1. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 1 Introduction to Psoriasis Denise Cook, M.D. Medical Officer Division of Dermatology and Dental Drug Products Denise Cook, M.D. Medical Officer Division of Dermatology and Dental Drug Products

2. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 2 Introduction to Psoriasis Prevalence Genetics and Pathogenesis Clinical Variants of Psoriasis State of the Armamentarium Prevalence Genetics and Pathogenesis Clinical Variants of Psoriasis State of the Armamentarium

3. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 3 PrevalencePrevalence Psoriasis occurs in 2% of the world’s population Prevalence in the U.S may be as high as 4.6% Highest in Caucasians In Africans, African Americans and Asians between 0.4% and 0.7% Psoriasis occurs in 2% of the world’s population Prevalence in the U.S may be as high as 4.6% Highest in Caucasians In Africans, African Americans and Asians between 0.4% and 0.7%

4. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 4 PrevalencePrevalence Equal frequency in males and females May occur at any age from infancy to the 10 th decade of life First signs of psoriasis –Females mean age of 27 years –Males mean age of 29 years Equal frequency in males and females May occur at any age from infancy to the 10 th decade of life First signs of psoriasis –Females mean age of 27 years –Males mean age of 29 years

5. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 5 PrevalencePrevalence Two Peaks of Occurrence –One at 20-30 years –One at 50-60 years Psoriasis in children –Low – between 0.5 and 1.1% in children 16 years old and younger –Mean age of onset - between 8 and 12.5 years Two Peaks of Occurrence –One at 20-30 years –One at 50-60 years Psoriasis in children –Low – between 0.5 and 1.1% in children 16 years old and younger –Mean age of onset - between 8 and 12.5 years

6. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 6 PrevalencePrevalence Two-thirds of patients have mild disease One-third have moderate to severe disease Early onset (prior to age 15) –Associated with more severe disease –More likely to have a positive family history Life-long disease –Remitting and relapsing unpredictably –Spontaneous remissions of up to 5 years have been reported in approximately 5% of patients Two-thirds of patients have mild disease One-third have moderate to severe disease Early onset (prior to age 15) –Associated with more severe disease –More likely to have a positive family history Life-long disease –Remitting and relapsing unpredictably –Spontaneous remissions of up to 5 years have been reported in approximately 5% of patients

7. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 7 Genetics and Pathogenesis Psoriasis and the Immune System –The major histocompatibility complex (MHC) Short arm of chromosome 6 –Histocompatibility Antigens (HLA) HLA-Cw6 HLA-B13, -B17, -B37, -Bw16 –T-lymphocyte-mediated mechanism Psoriasis and the Immune System –The major histocompatibility complex (MHC) Short arm of chromosome 6 –Histocompatibility Antigens (HLA) HLA-Cw6 HLA-B13, -B17, -B37, -Bw16 –T-lymphocyte-mediated mechanism

8. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 8 Psoriasis as a Systemic Disease Koebner Phenomenon Elevated ESR Increased uric acid levels → gout Mild anemia Elevated α 2 -macroglobulin Elevated IgA levels Increased quantities of Immune Complexes Koebner Phenomenon Elevated ESR Increased uric acid levels → gout Mild anemia Elevated α 2 -macroglobulin Elevated IgA levels Increased quantities of Immune Complexes

9. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 9 Psoriasis as a Systemic Disease Psoriatic arthropathy Aggravation of psoriasis by systemic factors –Medication –Focal infections –Stress Life-threatening forms of psoriasis Psoriatic arthropathy Aggravation of psoriasis by systemic factors –Medication –Focal infections –Stress Life-threatening forms of psoriasis

10. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 10 Clinical Variants of Psoriasis

11. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 11 Characteristic Lesion of Psoriasis Sharply demarcated erythematous plaque with micaceous silvery white scale Histopathology –Thickening of the epidermis –Tortuous and dilated blood vessels –Inflammatory infiltrate primarily of lymphocytes Sharply demarcated erythematous plaque with micaceous silvery white scale Histopathology –Thickening of the epidermis –Tortuous and dilated blood vessels –Inflammatory infiltrate primarily of lymphocytes

12. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 12 Psoriatic Plaque

13. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 13 Severity of Disease Three Cardinal Signs of Psoriatic Lesions –Plaque elevation –Erythema –Scale Body Surface Area Three Cardinal Signs of Psoriatic Lesions –Plaque elevation –Erythema –Scale Body Surface Area

14. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 14 Chronic Plaque Psoriasis Most Common Variant Plaques may be as large as 20 cm Symmetrical disease Sites of Predilection –Elbows –Knees –Presacrum –Scalp –Hands and Feet Most Common Variant Plaques may be as large as 20 cm Symmetrical disease Sites of Predilection –Elbows –Knees –Presacrum –Scalp –Hands and Feet

15. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 15 Chronic Plaque Psoriasis

16. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 16 Chronic Plaque Psoriasis

17. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 17 Chronic Plaque Psoriasis May be widespread – up to 90% BSA Genitalia involved in up to 30% of patients Most patients have nail changes –Nail pitting –“Oil Spots” –Involvement of the entire nail bed Onychodystrophy Loss of nail plate May be widespread – up to 90% BSA Genitalia involved in up to 30% of patients Most patients have nail changes –Nail pitting –“Oil Spots” –Involvement of the entire nail bed Onychodystrophy Loss of nail plate

18. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 18 Widespread Chronic Plaque Psoriasis

19. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 19 Chronic Psoriasis

20. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 20 Psoriasis of the Nail

21. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 21 Psoriasis of the Nail

22. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 22 Symptoms of Chronic Plaque Psoriasis Pruritus Pain Excessive heat loss Patient Complaints –Unsightliness of the lesions –Low self-esteem –Feelings of being socially outcast –Excessive scale Pruritus Pain Excessive heat loss Patient Complaints –Unsightliness of the lesions –Low self-esteem –Feelings of being socially outcast –Excessive scale

23. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 23 Guttate Psoriasis Characterized by numerous 0.5 to 1.5 cm papules and plaques Early age of onset Most common form in children Streptococcal throat infection often a trigger Spontaneous remissions in children Often chronic in adults Characterized by numerous 0.5 to 1.5 cm papules and plaques Early age of onset Most common form in children Streptococcal throat infection often a trigger Spontaneous remissions in children Often chronic in adults

24. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 24 Guttate Psoriasis

25. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 25 Life–Threatening Forms of Psoriasis Generalized Pustular Psoriasis Erythrodermic Psoriasis Generalized Pustular Psoriasis Erythrodermic Psoriasis

26. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 26 Generalized Pustular Psoriasis Unusual manifestation of psoriasis Can have a gradual or an acute onset Characterized by waves of pustules on erythematous skin often after short episodes of fever of 39˚ to 40˚C Weight loss Muscle Weakness Hypocalcemia Leukocytosis Elevated ESR Unusual manifestation of psoriasis Can have a gradual or an acute onset Characterized by waves of pustules on erythematous skin often after short episodes of fever of 39˚ to 40˚C Weight loss Muscle Weakness Hypocalcemia Leukocytosis Elevated ESR

27. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 27 Generalized Pustular Psoriasis Cause is obscure Triggering Factors –Infection –Pregnancy –Lithium –Hypocalcemia secondary to hypoalbuminemia –Irritant contact dermatitis –Withdrawal of glucocorticosteroids, primarily systemic Cause is obscure Triggering Factors –Infection –Pregnancy –Lithium –Hypocalcemia secondary to hypoalbuminemia –Irritant contact dermatitis –Withdrawal of glucocorticosteroids, primarily systemic

28. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 28 Generalized Pustular Psoriasis

29. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 29 Erythrodermic Psoriasis Classic lesion is lost Entire skin surface becomes markedly erythematous with desquamative scaling. Often only clues to underlying psoriasis are the nail changes and usually facial sparing Classic lesion is lost Entire skin surface becomes markedly erythematous with desquamative scaling. Often only clues to underlying psoriasis are the nail changes and usually facial sparing

30. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 30 Erythrodermic Psoriasis Triggering Factors –Systemic Infection –Withdrawal of high potency topical or oral steroids –Withdrawal of Methotrexate –Phototoxicity –Irritant contact dermatitis Triggering Factors –Systemic Infection –Withdrawal of high potency topical or oral steroids –Withdrawal of Methotrexate –Phototoxicity –Irritant contact dermatitis

31. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 31 Erythrodermic Psoriasis

32. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 32 State of the Armamentarium Wide range of therapies for the treatment of moderate to severe psoriasis None induce a permanent remission All have side effects that can place limits on their use Wide range of therapies for the treatment of moderate to severe psoriasis None induce a permanent remission All have side effects that can place limits on their use

33. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 33 State of the Armamentarium Therapies –Topical Corticosteroids –Topical Vitamin D 3 Analogues –Topical Retinoids –Photo(chemo)therapy –Systemic Therapies Oral Parenteral Therapies –Topical Corticosteroids –Topical Vitamin D 3 Analogues –Topical Retinoids –Photo(chemo)therapy –Systemic Therapies Oral Parenteral

34. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 34 Topical Corticosteroids High potency and Super potent topical steroids These include –Fluocinonide family (cream, ointment, gel) –Betamethasone dipropionate cream –Clobetasol propionate family (cream, ointment, gel, foam, lotion) –Diflorasone diacetate ointment –Betamethasone dipropionate ointment High potency and Super potent topical steroids These include –Fluocinonide family (cream, ointment, gel) –Betamethasone dipropionate cream –Clobetasol propionate family (cream, ointment, gel, foam, lotion) –Diflorasone diacetate ointment –Betamethasone dipropionate ointment

35. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 35 Topical Corticosteroids Side effects associated with use –Skin atrophy –Burning and stinging –Suppression of the hypothalamic- pituitary-adrenal (HPA) axis This may occur after 2 weeks of use with certain topical corticosteroids Side effects associated with use –Skin atrophy –Burning and stinging –Suppression of the hypothalamic- pituitary-adrenal (HPA) axis This may occur after 2 weeks of use with certain topical corticosteroids

36. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 36 Topical Vitamin D 3 Analogues Prototype for this group is calcipotriene 3 formulations – cream, ointment, and scalp solution Former two are approved for plaque psoriasis Latter for moderate to severe psoriasis of the scalp Prototype for this group is calcipotriene 3 formulations – cream, ointment, and scalp solution Former two are approved for plaque psoriasis Latter for moderate to severe psoriasis of the scalp

37. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 37 Topical Vitamin D 3 Analogues Side Effects –Cutaneous Burning Stinging Pruritus Skin irritation Tingling of the skin Side Effects –Cutaneous Burning Stinging Pruritus Skin irritation Tingling of the skin

38. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 38 Topical Retinoids Tazarotene Gel and Cream –Available in two strengths 0.05% and 0.1% –Side Effects Pruritus Burning/Stinging Erythema Worsening of psoriasis Irritation Skin pain Hypertriglyceridemia Tazarotene Gel and Cream –Available in two strengths 0.05% and 0.1% –Side Effects Pruritus Burning/Stinging Erythema Worsening of psoriasis Irritation Skin pain Hypertriglyceridemia

39. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 39 Topical Tazarotene Additional Indications –0.1% gel - approved for the treatment of facial acne vulgaris of mild to moderate severity –0.1% cream approved as an adjunctive agent for use in the mitigation of facial fine wrinkling, facial mottled hyper- and hypopigmentation, and benign facial lentigines in patients who use comprehensive skin care and sunlight avoidance programs Additional Indications –0.1% gel - approved for the treatment of facial acne vulgaris of mild to moderate severity –0.1% cream approved as an adjunctive agent for use in the mitigation of facial fine wrinkling, facial mottled hyper- and hypopigmentation, and benign facial lentigines in patients who use comprehensive skin care and sunlight avoidance programs

40. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 40 Topical Tazarotene (con’t) Both products are pregnancy category X Are contraindicated in women who are or may become pregnant Requirements before and during therapy –A negative pregnancy test 2 weeks prior –Therapy initiated during a normal menses –Women of childbearing potential should use adequate birth control Both products are pregnancy category X Are contraindicated in women who are or may become pregnant Requirements before and during therapy –A negative pregnancy test 2 weeks prior –Therapy initiated during a normal menses –Women of childbearing potential should use adequate birth control

41. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 41 Photo(chemo)therapyPhoto(chemo)therapy Two types of phototherapy –Ultraviolet B (UVB) –Ultraviolet A + psoralen (PUVA) Two types of phototherapy –Ultraviolet B (UVB) –Ultraviolet A + psoralen (PUVA)

42. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 42 UVBUVB Two types –Broadband UVB –Narrowband UVB (311-313 nm) Treatment is time consuming –2-3 visits/week for several months Side effect – possibility of experiencing an acute sunburn reaction Two types –Broadband UVB –Narrowband UVB (311-313 nm) Treatment is time consuming –2-3 visits/week for several months Side effect – possibility of experiencing an acute sunburn reaction

43. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 43 PUVAPUVA Consists of ingestion of or topical treatment with a psoralen followed by UVA Usually reserved for severe, recalcitrant, disabling psoriasis Time consuming – 2-3 visits/wk; at least 6 weeks Precautions –Patients must be protected from further UV light for 24 hours post treatment –With oral psoralen, wrap around UV-blocking glasses must be worn for 24 hours post treatment Consists of ingestion of or topical treatment with a psoralen followed by UVA Usually reserved for severe, recalcitrant, disabling psoriasis Time consuming – 2-3 visits/wk; at least 6 weeks Precautions –Patients must be protected from further UV light for 24 hours post treatment –With oral psoralen, wrap around UV-blocking glasses must be worn for 24 hours post treatment

44. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 44 PUVAPUVA Side effects with oral psoralen –Nausea –Dizziness –Headache Side effects with PUVA –Early Pruritus –Late Skin damage Increased risk for skin cancer, particularly squamous cell (SCC) and after 200 - 250 treatments, increased risk for melanoma Side effects with oral psoralen –Nausea –Dizziness –Headache Side effects with PUVA –Early Pruritus –Late Skin damage Increased risk for skin cancer, particularly squamous cell (SCC) and after 200 - 250 treatments, increased risk for melanoma

45. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 45 Contraindications to PUVA Patients less than 12 years of age Patients with a history of light sensitive disease states Patients with, or with a history of melanoma Patients with invasive SCC Patients with aphakia Patients less than 12 years of age Patients with a history of light sensitive disease states Patients with, or with a history of melanoma Patients with invasive SCC Patients with aphakia

46. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 46 Systemic Therapies Oral –Methotrexate –Neoral (cyclosporine) –Soriatane (acitretin) Parenteral –Amevive (alefacept) –Raptiva (efalizimab) –Enbrel (etanercept) Oral –Methotrexate –Neoral (cyclosporine) –Soriatane (acitretin) Parenteral –Amevive (alefacept) –Raptiva (efalizimab) –Enbrel (etanercept)

47. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 47 MethotrexateMethotrexate Folic acid antagonist Usually reserved for severe, recalcitrant, disabling psoriasis Maximum improvement can be expected after 8 -12 weeks Folic acid antagonist Usually reserved for severe, recalcitrant, disabling psoriasis Maximum improvement can be expected after 8 -12 weeks

48. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 48 Contraindications - Methotrexate Nursing mothers Patients with alcoholism Alcoholic liver disease Other chronic liver disease Patients with overt or laboratory evidence of immunodeficiency syndromes Patients who have preexisting blood dyscrasias Nursing mothers Patients with alcoholism Alcoholic liver disease Other chronic liver disease Patients with overt or laboratory evidence of immunodeficiency syndromes Patients who have preexisting blood dyscrasias

49. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 49 MethotrexateMethotrexate Pregnancy Category X drug product –Contraindicated in pregnant women with psoriasis –Pregnancy must be excluded in women of childbearing potential –Pregnancy should be avoided if either partner is receiving MTX during and for a minimum of 3 months after therapy for male patients and for at least one ovulatory cycle after therapy for female patients Pregnancy Category X drug product –Contraindicated in pregnant women with psoriasis –Pregnancy must be excluded in women of childbearing potential –Pregnancy should be avoided if either partner is receiving MTX during and for a minimum of 3 months after therapy for male patients and for at least one ovulatory cycle after therapy for female patients

50. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 50 Methotrexate – Side Effects Acute or chronic hepatotoxicity Hepatic cirrhosis Leukopenia Thrombocytopenia Anemia, including aplastic anemia Rarely, interstitial pneumonitis Stomatitis Nausea/vomiting Alopecia Photosensitivity Burning of skin lesions Acute or chronic hepatotoxicity Hepatic cirrhosis Leukopenia Thrombocytopenia Anemia, including aplastic anemia Rarely, interstitial pneumonitis Stomatitis Nausea/vomiting Alopecia Photosensitivity Burning of skin lesions

51. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 51 MethotrexateMethotrexate Multiple prescreening tests necessary Recommendations for hepatic monitoring –Periodic LFTs including serum albumin –Liver biopsy Pretherapy or shortly thereafter Cumulative dose of 1.5 grams After each additional 1.0 to 1.5 grams Multiple prescreening tests necessary Recommendations for hepatic monitoring –Periodic LFTs including serum albumin –Liver biopsy Pretherapy or shortly thereafter Cumulative dose of 1.5 grams After each additional 1.0 to 1.5 grams

52. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 52 NeoralNeoral Potent Immunosuppressive Adult, non-immunocompromised patients with severe, recalcitrant plaque psoriasis Maximum efficacy achieved at 16 weeks of therapy Potent Immunosuppressive Adult, non-immunocompromised patients with severe, recalcitrant plaque psoriasis Maximum efficacy achieved at 16 weeks of therapy

53. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 53 Contraindications - Neoral Concomitant PUVA or UVB therapy Methotrexate or other immunosuppressive agents Coal tar or radiation therapy Patients with abnormal renal function Patients with uncontrolled hypertension Patients with malignancies Nursing mothers Concomitant PUVA or UVB therapy Methotrexate or other immunosuppressive agents Coal tar or radiation therapy Patients with abnormal renal function Patients with uncontrolled hypertension Patients with malignancies Nursing mothers

54. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 54 Neoral – Side Effects Possibility of Irreversible renal damage Hypertension Headache Hypertriglyceridemia Hirsutism/hypertrichosis Paresthesia/hyperesthesia Influenza-like symptoms Nausea/vomiting Diarrhea Lethargy Arthralgia Possibility of Irreversible renal damage Hypertension Headache Hypertriglyceridemia Hirsutism/hypertrichosis Paresthesia/hyperesthesia Influenza-like symptoms Nausea/vomiting Diarrhea Lethargy Arthralgia

55. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 55 NeoralNeoral Multiple prescreening tests are required Tests must continue throughout treatment with dosage adjustment as necessary to prevent end-organ damage Multiple prescreening tests are required Tests must continue throughout treatment with dosage adjustment as necessary to prevent end-organ damage

56. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 56 SoriataneSoriatane Oral retinoid approved for the treatment of severe psoriasis in adults Significant improvement can be achieved with 8 weeks of therapy Oral retinoid approved for the treatment of severe psoriasis in adults Significant improvement can be achieved with 8 weeks of therapy

57. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 57 Soriatane - Contraindications Patients with severely impaired liver or kidney function Patients with chronic abnormally elevated blood lipid values Patients who are taking methotrexate Ethanol use when on therapy and for 2 months following therapy in female patients Patients with severely impaired liver or kidney function Patients with chronic abnormally elevated blood lipid values Patients who are taking methotrexate Ethanol use when on therapy and for 2 months following therapy in female patients

58. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 58 SoriataneSoriatane Pregnancy Category X drug product as it is a human teratogen Contraindicated in pregnant females or those who intend to become pregnant during therapy or any time up to three years post therapy Pregnancy Category X drug product as it is a human teratogen Contraindicated in pregnant females or those who intend to become pregnant during therapy or any time up to three years post therapy

59. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 59 Soriatane – Side Effects Those associated with retinoid therapy –Cheilitis –Alopecia –Skin peeling –Dry skin –Pruritus –Rhinitis –Xeropthalmia –Arthralgia Those associated with retinoid therapy –Cheilitis –Alopecia –Skin peeling –Dry skin –Pruritus –Rhinitis –Xeropthalmia –Arthralgia

60. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 60 Soriatane – Side Effects Laboratory Abnormalities –Hypertriglyceridemia (66%) –Decreased HDL (40%) –Hypercholesterolemia (33%) –Elevated liver function tests (33%) –Elevated alkaline phosphatase (10-25%) –Hyperglycemia (10-25%) –Elevated CPK (10-25%) Hepatitis and jaundice occurred in < 1% of patients in clinical trials on Soriatane Laboratory Abnormalities –Hypertriglyceridemia (66%) –Decreased HDL (40%) –Hypercholesterolemia (33%) –Elevated liver function tests (33%) –Elevated alkaline phosphatase (10-25%) –Hyperglycemia (10-25%) –Elevated CPK (10-25%) Hepatitis and jaundice occurred in < 1% of patients in clinical trials on Soriatane

61. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 61 SoriataneSoriatane Multiple prescreening tests must be obtained Continued monitoring throughout therapy necessary with possible dosage adjustment Multiple prescreening tests must be obtained Continued monitoring throughout therapy necessary with possible dosage adjustment

62. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 62 Parenteral Therapy Amevive Immunosuppressive dimeric fusion protein –Extracellular CD2-binding portion of the human leukocyte function antigen-3 (LFA-3) –Linked to the Fc portion of human IgG1 Immunosuppressive dimeric fusion protein –Extracellular CD2-binding portion of the human leukocyte function antigen-3 (LFA-3) –Linked to the Fc portion of human IgG1

63. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 63 AmeviveAmevive Indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis With 12 weeks of therapy, a disease state of clear or almost clear was achieved by 11% (via IV) and 14% (via IM) of patients, respectively Indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis With 12 weeks of therapy, a disease state of clear or almost clear was achieved by 11% (via IV) and 14% (via IM) of patients, respectively

64. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 64 Amevive – Side Effects Dose dependent reduction in circulating CD4+ and CD8+ T lymphocytes –Should not be administered to patients with low CD4+ counts –CD4+ counts must be monitored before and weekly throughout therapy Dose dependent reduction in circulating CD4+ and CD8+ T lymphocytes –Should not be administered to patients with low CD4+ counts –CD4+ counts must be monitored before and weekly throughout therapy

65. Dermatologic and Ophthalmic Drugs Advisory Committee July 12, 2004 65 Amevive – Side Effects Lymphopenia Increase risk of malignancies –Skin cancer – BCC and SCC –Lymphoma Serious infections requiring hospitalization Risk of reactivation of chronic, latent infections Hypersensitivity reactions Lymphopenia Increase risk of malignancies –Skin cancer – BCC and SCC –Lymphoma Serious infections requiring hospitalization Risk of reactivation of chronic, latent infections Hypersensitivity reactions