Dermatologic Therapeutics: Bread and Butter and Beyond Bonnie Mackool, MD, MSPH Assistant Professor of , Harvard Medical School Massachusetts General Hospital Disclosures

Neither I nor my spouse/partner has a relevant financial relationship with a commercial interest to disclose. Medication Overview: Anti-microbial Anti-inflammatory Anti-histaminic Anti-neoplastic Retinoids Biologics Immunosuppressive Hormonal

Therapy Systemic Agents Topical Agents Balneotherapy Cryotherapy Phototherapy Laser Radiation Surgical Dermatologic Medical Armamentarium Includes:

• Adapalene (Differin) cream/gel • Cyclosporine (Neoral) • Azelaic acid (Azelex) cream • Adalimumab (Humira) • Topical steroids • Etanercept (Enbrel) • • Intravenous Immunoglobulin IVIG • • • Anthralin (Drithrocream) • Dapsone (Aczone) gel • (Bactroban)ointment • Benzoyl peroxide + clinda or erythro • Tacrolimus ointment • Finasteride (Propecia) • cream • Tazarotene • (Metrocream/gel) • Tretinoin cream • Hydroxyzine (Atarax) • Methotrexate • Tri-Luma cream (tret, hydroquinone, ster) • Sodium thiosulfate IV • Hydroxychloroquine • Mycophenolate mofetil (cellcept) • Chloroquine • Azathioprine (Imuran) Dermatologic Medical Armamentarium (cont.):

• Spironolactone • Calcipotriene (Dovonex) oint/cr • Isotretinoin (Accutane) • Acyclovir (Zovirax) tabs/oint/cr • 5 Fluorouracil (Efudex) cream/solution • Naltrexone • (Aldara) cream • Gabapentin (Neurontin) • Rituximab (Rituxan) • Doxepin Hydrochloride • Ciclopirox (Loprox) cream • Amitriptyline • Efinaconazole (Jublia) solution • Permethrin cream • Naftifine (Naftin) gel/cream • Ivermectin • Terbinafine HCl (Lamisil) po • Lindane cream • Acitretin (Soriatane) • Santyl (Collagenase) ointment • Thiabendazole • Colchicine • (Silvadene) • Thalidomide Dermatologic Medical Armamentarium – Watch Points

• Side effects: • Monitoring – Topical steroids – Hydroxychloroquine – Topical – Minocycline – Tretinoin cream – Anthralin (Drithrocream) • Drug Interactions: – Tri-Luma cream (tretinoin, – Methotrexate hydroquinone, steroid) – Cyclosporine (Neoral) – Mycophenolate mofetil (cellcept) • Phototoxicity/side effects – Doxycycline • Choosing the appropriate patient” – Tetracycline – Adalimumab (Humira) – Minocycline – Etanercept (Enbrel) ?Newer? Therapeutics

• Dupilumab(Dupixent) s.c. – Asthma, Atopic , sinusitis • Dapsone 5% and 7/5% Gel() – (FDA: Dermatitis herpetiformis, Leprosy, acne) – Non FDA include: PCP prophylaxis, idiopathic urticaria*) • IXEKIZUMAB (Taltz) *Morgan M, Cooke A, Rogers L et al. Double blind – (psoriasis, ankylosing spondylitis- psoriatic arthritis, placebo controlled trial of dapsone in antihistamine non-radiographic axial spondyloarthritis refractory chronic idiopathic urticaria. J Clin Immunol Pract 2014, 2(5), 601-606. – Ankylosing spondylitis, non-radiographic axial spondyloarthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis(not FDA approved for RA)

• Efinaconazole 10 % solution (Jublia) • Melanoma Immunotherapy First Do No Harm

• Side effects of systemic and topical agents • The informed patient – is she/he? • Drug Interactions • Topical does not necessarily mean safe • Systemic Effects of Topical Agents • Compounding dangers Side Effects of Topical Glucocorticoids

Topical Side Effects Systemic Side Effects • Atrophy (sheen) • Sodium Retention • Telangiectases • Hyperglycemia • Striae • CHF • Acne () • Femoral Head Necrosis • Worsening cutaneous fungal infection • Cataracts • Tachyphylaxis • Glaucoma • Hypokalemia (digoxin toxicity) • Adrenal suppression • Growth retardation 30 year old woman with purpuric eruption and peri-areolar dermatitis

Betamethasone valerate applied bid x 3 weeks

Skin Thickness Dictates Choice for Potency

Eyelid < Face < creases,genitals, breast< neck< palms/soles,Back 758.9. 1969.2 micrometer 4629 micrometers 5834 micrometer

. Additional Factors Related to Absorption Increasing Potency for All Topical Agents

• Occlusion increases potency(band aids, skin folds) • Sweating and Moisture increase absorption/potency • Atrophy increases absorption • Loss of barrier function(erosions/ulcers) • Host(elderly and infant factors: – Infant: high ratio of skin surface/body weight results in increase relative dose – Elderly: thinned skin, consider renal function for topicals like sal acid

Topical Steroids – Potency

Mild Mid Strength High Hydrocortisone ointment 2.5% Fluocinolone acetonide ointment .025% ointment Hydrocortisone cream 2.5% Hydrocortisone Valerate 02% Clobetasol propionate cream Hydrocortisone cream 1 % Triamcinolone ointment* *Betamethasone dipropionate Hydrocortisone ointment 1 % ointment Lower Mid Strength valerate gel Fluocinolone acetonide cream .025% Triamcinolone cream *Note: clotrimazole and betamethasone cream – high potency TAC: cream, dental paste, lotion, ointment

Atopic Dermatitis Treatment options include:

Topical Steroids Tacrolimus/Pimecrolimus Dupixen Bleach baths Tacrolimus Ointment and Cream and Pimecrolimus: Calcineurin Inhibitors

• Do not have the topical nor systemic side effects of topical steroids • “Considered second-line therapy” for atopic dermatitis • Expect typically improvement over 4 to 6 weeks • Low systemic absorption: levels decrease as skin improves from atopic dermatitis Tacrolimus (Protopic) ointment

• Children 2 years and older: .03 percent bid • Adults .1 percent bid • For atopic dermatitis (FDA approved), vitiligo, refractory seborrheic dermatitis, , oral lichen planus, LSA • No tachyphylaxis • No atrophy • Black box warning • Most common side effect: irritation • Crosses placenta, excreted in human breast milk Vitiligo

Topical steroids Calcineurin inhibitors Psoriasis

Topical Treatment: Calcipotriene ointment/cream/solution Tazarotene cream .05%, .1 Topical tar (MG217, Exorex cream) Salicylic acid Psoriasis – Common Therapies

Topical Systemic • Glucocorticoids • Acitretin (systemic Vit A) – • Calcipotriene contraindicated in women of child cream/ointment/solution (Dovonex) bearing age • Topical tar preparations • Methotrexate • Salicylic acid(beware of systemic • TNF alpha inhibitors: Etanercept, absorption) Adalimumab, Infliximab • Tazarotene(topical vit a) (Tazorac) • Newer: ixekizumab (Taltz), Ustekinumab (Stelara), Secukinumab (Cosentyx)

Calcipotriene

• Ideal for intertrigo • Ointment and cream for skin • Scalp solution • Used twice daily • Maximum use: cream/ointment – 100 gram tube every week

Psoriasis

Systemic Agents (Partial list) TNF alpha inhibition Methotrexate (oral) Contraindications to TNF Alpha Treatment Include:

• Demyelinating disorders • CHF • Recent malignancies • Acute and chronic infections Tinea pedis

Scale is fine, branny.

Systemic vs Topical Treatment Onychomycosis

Systemic Topical • Terbinafine (Lamisil) • Efinaconazole 10% solution • Mycologic cure rate: 70 percent • Mycologic cure rate: 55.2% – Mycologic + clinical cure: 38% – Complete cure: 17.8 % • 250 mg po qd x 6 week (fingernails) • Applied daily x 48 weeks • 250 mg po qd x 12 weeks (toenails) • Interactions include: – Cimetidine (increased GI symptoms, • Ciclopirox lacquer 8% (data at 48 weeks) ha, LFT abnormalities) – Negative mycology: 29% – Caffeine (decreased clearance) – Complete cure: 5.5% – Metoprolol (bradycardia) – Fluoxetine (risk of QT prolongation) Terbinafine HCL

• Adults: • 250 mg daily x 6 weeks(fingernails), x 12 weeks (toenails) • Pediatric: tinea capitis: 4 years + Granules and dosing is by weight – <25 kg: 125 mg qd x 6 weeks – 25-35 kg: 187.5 mg qd x 6 weeks – >35 kg: 250 mg qd x 6 weeks • Contraindications: Chronic or active Liver disease • Adjustments; Geriatric (Cr cl < 50 mL/min not studied • Monitoring: LFTS baseline and periodically during treatment Terbinafine Hydrochloride (Lamisil) Tabs, Granules

tabs granules

• Dermatologic 5.6 % • 2% • Diarrhea 5.6%; • 3% • Taste disorder: 2.8% • Nausea: • 2 % • Fever • 7 % • Hepatic (Increased enzymes) 3.3 % • Headache 12.9% • 7% Terbinafine Is an Inhibitor of CYP450 2D6 Isozyme

• Drugs metabolized by this isozyme are: – Tricyclic antidepressants – Selective serotonin reuptake inhibitors – Beta-blockers – Antiarrhythmics class 1C – Monoamine oxidase inhibitor Terbinafine Hydrochloride: Serious Side Effects

• Skin: Cutaneous LE, • Hepatic: Liver failure , • Immunologic: DRESS, SLE Generalized exanthematous • Otic: hearing loss pustulosis, SJS, TEN • Hematologic: Neutropenia, thrombotic microangiopathy Acne

Topical (benzoyl peroxide, topical antibiotics- clindamycin, erythromycin, salicylic acid, azelaic acid, topical retinoids) Systemic (antibiotics, hormonal, systemic retinoids) Acne

• Excess sebum • Idea: retinoid through effect • Keratin Disturbance on keratin allows • Propionbacterium acnes to enter pilosebaceous duct colonizing pilosebaceous duct •

Golmick. Jour of Eur Acad of Derm and Vene29, 1-7, 2015. Combination Products for Acne

• Clindamycin + benzoyl peroxide • Duac (1.2%/5%) Benzaclin (1%/5%) • Benzoyl peroxide + erythromycin • Benzamycin • Tretinoin cream + clindamycin • Ziana gel • Adapalene .1% + benzoyl peroxide • Epiduo 2.5% gel • Epiduo Forte • Adapalene .3% + benzoyl peroxide 2.5% Tetracycline Class

• Permanent discoloration of teeth during tooth development (last half of , infancy and childhood to age of 8 yo) • Sun AVOIDANCE (“sunscreen or sunblock should be considered.” Micromedex) • Cross placenta(animal studies: retardation of skeletal development) • Tetracycline: absorption impaired by foods (esp Calcium) • Doxycycline: not impaired by food • Do not ingest outdated or poorly stored • Increase water ingestion to avoid esophageal irritation and ulceration • Remain upright for 1 hour after taking • Intracranial htn (pseudotumor cerebri has been associated with tetracyclines) Dosing

• Tetracycline: 250 mg to 500 mg bid • Minocycline: 50 to 100 mg bid • Doxycycline: 50 to 100 mg bid • Photosensitivity: doxycycline>tetracycline>minocycline

Rosacea – some treatment options

Not: Topical Steroids – Systemic Antibiotics: Tetracyclines Topical metronidazole (cream, gel) Azeleic acid (Finacea, Azelex cream) For Granulomatous : isotretinoin Hydroxychloroquine

Potential side effects Dermatologic Medical Armamentarium – Watch Points

• Side effects: • Monitoring – Topical steroids – Hydroxychloroquine – Topical antibiotics – Minocycline – Tretinoin cream – Anthralin (Drithrocream) – Tri-Luma cream (tretinoin, • Drug Interactions: hydroquinone, steroid) – Methotrexate – Cyclosporine (Neoral) • Phototoxicity/side effects – Mycophenolate mofetil (cellcept) – Doxycycline – Tetracycline – Minocycline • Choosing the appropriate patient” – Adalimumab (Humira) – Etanercept (Enbrel) Dermatologic Therapeutics: Bread and Butter and Beyond Bonnie Mackool, MD, MSPH Assistant Professor of Dermatology, Harvard Medical School Massachusetts General Hospital