Solution:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Acne; dizziness; flushing; headache; increased hair growth; nausea; runny nose; sleeplessness; stomach discomfort; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; blood in the urine; change in the appearance of a mole; chest pain; confusion; dark urine; diarrhea; fast or irregular heartbeat; gum disease or overgrowth; increased or decreased urination; loss of coordination; mental or mood changes; muscle cramps; numbness or tingling of the skin; seizures; severe or persistent headache or dizziness; shortness of breath; symptoms of infection (eg, chills, cough, fever, painful urination, sore throat); tremors; unusual bleeding or bruising; unusual lumps; unusual thickening or growth on the skin; unusual tiredness or weakness; vision changes; wheezing; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Sandimmune side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Sandimmune Solution:

Store Sandimmune Solution at room temperature, below 86 degrees F (30 degrees C), in its original container. Store away from heat, moisture, and light. Do not store in refrigerator. Protect from freezing. Once opened, the contents must be used within 2 months. Do not store in the bathroom. Keep Sandimmune Solution out of the reach of children and away from pets.

General information:

• If you have any questions about Sandimmune Solution, please talk with your doctor, pharmacist, or other health care provider.


• Sandimmune Solution is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Sandimmune Solution. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Sandimmune resources

• Sandimmune Side Effects (in more detail)
• Sandimmune Use in Pregnancy & Breastfeeding
• Drug Images
• Sandimmune Drug Interactions
• Sandimmune Support Group
• 0 Reviews for Sandimmune - Add your own review/rating

Compare Sandimmune with other medications

• Crohn's Disease
• Idiopathic Thrombocytopenic Purpura
• Inflammatory Bowel Disease
• Organ Transplant, Rejection Prophylaxis
• Organ Transplant, Rejection Reversal
• Ulcerative Colitis

Sprix Nasal Spray

ketorolac tromethamine

Dosage Form: nasal spray
FULL PRESCRIBING INFORMATION

WARNING; LIMITATIONS OF USE, GASTROINTESTINAL, BLEEDING, CARDIOVASCULAR, and RENAL RISK

Limitations of Use

SPRIX (ketorolac tromethamine), a nonsteroidal anti-inflammatory drug (NSAID), is indicated for short-term (up to 5 days in adults) management of moderate to moderately severe pain that requires analgesia at the opioid level. Do not exceed a total combined duration of use of SPRIX and other ketorolac formulations (IM/IV or oral) of 5 days [see Dosage and Administration, (2.1) and Warnings and Precautions (5.1)].

SPRIX is not indicated for use in pediatric patients and it is not indicated for minor or chronic painful conditions.

Gastrointestinal Risk

Ketorolac tromethamine, including SPRIX, can cause peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, SPRIX is contraindicated in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Elderly patients are at greater risk for serious gastrointestinal events [see Contraindications (4), Warnings and Precautions (5.2)].

Bleeding Risk

Ketorolac tromethamine inhibits platelet function and is, therefore, contraindicated in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding [see Contraindications (4), Warnings and Precautions (5.3)].

Cardiovascular Risk

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and Precautions (5.6)].

Sprix Nasal Spray is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4)].

Renal Risk

SPRIX is contraindicated in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion [see Contraindications (4), Warnings and Precautions (5.4)].

Indications and Usage for Sprix Nasal Spray

SPRIX is indicated in adult patients for the short term (up to 5 days) management of moderate to moderately severe pain that requires analgesia at the opioid level.

Sprix Nasal Spray Dosage and Administration

Limitations of Use

The total duration of use of SPRIX alone or sequentially with other formulations of ketorolac (IM/IV or oral) must not exceed 5 days because of the potential for increasing the frequency and severity of adverse reactions associated with the recommended doses [see Warnings and Precautions (5.1)]. Treat patients for the shortest duration possible, and do not exceed 5 days of therapy with SPRIX.

Do not use SPRIX concomitantly with other formulations of ketorolac or other NSAIDs [see Warnings and Precautions (5.1)].

SPRIX has not been shown to be safe and effective in pediatric patients 17 years of age and younger.

Adult Patients < 65 Years of Age

The recommended dose is 31.5 mg SPRIX (one 15.75 mg spray in each nostril) every 6 to 8 hours. The maximum daily dose is 126 mg (four doses).

Reduced Doses for Special Populations

For patients ≥ 65 years of age, renally impaired patients, and adult patients less than 50 kg (110 lbs), the recommended dose is 15.75 mg SPRIX (one 15.75 mg spray in only one nostril) every 6 to 8 hours. The maximum daily dose is 63 mg (four doses) [see Warnings and Precautions (5.2, 5.4)].

Discard Used SPRIX Bottle after 24 Hours

Do not use any single SPRIX bottle for more than one day as it will not deliver the intended dose after 24 hours. Therefore, the bottle must be discarded no more than 24 hours after taking the first dose, even if the bottle still contains some liquid.

Dosage Forms and Strengths

Nasal spray: 15.75 mg of ketorolac tromethamine in each 100 μL spray. Each 1.7 g bottle contains 8 sprays.

Contraindications

• Known hypersensitivity to ketorolac tromethamine [see Warnings and Precautions (5.5, 5.7, 5.11)]


• Use in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding [see Warnings and Precautions (5.2)]


• Use in patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs [see Warnings and Precautions (5.5, 5.7, 5.11)]


• Use as a prophylactic analgesic before any major surgery [see Warnings and Precautions (5.3)]


• Use during the perioperative period in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.6)]


• Use in patients with advanced renal disease or patients at risk for renal failure due to volume depletion [see Warnings and Precautions (5.4,5.6)]


• Use in labor and delivery. Through its prostaglandin synthesis inhibitory effect, ketorolac may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage.[see Warnings and Precautions (5.8), Use in Specific Populations (8.1, 8.2)]


• Use in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates


• Use in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis, or those for whom hemostasis is critical [see Warnings and Precautions (5.3), Drug Interactions (7.1, 7.10)]


• Known hypersensitivity to aspirin or to other NSAIDs [see Warnings and Precautions (5.5, 5.7, 5.11)]


• Known hypersensitivity to ethylenediamine tetraacetic acid (EDTA) [see Description (11)]


• Concomitant use with probenecid [see Drug Interactions (7.4)]


• Concomitant use with pentoxifylline [see Drug Interactions (7.10)]

Warnings and Precautions

Limitations of Use

The total duration of use of SPRIX alone or sequentially with other forms of ketorolac is not to exceed 5 days. SPRIX must not be used concomitantly with other forms of ketorolac or other NSAIDs [see Dosage and Administration (2.1)].

Gastrointestinal (GI) Effects - Risk of Ulceration, Bleeding, and Perforation

SPRIX is contraindicated in patients with previously documented peptic ulcers and/or GI bleeding [see Contraindications (4)]. Ketorolac tromethamine can cause serious GI adverse events including bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with ketorolac.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Minor upper GI problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. The incidence and severity of GI complications increases with increasing dose of, and duration of treatment with, ketorolac. Even short-term therapy is not without risk. In addition to past history of ulcer disease, other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of SPRIX until a serious GI adverse event is ruled out. For high risk patients, consider alternate therapies that do not involve NSAIDs. Use great care when giving SPRIX to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated.

Hematological Effects

Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet aggregation as well, use caution with use of ketorolac tromethamine in patients who have coagulation disorders, and monitor these patients carefully. The effects of NSAIDs other than aspirin on platelet function are reversible. Patients on therapeutic doses of anticoagulants (e.g., heparin or dicumarol derivatives) have an increased risk of bleeding complications if given ketorolac tromethamine concurrently; therefore, administer such concomitant therapy only with extreme caution. The concurrent use of ketorolac tromethamine and therapy that affects hemostasis, including prophylactic low dose heparin (2500 to 5000 units q12h), warfarin and dextrans, has not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, carefully weigh the benefits against the risks and use such concomitant therapy in these patients only with extreme caution. Monitor patients receiving therapy that affects hemostasis closely.

In clinical trials, serious adverse events related to bleeding were more common in patients treated with SPRIX than placebo. In clinical trials and in postmarketing experience with ketorolac IV and IM dosing, postoperative hematomas and other signs of wound bleeding have been reported in association with peri-operative use. Therefore, use SPRIX with caution in the postoperative setting when hemostasis is critical.

Anemia is sometimes seen in patients receiving NSAIDs. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Do not use SPRIX in patients for whom hemostasis is critical [see Contraindications (4), Drug Interactions (7.1, 7.2, 7.10)].

Renal Effects

Ketorolac and its metabolites are eliminated primarily by the kidneys. Patients with reduced creatinine clearance will have diminished clearance of the drug [see Clinical Pharmacology (12.4)]. SPRIX is contraindicated in patients with advanced renal impairment [see Contraindications (4)].

In patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and renal blood flow, which may precipitate overt renal decompensation. Decreased intravascular volume such as when oral intake is poor increases the risks of renal toxicity with NSAIDs. Therefore, patients treated with SPRIX should be adequately hydrated. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Use SPRIX with caution in patients with impaired renal function, heart failure, liver dysfunction, those taking diuretics or ACE inhibitors, and the elderly. Assess the risks and benefits prior to giving SPRIX to these patients, and follow these patients closely during SPRIX therapy. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury such as interstitial nephritis and nephrotic syndrome.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients with or without a history of allergic reactions to aspirin or NSAIDs and in patients without known prior exposure to ketorolac. SPRIX should be discontinued immediately in patients with allergic reactions. SPRIX should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications (4), Warnings and Precautions (5.11)]. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Cardiovascular Effects

• Cardiovascular (CV) Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious CV thrombotic events, myocardial infarction and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID increases the risk of serious GI events. Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see Contraindications (4), Warnings and Precautions (5.2), Drug Interactions (7.2, 7.3, 7.7)].

• Hypertension

NSAIDs can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7.3)].

• Congestive Heart Failure and Edema

Fluid retention, edema, retention of NaCl, oliguria, and elevations of serum urea nitrogen and creatinine have been reported in clinical trials with ketorolac. Therefore, only use SPRIX very cautiously in patients with cardiac decompensation or similar conditions.

Skin Reactions

NSAIDs, including ketorolac, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin manifestations, and discontinue use of the drug at the first appearance of skin rash or any other sign of hypersensitivity [see Contraindications (4)].

Pregnancy

Starting at 30 weeks gestation, SPRIX can cause fetal harm when administered to a pregnant woman due to an increased risk of premature closure of the ductus arteriosus. If SPRIX is used at or after 30 weeks gestation, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Hepatic Effects

Use SPRIX with caution in patients with impaired hepatic function or a history of liver disease. Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including ketorolac. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes, have been reported [see Warnings and Precautions (5.4, 5.6),Clinical Pharmacology (12.4)].

Evaluate patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, for evidence of the development of a more severe hepatic reaction while on therapy with SPRIX. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue SPRIX.

Inflammation and Fever

The pharmacological activity of SPRIX in reducing inflammation and fever may diminish the utility of these diagnostic signs in detecting infections.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, do not administer SPRIX to patients with this form of aspirin sensitivity, and use with caution in patients with preexisting asthma [see Contraindications (4), Warnings and Precautions (5.5)].

Eye Exposure

Avoid contact of SPRIX with the eyes. If eye contact occurs, wash out the eye with water or saline, and consult a physician if irritation persists for more than an hour.

Adverse Reactions

The following serious adverse reactions are discussed elsewhere in the labeling:

• Gastrointestinal effects [see Boxed Warning and Warnings and Precautions (5.2)]


• Hemorrhage [see Boxed Warning and Warnings and Precautions (5.3)]


• Renal effects [see Boxed Warning and Warnings and Precautions (5.4)]


• Anaphylactoid reactions [see Warnings and Precautions (5.5)]


• Cardiovascular thrombotic events [see Boxed Warning and Warnings and Precautions (5.6)]


• Hypertension [see Warnings and Precautions (5.6)]


• Congestive heart failure and edema [see Warnings and Precautions (5.6)]


• Serious skin reactions [see Warnings and Precautions (5.7)]


• Hepatic effects [see Warnings and Precautions (5.9)]

The most frequently reported adverse reactions were related to local symptoms, i.e., nasal discomfort or irritation. These reactions were generally mild and transient in nature.

The most common drug-related adverse events leading to premature discontinuation were nasal discomfort or nasal pain (rhinalgia).

Experience from SPRIX Clinical Studies

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to SPRIX in patients enrolled in placebo-controlled efficacy studies of acute pain following major surgery. The studies enrolled 828 patients (183 men, 645 women) ranging from 18 years to over 75 years of age.

The patients in the postoperative pain studies had undergone major abdominal, orthopedic, gynecologic, or other surgery; 455 patients received SPRIX (31.5 mg) three or four times a day for up to 5 days, and 245 patients received placebo. Most patients were receiving concomitant opioids, primarily PCA morphine.

Table 1. Post-operative Patients with Adverse Reactions Observed at a rate of 2% or more and at least twice the incidence of the placebo group.

	SPRIX (N=455)	Placebo (N= 245)
Nasal discomfort	15%	2%
Rhinalgia	13%	<1%
Lacrimation increased	5%	0%
Throat irritation	4%	<1%
Oliguria	3%	1%
Rash	3%	<1%
Bradycardia	2%	<1%
Urine output decreased	2%	<1%
ALT and/or AST increased	2%	1%
Hypertension	2%	1%
Rhinitis	2%	<1%

In controlled clinical trials in major surgery, primarily knee and hip replacements and abdominal hysterectomies, seven patients (N=455, 1.5%) treated with SPRIX experienced serious adverse events of bleeding (4 patients) or hematoma (3 patients) at the operative site versus one patient (N=245, 0.4%) treated with placebo (hematoma).  Six of the seven patients treated with SPRIX underwent a surgical procedure and/or blood transfusion and the placebo patient subsequently required a blood transfusion.

Adverse Reactions Reported in Clinical Trials with Other Dosage Forms of Ketorolac or Other NSAIDs

Adverse reaction rates increase with higher doses of ketorolac. It is necessary to remain alert for the severe complications of treatment with ketorolac, such as GI ulceration, bleeding, and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions, and liver failure. These complications can be serious in certain patients for whom ketorolac is indicated, especially when the drug is used inappropriately.

In patients taking ketorolac or other NSAIDs in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are:

Gastrointestinal (GI) experiences including:

*Incidence greater than 10%
abdominal pain	constipation/diarrhea	dyspepsia
flatulence	GI fullness	GI ulcers (gastric/duodenal)
gross bleeding/perforation	heartburn	nausea*
stomatitis	vomiting
Other experiences:
abnormal renal function	anemia	dizziness
drowsiness	edema	elevated liver enzymes
headache*	hypertension	increased bleeding time
injection site pain	pruritus	purpura
rash	tinnitus	sweating

Additional adverse experiences reported occasionally (<1% in patients taking ketorolac or other NSAIDs in clinical trials) include:

Body as a Whole: fever, infection, sepsis

Cardiovascular System: congestive heart failure, palpitation, pallor, tachycardia, syncope

Digestive System: anorexia, dry mouth, eructation, esophagitis, excessive thirst, gastritis, glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding

Hemic and Lymphatic: ecchymosis, eosinophilia, epistaxis, leukopenia, thrombocytopenia

Metabolic and Nutritional: weight change

Nervous System: abnormal dreams, abnormal thinking, anxiety, asthenia, confusion, depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesis, inability to concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremors, vertigo, malaise

Respiratory: asthma, dyspnea, pulmonary edema, rhinitis

Special Senses: abnormal taste, abnormal vision, blurred vision, hearing loss

Urogenital: cystitis, dysuria, hematuria, increased urinary frequency, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention

Adverse Reactions from Postmarketing Experience with Other Dosage Forms of Ketorolac or Other NSAIDs

Other observed reactions (reported from postmarketing experience in patients taking ketorolac or other NSAIDs) are:

Body as a Whole: angioedema, death, hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema, myalgia

Cardiovascular: arrhythmia, bradycardia, chest pain, flushing, hypotension, myocardial infarction, vasculitis

Dermatologic: exfoliative dermatitis, erythema multiforme, Lyell's syndrome, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis

Gastrointestinal: acute pancreatitis, liver failure, ulcerative stomatitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease)

Hemic and Lymphatic: agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, postoperative wound hemorrhage (rarely requiring blood transfusion)

Metabolic and Nutritional: hyperglycemia, hyperkalemia, hyponatremia

Nervous System: aseptic meningitis, convulsions, coma, psychosis

Respiratory: bronchospasm, respiratory depression, pneumonia

Special Senses: conjunctivitis

Urogenital: flank pain with or without hematuria and/or azotemia, hemolytic uremic syndrome

Drug Interactions

Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence in animal or human studies that ketorolac induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.

Warfarin, Digoxin, Salicylate, and Heparin

The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac (99.5% control vs. 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide did not alter ketorolac protein binding.

The effects of warfarin and NSAIDs, in general, on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than the users of either drug alone.

Aspirin

When ketorolac is administered with aspirin, its protein binding is reduced, although the clearance of free ketorolac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of SPRIX and aspirin is not generally recommended because of the potential of increased adverse effects [see Warnings and Precautions (5.2, 5.5, 5.11)].

Diuretics

Clinical studies, as well as postmarketing observations, have shown that ketorolac can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with SPRIX, observe the patient closely for signs of renal failure [see Warnings and Precautions (5.4, 5.6)], as well as to assure diuretic efficacy.

Probenecid

Concomitant administration of oral ketorolac and probenecid resulted in decreased clearance and volume of distribution of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 mcg/h/mL), and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore, concomitant use of SPRIX and probenecid is contraindicated.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when SPRIX and lithium are administered concurrently, observe patients carefully for signs of lithium toxicity.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Use caution when SPRIX is administered concomitantly with methotrexate.

ACE Inhibitors/Angiotensin II Receptor Antagonists

Concomitant use of ACE inhibitors and/or angiotensin II receptor antagonists may increase the risk of renal impairment, particularly in volume-depleted patients. Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors and/or angiotensin II receptor antagonists. Consider this interaction in patients taking SPRIX concomitantly with ACE inhibitors and/or angiotensin II receptor antagonists [see Warnings and Precautions (5.4, 5.6)].

Antiepileptic Drugs

Sporadic cases of seizures have been reported during concomitant use of ketorolac and antiepileptic drugs (phenytoin, carbamazepine).

Psychoactive Drugs

Hallucinations have been reported when ketorolac was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).

Pentoxifylline

When ketorolac is administered concurrently with pentoxifylline, there is an increased tendency to bleeding. Therefore, concomitant use of SPRIX and Pentoxifylline is contraindicated [see Contraindications (4) and Warnings and Precautions (5.3)].

Nondepolarizing Muscle Relaxants

In postmarketing experience there have been reports of a possible interaction between ketorolac and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac with muscle relaxants has not been formally studied.

Selective Serotonin Reuptake Inhibitors (SSRIs)

There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Use caution when SPRIX is administered concomitantly with SSRIs.

Fluticasone

The rate and extent of absorption of ketorolac from SPRIX administration (31.5 mg dose) were assessed in subjects with allergic rhinitis before and after the administration of a single daily dose of 200 mcg (as 2 x 50 mcg in each nostril) of fluticasone propionate nasal spray for 7 consecutive days. There was no effect on the pharmacokinetic characteristics of SPRIX that can be considered clinically significant [see Clinical Pharmacology (12.4)].

Oxymetazoline

The rate and extent of absorption of ketorolac from SPRIX administration were assessed in subjects with allergic rhinitis before and 30 min after a single dose (3 sprays in each nostril) of oxymetazoline hydrochloride nasal spray. There was no effect on the pharmacokinetic characteristics of SPRIX that can be considered clinically significant [see Clinical Pharmacology (12.4)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects: Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation.

SPRIX can cause fetal harm when administered to a pregnant woman. Human data demonstrate that use of NSAIDs at or after 30 weeks gestation increases the risk of premature closure of the ductus arteriosus. If SPRIX is used at or after 30 weeks gestation, the patient should be apprised of the potential hazard to a fetus. There are no adequate, well-controlled studies in pregnant women. Prior to 30 weeks gestation, SPRIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.6 times the human systemic exposure at the recommended maximum IN dose of 31.5 mg qid, based on area-under-the-plasma-concentration curve [AUC]) in rabbits and at 10 mg/kg (1.7 times the human AUC) in rats. These studies did not reveal evidence of teratogenicity or other adverse developmental outcomes. However, because animal dosing was limited by maternal toxicity, these studies do not adequately assess ketorolac's potential to cause adverse developmental outcomes in humans.

Labor and Delivery

The effects of SPRIX on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia and delayed parturition, and decreased pup survival.

Nursing Mothers

Ketorolac is excreted in human milk. Ten nursing mothers received 10 mg of oral ketorolac, four times a day, for two days. In four women, ketorolac was undetectable in milk (assay limit 5 ng/mL). In the remaining six women, ketorolac concentrations in milk ranged from 5.2 to 7.9 ng/mL. Based on these concentrations, the estimated maximum infant daily dose of ketorolac from breast milk is 1.185 mcg/kg/day. Exercise caution when administering SPRIX to a nursing woman.

Pediatric Use

The safety and effectiveness of ketorolac in pediatric patients 17 years of age and younger have not been established.

Geriatric Use (≥ 65 years of age)

Exercise caution when treating the elderly (65 years and older) with SPRIX. Carefully consider the potential benefits and risks of SPRIX and other treatment options before deciding to use SPRIX. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Dosage and Administration (2.3), Warnings and Precautions (5.2), Clinical Pharmacology (12.4)]. After observing the response to initial therapy with SPRIX, then adjust the dose and frequency to suit an individual patient's needs.

Drug Abuse and Dependence

Ketorolac does not bind to opiate receptors. A study to evaluate the sedative and addictive potential of ketorolac in volunteers showed no withdrawal symptoms upon cessation of dosing with ketorolac 30 mg IM 4 times daily for 5 days. A single-dose clinical study of IM ketorolac showed no significant adverse effects on psychomotor measurements, including reaction time, computerized driving skills, ataxia, and sedation.

Overdosage

There has been no experience with overdosage of SPRIX. In controlled overdosage studies with IM ketorolac injection, daily doses of 360 mg given for five days (approximately 3 times the maximum daily dose of SPRIX) caused abdominal pain and peptic ulcers, which healed after discontinuation of dosing. Single overdoses of ketorolac tromethamine have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and renal dysfunction.

Symptoms and Signs

Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare.

Treatment

Manage patients using symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Activated charcoal (60 g to 100 g in adults, 1 g/kg to 2 g/kg in children) may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large oral overdose (5 to 10 times the usual dose). Forced diuresis, alkalization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

Sprix Nasal Spray Description

Ketorolac tromethamine is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and the structural formula is:

The molecular weight of ketorolac tromethamine is 376.41. Ketorolac tromethamine is highly water-soluble, allowing its formulation in an aqueous nasal spray product at pH 7.2.

SPRIX is available as an intranasal spray product containing the active ingredient (ketorolac tromethamine) and the excipients edetate disodium (EDTA), monobasic potassium phosphate, sodium hydroxide, and water for injection.

Sprix Nasal Spray - Clinical Pharmacology

Mechanism of Action

SPRIX contains ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID).  Ketorolac is an analgesic that inhibits the enzyme cyclooxygenase (COX), an early component of the arachidonic acid cascade, resulting in the reduced synthesis of prostaglandins, thromboxanes, and prostacyclin.    

Ketorolac does not bind to the opiate receptor subtypes (mu, kappa, delta), but a 30 mg dose of ketorolac tromethamine IM has demonstrated an overall analgesic effect between that obtained with morphine 6 mg and 12 mg. Ketorolac possesses no sedative or anxiolytic properties, and has no effect on gut motility.

Pharmacodynamics

Ketorolac tromethamine is a racemic mixture of [-]S and [+]R-enantiomeric forms, with the S-form having analgesic activity. Ketorolac, the active component of SPRIX, has anti-inflammatory, analgesic, and anti-pyretic effects. Studies directly comparing the analgesic effects of SPRIX and opioids have not been conducted.

Pharmacokinetics

The half-lives of ketorolac by the IN and IM routes were similar. The bioavailability of ketorolac by the IN route of administration of a 31.5 mg dose was approximately 60% compared to IM administration. (See Table 2.)

Table 2: Pharmacokinetic Parameters of Ketorolac Tromethamine after Intramuscular (IM) and Intranasal (IN) Administration

Cmax = maximum plasma concentration; tmax = time of Cmax; AUC0-∞ = complete area under the concentration-time curve; T½ = half-life; SD = standard deviation. All values are means, except tmax, for which medians are reported.
Ketorolac Tromethamine	Cmax (SD) ng/mL	tmax (range) hours	AUC 0-∞ (SD) ng•h/mL	T½ (SD) hours
30 mg IM (1.0 mL of a 30 mg/mL solution)	2382.2 (432.7)	0.75 (0.25-1.03)	11152.8 (4260.1)	4.80 (1.18)
31.5 mg IN (SPRIX) (2 x 100 μL of a 15% w/w solution)	1805.8 (882.8)	0.75 (0.50-2.00)	7477.3 (3654.4)	5.24 (1.33)
15 mg IM (0.5 mL of a 30 mg/mL solution)	1163.4 (279.9)	0.75 (0.25-1.50)	5196.3 (2076.7)	5.00 (1.72)

Absorption: In a study in which SPRIX (31.5 mg) was administered to healthy volunteers four times daily for 5 days, the Cmax, tmax, and AUC values following the final dose were comparable to those obtained in the single-dose study. Accumulation of ketorolac has not been studied in special populations, geriatric, pediatric, renal failure or hepatic disease patients.

Distribution: Scintigraphic assessment of drug disposition of ketorolac following SPRIX intranasal dosing demonstrated that most of the ketorolac was deposited in the nasal cavity and pharynx, with less than 20% deposited in the esophagus and stomach, and zero or negligible deposition in the lungs (<0.5%).

The mean apparent volume (Vβ) of ketorolac tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single-dose data. The ketorolac tromethamine racemate has been shown to be highly protein bound (99%). Nevertheless, plasma concentrations as high as 10 mcg/mL will only occupy approximately 5% of the albumin binding sites. Thus, the unbound fraction for each enantiomer will be constant over the therapeutic range. A decrease in serum albumin, however, will result in increased free drug concentrations. Ketorolac tromethamine is excreted in human milk.

Metabolism: Ketorolac tromethamine is largely metabolized in the liver. The metabolic products are hydroxylated and conjugated forms of the parent drug. The products of metabolism, and some unchanged drug, are excreted in the urine.

Excretion: The principal route of elimination of ketorolac and its metabolites is renal. About 92% of a given dose is found in the urine, approximately 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of a dose is excreted in the feces. A single-dose study with 10 mg ketorolac trom