痤瘡治療共識小組專家委員會議

Systemic isotretinoin

高雄榮總魏楷哲

感謝楊麗珍醫師指導、提供臨床教育資料

健保給付規定

• Isotretinoin口服製劑 (如Roaccutane)：（86/9/1、87/4/1、94/3/1）

• 1.限皮膚科專科醫師使用。

• 2.需檢附病人之服藥同意書 (詳附表十)，以及經傳統治療無效之病歷資料或治療前之照片，經事前審查核准後使用。

• 3.每次申請以一療程為限，若需再次療程，請檢附原來照片與最近照片再次申請事前審查核准後使用（每一療程最高總劑量為100 mg –120 mg/kg，於四至六個月完成)。

服用同意書

Isotretinoin

• The only therapy for acne that is capable of inducing remission after an adequate course of therapy is completed

• Isotretinoin與血漿蛋白質高度結合，主要為白蛋白(≧99.9％)

• 原藥最終排除半衰期平均為19小時，4-oxo-isotretinoin的最終排除半衰期較長，平均為29小時。

How Isotretinoin works

shrinkage of sebaceous glands

inhibition of the sebum-dependent bacterium Propionibacterium acnes

fostering keratinocyte differentiation and by normalizing desquamation

Isotretinoin 治療痤瘡:近年國際上的建議規範

地點 出處 年度 適應症 建議劑量

European Evidence-Based Guidelines for Treatment of Acne S3

Journal of the European Academy of Dermatology and Venereology

(2012) severe papulopustularor conglobate acne

 100–120 mg/kg

American Academy of Dermatology

Journal of the American Academy of Dermatology

(2007)(新版:預計2015)

Severe recalcitrant nodular acne

cumulative dose of 120–150mg/kg

Consensus on Evidence-Based Practice in Acne (Asian Working Group)

The Journal of Dermatology

(2011) Not conclusive

建議適應症

• 囊腫型痤瘡(acne cystica)或結節型痤瘡(nodular acne)

• 嚴重型且難控制的發炎性痤瘡 (severe nodular and recalcitrant inflammatory acne)– Treatment-resistant acne

• Scarring acne, severe

• Acne causing significant psychological distress

• Antibiotic-induced gram-negative folliculitis in patients with acne vulgaris

其他適應症

• Acne fulminans

The treatment of acne fulminans: a review of 25 cases.Br J Dermatol. 1999;141(2):307.

Acne fulminans: report of clinical findings and treatment of twenty-four patients. J Am Acad Dermatol. 1993;28(4):572.

J Eur Acad Dermatol Venereol. 2011 May;25(5):501-7.

不同劑量的療效與復發率

J Clin Aesthet Dermatol. 2014 Feb;7(2 Suppl):S3-S21.The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions.

J Am Acad Dermatol. 2007;56(4):651.

J Am Acad Dermatol. 2006;54(4):644Low-dose isotretinoin in the treatment of acne vulgaris.

建議劑量

• FDA: starting daily dose is 0.5mg/kg/day, which is increased to l mg/kg/day, as tolerated

- 0.5mg/kg/day to 2.0mg/kg/day

- Once or twice daily for 15 to 20 weeks

- (QD vs. BID is not studied)

• Cumulative dose: >120 to 150mg/kg if isotretinoin is administered over the maximum duration of treatment (20 weeks [5 months]) indicated in the FDA-approved package inserts.

現實生活中使用isotretinoin持續治療時間:

J Clin Aesthet Dermatol. 2014 Feb;7(2 Suppl):S3-S21.

（20週)

口服isotretinoin停藥後，Acne復發的機會:

Actas Dermosifiliogr. 2013 Jan;104(1):61-6. Acne relapse rate and predictors of relapse following treatment with oral isotretinoin.

復發機會高，復發比例差異極大，但是機會隨著追蹤時間拉長而增加

口服isotretinoin停藥後，影響Acne復發的可能因素

Actas Dermosifiliogr. 2013 Jan;104(1):61-6. Acne relapse rate and predictors of relapse following treatment with oral isotretinoin.

高劑量是否會有比較好的療效呢?Higher dose for isotretinoin

• 高劑量的療效是否較好?

• 停藥後復發的機會是否減少?

• 副作用的機會是否增加? (Benefit vs. Risk)

• lower-dose vs. high dose: <220 mg/kg vs. > 220 mg/kg

• The rate of relapse: 43.8% (95% CI, 16.3%-40.3%) vs. 26.6% (24.1%-65.7%) (P = .22)

From: High-Dose Isotretinoin Treatment and the Rate of Retrial, Relapse, and Adverse Effects in Patients With

Acne Vulgaris

JAMA Dermatol. 2013;149(12):1392-1398. N=78, with comparison 74.1% were white people.

From: High-dose isotretinoin in acne vulgaris: improved treatment outcomes and quality of life.

Int J Dermatol. 2012 Sep, 51(9):1123-30 cumulative dose:290 mg/kg. USA. N=80, no comparison group.

From: High-Dose Isotretinoin Treatment and the Rate of Retrial, Relapse, and Adverse Effects in Patients With

Acne Vulgaris

JAMA Dermatol. 2013;149(12):1392-1398.

From: High-Dose Isotretinoin Treatment and the Rate of Retrial, Relapse, and Adverse Effects in Patients With

Acne Vulgaris

JAMA Dermatol. 2013;149(12):1392-1398. doi:10.1001/jamadermatol.2013.6746

低劑量是否會真的療效比較差呢?Lower dose of isotretinoin for acne

• 藥物的反應是否有人種差異?

• 多低的劑量算是低劑量呢?

Indian J Dermatol. 2014 May;59(3):316. Safety and efficacy of low-dose isotretinoin in the treatment of moderate to severe acne vulgaris.

20 mg QD for 3 months

Fifty cases. India

Indian J Dermatol. 2014 May;59(3):316. Safety and efficacy of low-dose isotretinoin in the treatment of moderate to severe acne vulgaris.

低劑量的起始療效不會比較不好。但是復發率呢?

J Am Acad Dermatol. 2001 Aug;45(2):187-95.

Israel.

J Am Acad Dermatol. 2006 Apr;54(4):644-6.

Follow: 4 yrs

Arch Dermatol Res. 2007 Dec;299(10):467-73.

Turkey.Follow: 12 mo

India. Follow: 6mo

J Eur Acad Dermatol Venereol. 2009 May;23(5):556-60

建議禁忌症

• 禁止使用於懷孕孕婦或在治療期間可能懷孕的婦女:使用前一個月，使用期間，使用後一個月，都要完全避孕

• 肝功能不全或異常• 維生素A過多症• 血脂值過高的病患

• 已知對本藥和其任何成分過敏者peanut oil? Paraben敏感?

• 飛行員，以及需要敏銳夜間視力者

24

Isotretinoin in pregnancy

• labeling: pregnancy category X

• Increased risk of spontaneous abortion and premature birth

• Congenital malformations: craniofacial, cardiac, thymus, CNS28% of exposed pregnancies affected at birth

iPLEDGE

teratogen

• Risk management

• But what should we do if exposure or unexpected pregnancy happens?

- spontaneous abortion, malformation?

- or nothing?

副作用、後遺症

Predictable:• 皮膚：唇炎，發疹，皮膚乾燥，對光敏感• 耳鼻喉︰鼻出血、鼻乾燥• 血液：血清中三酸甘油脂濃度增加50%~70%

Unpredictable:• 中樞神經：頭痛，倦感• 口服A酸後，發生良性顱內高血壓(pseudo-tumor

cerebri)• 肝臟：SGOT，SGPT，鹼性磷酯酶上昇• 貧血，血小板增多

JAMA Dermatol. 2013;149(12):1392-1398. doi:10.1001/jamadermatol.2013.6746

JAMA Dermatol. 2013;149(12):1392-1398. doi:10.1001/jamadermatol.2013.6746

追蹤

• Triglycerides, Cholesterol, Transaminase, Complete blood counts

• 應於治療前及開始服藥4-6週後檢查，然後每3個月檢查一次。

• Hyperostosis, premature epiphyseal closure, bone demineralization.

– routine screen is not required. (JAAD)

• Mood disorder: not routine required.

目前有爭議的幾個問題

Psychosocial “Complications”

of acne

Depression

Anxiety

Social withdrawal

Poor self esteem

Suicide ideation

Overall quality of life

Isotretinoin increases the risk of inflammatory bowel disease?

• 一年內發生潰瘍性結腸炎的機率將會比未服用者，高出四倍?

• 真的是如此嗎？

Am J Gastroenterol. 2014 Apr;109(4):563-9.Isotretinoin and risk of inflammatory bowel disease: a French nationwide study.

J Invest Dermatol. 2013 Apr;133(4):907-12.Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study.

Am J Gastroenterol. 2006 Jul;101(7):1569-73.Possible association between isotretinoin and inflammatory bowel disease.

From: Isotretinoin Exposure and Risk of Inflammatory Bowel Disease

JAMA Dermatol. 2014;150(12):1322-1326. doi:10.1001/jamadermatol.2014.1540

Isotretinoin 和嚴重的疤痕增生

• 可能造成無法預期的組織修復作用，讓傷口癒合不良，有可能造成疤痕形成，例如肥厚性疤痕或蟹足腫，所以進行磨皮雷射或侵入性治療、手術後，建議避免使用A酸。若正在進行口服A酸療程，也應停藥「一段時間」才能進行磨皮或侵入性治療。

• J Am Acad Dermatol. 1986 Aug;15(2 Pt 1):280-5.• Br J Dermatol. 1988 May;118(5):703-6. • J Am Acad Dermatol. 1994 May;30(5 Pt 2):852-3.

Dermabrasion for acne scars during treatment with oral isotretinoin.Dermatol Surg. 2010 Apr;36(4):483-9.

Early chemabrasion for acne scars after treatment with oral isotretinoin.Dermatol Surg. 2012 Sep;38(9):1521-6.)

Safety of performing invasive acne scar treatment and laser hair removal in patients on oral isotretinoin: a retrospective study of 110 patients.Int J Dermatol. 2014 Oct;53(10):1281-5.

Isotretinoin不會引起嚴重的疤痕增生