49．疗霉舒
出处：按学科分类—医药、卫生 军事医学科学出版社《临床常用进口药物手册》第271页（15789字）
【中文释文】：
口服抗真菌剂
〔组成〕
活性成分：盐酸特比萘芬(Terbinafine*，INNrec．*)。
片剂(中央有割线)：125mg(儿童使用)和250mg，赋形剂。
*INNrec．：国际非专利药名记载。
〔特性与作用〕
特比萘芬是一种具有抗真菌活性的丙烯胺类药物。它对皮肤癣菌、霉菌和双相真菌有杀菌作用，对不同种属的酵母菌有杀灭或抑制作用。本品能干扰真菌麦角固醇的早期生物合成，从而导致麦角固醇的缺乏及细胞内角鲨烯堆积，造成真菌细胞死亡。特比萘芬是通过抑制真菌细胞膜中的角鲨烯环氧化酶发挥抗真菌作用的，而该酶与细胞色素P450酶系无关，故本品不影响激素或其它药物的代谢。
体外的最低抑制浓度(μg／ml)
敏感菌属
红色毛癣菌 0．003～0．006
须毛癣菌 0．003～0．01
断毛癣菌 0．003
疣状毛癣菌 0．003
黄癣菌 0．006
犬小孢子菌 0．006～0．01
花斑小孢子菌 0．003
石膏样小孢子菌 0．006
絮状表皮癣菌 0．003～0．006
中度敏感菌属
烟曲菌 0．1～1．56
申克孢子丝菌 0．1～0．4
白色念珠菌：酵母菌 25～100
菌丝 0．23～0．7
近平滑念珠菌 0．8～3．1
卵圆瓶形酵母菌 0．2～0．8
正圆瓶形酵母菌 0．8
动物研究表明，口服给药后，皮肤、头发、甲中的药物浓度，可达杀真菌活性。
〔药代动力学〕
1．吸收 口服单剂量250mg特比萘芬，2h内血药峰浓度为0．97 μg／ml。本品吸收半衰期为1h，分布半衰期为4．6h。其生物利用度可因高脂食物的摄入而增加约40%，这是由于药物吸收的减慢、峰浓度(Cmax)和血药浓度-时间曲线下面积(AUC)增加而引起，无需作剂量调整。
2．分布 特比萘芬与血浆蛋白结合率高达99%，表观分布容积大于2000l，它能经真皮层迅速(几分钟内)弥散并集中于亲脂的角质层，它还能随皮脂分泌，因此在头发、毛囊和皮脂丰富的皮肤处可达很高浓度。临床前研究表明，在给药的最初几周，药物即可分布于甲板中。尚无充足的证据说明该药能通过胎盘屏障。该药经母乳排泄率低于给药剂量的0．2%。
3．代谢／清除 本品生物转化后的代谢产物无抗真菌活性，它主要随尿液排出(71%)，部分随粪便排出(22%)。消除半衰期为17h。尿中排出量的85%在72h内被排出，故该药无蓄积作用。
4．特定临床环境的动力学 本品的稳态血药浓度不受年龄影响，总体血浆清除率为1300ml／min(生物利用度80%的基础上)，但肝、肾功能不全的病人清除率会下降，导致血药浓度升高。
〔适应证与用途〕
1．由毛癣菌(红色毛癣菌、须毛癣菌、疣状毛癣菌、断发癣菌和紫色毛癣菌等)、犬小孢子菌和絮状表皮癣菌等引起的皮肤、头发感染。
2．各种癣病(体癣、股癣、手足癣和头癣等)以及由念珠菌(白色念珠菌等)引起的皮肤酵母菌感染。
3．由皮霉菌(丝状菌等)引起的甲癣。
口服疗霉舒对阴道念珠菌病、花斑癣无效。
〔剂量和用法〕
1．常用量 成人，250mg，每天一次。
儿童(2岁以上)：
＜20kg：62．5mg(125mg的片剂用半片)，每天一次。
20～40kg：125mg(125mg的片剂用1片)，每天一次。
＞40kg：250mg(125mg的片剂用2片)，每天一次。
2．疗程(根据感染类型和程度而定)
(1)皮肤感染
手足癣[趾(指)间型和跖型]：2～6周。
体癣、股癣：2～4周。
皮肤念珠菌病：2～4周。
(2)头发和头皮感染
头癣：4周。头癣多发于儿童。要告知病人，若要避免再次感染，服药必须定时，疗程必须足够长。
(3)指(趾)甲癣
绝大多数病人的疗程为6～12周，其中年青病人因甲生长正常而可能缩短疗程。某些病人，如大拇趾甲感染或甲生长缓慢，可能需6个月的疗程。在真菌学治愈后(真菌培养阴性)几个月，临床症状才能逐渐消失，甲板外观才能完全正常，因为健康的甲组织生长需要时间。
〔特殊剂量的应用〕
1．在老年人中的应用 无证据显示老年病人需用不同于年青病人的剂量或会产生与年青用药病人不同的不良反应。不过，该年龄组的病人在口服此药时，须考虑到损害肝、肾功能的可能性(见下面3)。
2．在儿童中的应用 尚无2岁以下儿童使用口服疗霉舒的经验，故不能推荐。
3．肝、肾功能不全病人的剂量 患有慢性稳定性肝功能障碍或肾功能不全的病人(肌酐清除率＜50ml／min或血清肌酐＞300μml／l)，应将剂量减少一半。
总之，良好的卫生习惯对于疗霉舒的有效治疗是很必要的，这样可避免再次感染(如由内衣、袜子、鞋等感染)。
〔使用限制〕
1．禁忌证 对疗霉舒中任一成分过敏者。
2．注意事项 肝、肾功能不全者使用注意事项，见“特殊剂量的应用”。只有当外用药无效时才能使用口服疗霉舒片剂。尚无2岁以下儿童使用该药的经验，故不作推荐。
3．妊娠期与哺乳期 动物研究显示，本品对胎儿无损伤作用，但未经临床孕妇对照试验确证，由于本品用于孕妇的临床经验极有限，故除非可能的益处超过可能的危险，原则上孕妇不应使用。
本品可进乳汁排出，尽管量很少，因此服用本品的母亲不应哺乳。
〔不良反应〕
本品耐受性好，不良反应的为轻度至中度，且为一过性的。
1．胃肠道反应 仅在少数病例(5%)中见到，如腹胀、恶心、轻度腹痛、腹泻和食欲不振。
2．皮肤反应 仅有轻微反应，如皮疹、荨麻疹等(3%)，个别严重的皮肤反应病例(如Stevens-Johnson综合征，中毒性表皮坏死松解症)曾见报道，若发生进行性皮疹，则应停药。
3．其它 非特异性症状(如全身不适、头痛等)偶有报道。罕见味觉改变(包括味觉丧失)，于停药后可恢复正常，个别病例出现肝功能损害。对于有慢性稳定性肝功能障碍的病人，一旦发现肝功能损伤或进一步恶化的指征，必须立即停药。另有报道，个别病人发生中性粒细胞减少。
〔相互作用〕
离体试验以及在健康志愿者身上进行的试验表明，特比萘芬不抑制也不降低经由细胞色素P450酶系代谢的药物的清除率，如环孢菌素、甲糖宁和口服避孕药(然而有报道，使用口服避孕药的妇女同时服用疗霉舒后出现子宫出血，故使用口服避孕药的妇女应慎用本品)。相反，肝药酶诱导剂(如利福平)可加快特比萘芬的清除率，细胞色素P450抑制剂(如西咪替丁)可抑制其清除。因此，如需合用这些药物，必须相应调整疗霉舒的剂量。
〔过量的处理〕
至今尚无过量的病例报告，人的不良反应提示主要的急性过量反应为胃肠道症状(如恶心、呕吐)，可采用洗胃和／或支持性对症处理。
〔其他〕
疗霉舒应放在儿童接触不到的地方。
本品应避光保存，在包装盒上注明的有效期内使用。
〔生产厂家〕
瑞士山德士药厂
(附本品别名：特比萘芬，Terbinafine，疗霉素)
【外文释文】：
An oral antifungal agent
Composition
Active ingredient：Terbinafine(INN rec．)，as the hydrochloride Scored tablets of 125mg(for use in children)and 250mg．Excipients
Properties／Actions
Terbinafine is an allylamine with a range of antifungal activity，its action being fungicidal against dermatophytes，moulds and certain dimorphic fungi，and either fungicidal or fungistalic against yeasts，depending on the species．
Terbinafine interferes with fungal ergosterol biosynthesis at an early stage．This leads to a deficiency of ergosterol and to intracellular accumulation of squalene，resulting in fungal cell death．Terbinafine acts by inhibiting squalene epoxidase in the fungal cell membrane．The enzyme squalene epoxidase is not linked to the cytochrome P450 system．
Terbinafine dose not affect the metabolism of hormones or other drugs．
Minimum inhibitory concentration in vitro
Sensitive species μg／ml
Trichophyton rubrum 0．003-0．006
Trichophyton mentagrophytes 0．003-0．01
Trichophyton tonsurans 0．003
Trichophyton verrucosum 0．003
Trichophyton schonleinii 0．006
Microsporum canis 0．006-0．01
Microsporum versicolor 0．003
Microsporum gypseum 0．006
Epidermophyton floccosum 0．003-0．006
Moderately sensitive species μg／ml
Aspergillus tumigatus 0．1-1．56
Sporothrix schenckii 0．1-0．4
Candida albicans
Yeast 25．0-100
Hyphae 0．23-0．7
Candida parapsilosis 0．8-3．1
Pityrosporum ovale 0．2-0．8
Pityrosporum orbiculare 0．8
Studies in animals have shown that fungicidal concentrations of terbinafine are attained in the skin，hair and nails after oral dosing．
Pharmacokinetics
Absorption
A single oral dose of 250mg terbinafine results in a peak plasma concentration of 0．97 μg／ml within 2 hours after administration．The half-life of absorption is 1 hour and the halflife of distribution 4．6 hours．The bioavailability of terbinafine is increased by approx．40% by the ingestion of high-fat foods，as a result of slower absorption and a higher Cmax and AUC．Dose adjustment is not，however，necessary．
Distribution
Terbinafine binds extensively to plasma proteins(99%)．It has a volume of distribution in excess of 2 000 L．It diffuses rapidly(within minutes)through the dermis and concentrates in the lipophilic stratum corneum．It is also excreted in sebum and achieves high concentrations in hair，hair follicles，and sebum-rich skin．Preclinical evidence suggests that terbinafine is also distributed into the nail plate in the course of the first few weeks of administration．
There is as yet insufficient evidence on whether terbinafine crosses the placental barrier．Less than 0．2% of the dose given is excreted in breastmilk．
Metabolism／Elimination
Biotranstormation results in metabolites with no antifungal activity，which are excreted predominanlly in the urine(71%)but also in the faeces(22%)．The elimination half-life (β-phase)is 17 hours．85%of the amount eliminated in the urine is excreted within 72 hours．The fraction of the dose eliminated extrarenally(Qo)amounts to 0．29．There is no evidence of accumulation．
Kinetics in particular clinical situations
No age-dependent changes in steady-state plasma levels have been observed．Total plasma clearance is 1300ml／min based on a bioavailability of over 80%，but this may be reduced in patients with renal or hepatic impairment，resulting in higher blood levels of terbinafine．
Indications／Uses
Substantiated uses
Fungal infections of the skin and hair caused by dermatophytes such as Trichophylon(e．g．T．rubrum，T．mentagrophytes，T．verrucosum．T．tonsurans，T．Violaceum)，Microsporum canis and Epidermophyton floccosum．
Oral Lamisil should only be used to treat extensive，severe ringworm infections(tinea corporis，tinea cruris，tinea pedis and tinea capilis)and infections of the skin caused by the genus Candida(e．g．Candida albicans)where oral therapy is considered appropriate owing to the site，severity or extent of the infection．
Onychornycoses(tinea unguium，ringworm of the nails)due to infection with dermatophyte organisms(hyphomycetes)．Oral Lamisil is not effective against vaginal candidiasis or pityriasis(tinea)versicolor．
Dosage／Administration
Usual doseage
Adults：250 mg once daily
Children aged over 2 years
＜20kg 62．5mg(1／2 a 125mg tablet once daily)
20-40kg 125mg once daily
＞40kg 250mg once daily
The duration of treatment depends on the type and severity of infection．
Duration of treatment
Skin infections：
Tinea pedis(interdigital，plantar／moccasin-type)： 2-6 weeks
Tinea corporis，Tinea cruris 2-4 weeks
Cutaneous candidiasis 2-4 weeks
Infections of the hair and scalp
Tinea capitis：4 weeks．
Tinea capitis occurs primarily in children．
Patients should be made aware that，if recurrence of infection is to be avoided，the treatment must be used regularly and for an adequate length of time．
Dermatophyte infection of the finger and／or toe nails
Six to twelve weeks is normally sufficient for most infections，particularly in younger patients with normal nail growth．In other cases，however，such as cases of big-toe involvement or reduced nail growth，treatment for up to six months may be necessary．
Oral Lamisil should only be used to treat fungal infections of the nails for as long as mycological culture is positive．
It should be borne in mind that mycological culture is often negative for several months before clinical cure becomes apparent．This is because it takes time for healthy nail tissue to grow．
Special dosage information
Use in the elderly．There is no evidence to suggest that elderly patients require different dosages to those recommended for younger patients．However，the possibility of impaired liver or kidney function should be considered in this age group(see below)．
Use in children：There is no experience with oral Lamisil in children under two years of age and its use cannot be recommended．
Dosage in patients with impaired renal or hepatic function：Patients with stable chronic liver dysfunction or impaired renal function(creatinine clearance less than 50 ml／minute or serum creatinine of more than 300μmol／L)should be given half the recommended dose．
General：Good general hygiene is necessary in conjunction with the use of Lamisil in order to prevent reinfection(e．g．from underwear，socks，shoes，etc．)．
Restrictions on use
Contraindications
Hypersensitivity to any of the ingredients of Lamisil．
Precautions
Impaired kidney or liver function：see”Special dosage information”above．
Oral Lamisil should only be used where topical treatment is not practicable．
There is no experience with oral Lamisil in children under two years of age and its use cannot be recommended．
Pregnancy and laclation
Reproduction studies in animals do not suggest that there is any risk of foetal damage but this has not been confirmed by controlled trials in pregnant women．Clinical experience with Lamisil in pregnant women is extremely limited．Lamisil should therefore not be given during pregnancy unless the potential benefits clearly outweigh the risks．
Terbinafine is excreted in breast milk and，although the amount involved is small，mothers taking Lamisil should not breastfeed．
Adverse reactions
Where they occur，these are normally mild to moderate and transient．
Gastrointestinal：Reactions such as a bloated feeling，nausea，mild abdominal pain，diarrhoea and loss of appetite occur in a few cases(5%)．
Cutaneous：Mild reactions such as rash and urticaria may occur(3%)．There have also been isolated reports of severe cutaneous changes such as Stevens-Johnson or Lyell′s syndrome，however，and Lamisil should be withdrawn if cutaneous reactions show a progressive course．
Other：Non-specific symptoms such as general malaise and headache have occasionally been reported．
Impairment of the sense of taste(including complete loss)has been observed in a few cases(incidence of 0．125%in clinical trials)，with reversion to normal following withdrawal．There have been isolated reports of disturbed hepalic function with hepatitis and cholestasis，and Lamisil must be discontinued if there are signs of liver function impairment or of further deterioration in patients with existing chronic but stable liver dysfunction．
There have been isolated reports of neutropenia．
Interactions
Studies performed in vitro and in healthy volunteers have shown that terbinafine neither inhibits nor induces the clearance of drugs that are metabolized via the cytochrome P450 system，such as cyclosporin，tolbutamide and oral contraceptives(although metrorrhagia has been reporled in some women taking oral contraceptives concomitantly with Lamisil)．Conversely，terbinafine clearance may be acceleraled by drugs which induce metabolism( e．g．rifampicin)and slowed by drugs which inhibit cytochrome P450(e．g．cimetidine)．
Where co-administration of such agents is necessary the dosage of Lamisil must therefore be adjusted accordingly．
Overdosage
No case of overdosage has been repored so far．The adverse reactions observed in humans suggest that main symptoms of acute overdosage would be gastrointestinal(e．g．nausea or vomiting)．Gastric lavage and／or symptomatic supportive treatment would then be required．
Other information
Lamisil should be kept out of reach of children．
Shelf-life
The drug should not be used after the expiry dale(=EXP)printed on the pack and should be protecled from light．
Manufacturer
Sandoz Pharma Ltd，Basle，Switzerland