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panretin（alitretinoin,阿利维甲酸0.1%凝胶)

2012-10-21 18:16:34 作者：新特药房来源：中国新特药网天津分站浏览次数：372 文字大小：【大】【中】【小】

简介： 药品信息:阿利维甲酸（alitretinoin）是一种能激活所有已知的细胞内维甲酸类受体亚型（RARα、RARβ、RARγ、RXRα、RXRβ和RXRγ）的内源性维甲酸。0．1％阿利维甲酸凝胶剂（商品名：Panretin）已于19 ...

关键字：panretin（alitretinoin 阿利维甲酸0.1%凝胶)

药品信息:
阿利维甲酸（alitretinoin）是一种能激活所有已知的细胞内维甲酸类受体亚型（RARα、RARβ、RARγ、RXRα、RXRβ和RXRγ）的内源性维甲酸。0．1％阿利维甲酸凝胶剂（商品名：Panretin）已于1999年被批准用于治疗皮肤卡波济肉瘤。尽管目前已对经口给予阿利维甲酸治疗卡波济肉瘤（和其他肿瘤）的效果进行了研究，且证明其有一定疗效，但阿利维甲酸的口服制剂尚未获得美国、日本以及欧盟的批准。在欧盟进行的一项Ⅲ期临床试验表明，口服阿利维甲酸对治疗慢性手部皮炎（湿疹）有效。如果得到批准，阿利维甲酸将成为第一个用于治疗慢性手部皮炎的口服药。Basilea制药公司已向欧洲和瑞士卫生署提出了将阿利维甲酸用于治疗重度顽固性慢性手部湿疹的上市申请.

Panretin® (alitretinoin) gel 0.1%
Panretin® (alitretinoin) gel is a prescription medicine that is applied to the skin for the treatment of skin lesions in patients with AIDS-related Kaposi's sarcoma (KS). Panretin gel should not be used when systemic (oral or injectable) anti-KS therapy is required (e.g. more than 10 new KS lesions in the prior month, symptomatic lymphedema [swelling in tissues], symptomatic pulmonary KS [affecting the lungs], or symptomatic visceral involvement [affecting internal organs]). There is no experience to date using Panretin gel with systemic anti-KS treatment.
Kaposi's sarcoma is a cancer that causes patches of abnormal tissue to grow under the skin, in the lining of the mouth, nose and throat or in other organs. In the United States, approximately 1.21 men per 100,000, in 2007, were diagnosed with Karposi's sarcoma.
Important Safety Information
Panretin gel is not indicated in patients with a known hypersensitivity to retinoids or to any of the ingredients of the product.
Pregnancy Category D - Panretin gel could cause fetal harm if significant absorption were to occur in a pregnant woman. If Panretin gel is used during pregnancy, or if the patient becomes pregnant while taking it, the patient should be made aware of the potential harm to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant. Because of the potential for adverse reactions from Panretin gel in nursing infants, mothers should discontinue nursing prior to using the drug.
Patients with cutaneous T-cell lymphoma were less tolerant of Panretin gel; 5 of 7 patients had 6 episodes of treatment limiting toxicities - grade 3 dermal irritation - with Panretin gel (0.01 or 0.05%).
Patients should minimize exposure of treated areas to sunlight and sunlamps during the use of Panretin gel. Patients should not use products that contain DEET (N,N-diethyl-m-toluamide), a common ingredient of insect repellant products, while using Panretin gel.
The safety of Panretin gel was assessed in clinical studies of 385 patients with AIDS-related KS. Adverse events associated with the use of Panretin occurred almost exclusively at the gel application site. Dermal toxicity begins with erythema, with continued application of Panretin gel, erythema may increase and edema may develop. Dermal toxicity may become treatment limiting with intense erythema, edema, and vesiculation. Usually adverse events were mild to moderate to in severity and led to withdrawal from the study in 7% of the patients. Severe local (application site) skin adverse events occurred in about 10% of patients.
The most common adverse events with an incidence of at least 10% at the application site in Panretin gel-treated patients were; rash, pain, pruritus, and paraesthesia.
Please also see the Panretin Gel Full Prescribing Information.
Patients should consult their healthcare provider if they have any questions about, or are experiencing any side effects from, this product.

Panretin is a registered trademark of Eisai Inc.

分类名称

一级分类：抗肿瘤药物二级分类：其他抗肿瘤药物三级分类：

药品英文名

Alitretinoin

药品别名

Panretin、Panrexin

药物剂型

局部凝胶剂：1%。

药理作用

本品可结合并激活细胞内的视黄酸受体(RAR)(如RARα，RARβ，RARγ)和视黄醛X受体(RXR)(如RXRα，RXRβ，RXRγ)，从而增强基因转录。本品治疗与卡波济肉瘤有关损害的实际作用机制尚未完全阐明；不过，本品似乎可以影响基因表达，从而抑制细胞增殖，诱导细胞分化，激发健康细胞和癌细胞的凋亡。体外证实，本品可抑制卡波济肉瘤细胞生长。

药动学

局部应用本品后，未从血浆中检出本品及其代谢物的明显浓度。体外证实本品通过P450CYP2C9，3A4，1A1和1A2代谢。

适应证

局部治疗与卡波济肉瘤有关的皮肤损害。

禁忌证

对本品过敏者、哺乳者禁用。

注意事项

1.有过敏性皮炎史者慎用。
2.18以下岁儿童的安全性和有效性尚未确定。
3.本品凝胶不可接触眼、鼻孔、口唇、阴道、阴茎头、直肠和肛门。

不良反应

1.常见皮疹、瘙痒、剥脱性皮炎、皮肤病(表皮脱落、表皮裂开、结痂、排出液体、焦痂和渗出)。
2.有胚胎毒并致畸。
3.有光敏反应(包括日光或人工日光灯管)。
4.可能发生严重的局部皮肤反应(如严重的红斑、水肿和起疱)。

用法用量

1.局部使用本品0.1%凝胶的患者在应用之前沐浴或淋浴之后，须等候20min。局部用药后应使之干燥3～5min后才能穿衣。用药后至少3h内不能沐浴或淋浴
仅在局部病损区使用充分的凝胶，每天2次。根据耐受情况，用药次数可逐渐增加到3～4次。如用药范围已产生毒性，直至刺激感消除后才可恢复用药。3.患者感到用药有益处，就可持续给药。有些患者在超过14周治疗后才见到效应。在临床研究中有用到175周的。

药物相应作用

1.动物试验证实，本品与二乙甲苯酰胺(diethyl-toluamide)合用，可增加后者的毒性。
2.在接受抗病毒药(包括蛋白酶抑制剂在内的抗逆转病毒药)、大环内酯类抗生素或唑类抗真菌药的患者中使用本品凝胶剂，并未发现相互作用。

专家点评

本品主要用于与卡波济肉瘤有关的皮肤损害，且能长期局部使用，使用疗效尚未确定，如患者感到使用有好处，且能耐受，可持续使用，有临床报道使用本品175周仍未见明显局部刺激反应。

PANRETIN (alitretinoin) gel
[Eisai Inc.]

DESCRIPTION

Panretin® gel 0.1% contains alitretinoin and is intended for topical application only. The chemical name is 9-cis-retinoic acid and the structural formula is as follows:

Chemically, alitretinoin is related to vitamin A. It is a yellow powder with a molecular weight of 300.44 and a molecular formula of C20H28O2. It is slightly soluble in ethanol (7.01 mg/g at 25°C) and insoluble in water. Panretin® gel is a clear, yellow gel containing 0.1% (w/w) alitretinoin in a base of dehydrated alcohol USP, polyethylene glycol 400 NF, hydroxypropyl cellulose NF, and butylated hydroxytoluene NF.

CLINICAL PHARMACOLOGY

Mechanism of Action

Alitretinoin (9-cis-retinoic acid) is a naturally-occurring endogenous retinoid that binds to and activates all known intracellular retinoid receptor subtypes (RARα, RARβ, RARγ, RXRα, RXRβ and RXRγ). Once activated these receptors function as transcription factors that regulate the expression of genes that control the process of cellular differentiation and proliferation in both normal and neoplastic cells. Alitretinoin inhibits the growth of Kaposi's sarcoma (KS) cells in vitro.

Pharmacokinetics

No studies have examined plasma 9-cis-retinoic acid concentrations before and after treatment with Panretin® gel. There is, however, indirect evidence that absorption is not extensive. Plasma concentrations of 9-cis-retinoic acid were evaluated during clinical studies in patients with cutaneous lesions of AIDS-related KS after repeated multiple-daily dose application of Panretin® gel for up to 60 weeks. The range of 9-cis-retinoic acid plasma concentrations in these patients was similar to the range of circulating, naturally-occurring 9-cis-retinoic acid plasma concentrations in untreated healthy volunteers.

Although there are no detectable plasma concentrations of 9-cis-retinoic acid metabolites after topical application of Panretin® gel, in vitro studies indicate that the drug is metabolized to 4-hydroxy-9-cis-retinoic acid and 4-oxo-9-cis-retinoic acid by CYP 2C9, 3A4, 1A1, and 1A2 enzymes. In vivo, 4-oxo-9-cis-retinoic acid is the major circulating metabolite following oral administration of 9-cis-retinoic acid.

No formal pharmacokinetic drug interaction studies between Panretin® gel and antiretroviral agents have been conducted.

Clinical Studies

Panretin® gel is not a systemic therapy; it therefore cannot treat visceral Kaposi's sarcoma (KS) nor prevent the development of new KS lesions where it has not been applied. Visceral KS disease was not monitored in these trials, and the appearance of new KS lesions was not considered part of the response assessment in clinical trials.

Panretin® gel was evaluated in two multicenter, prospective, randomized, double-blind, vehicle-controlled studies in patients with cutaneous lesions of AIDS-related KS. In both studies the primary efficacy endpoint was the patients' cutaneous KS tumor response rate through 12 weeks of study drug treatment which was assessed by evaluating from 3 to 8 KS index lesions according to the modified AIDS Clinical Trials Group (ACTG) response criteria as applied to topical therapy (i.e., evaluation of height and area reductions of the index lesions only; progressive disease in non-index lesions and new lesions were not considered progressive disease; progressive disease was scored only in the treated index lesions). A global evaluation by physicians was also carried out. It considered all of the patient's treated lesions (index and other) compared to baseline. In this evaluation, patients with at least a 50% improvement in the KS lesions were considered responders. In addition, photographs of lesions in patients considered responders by the modified ACTG criteria were examined by the FDA for a cosmetically beneficial response, defined as at least a 50% improvement in appearance compared to baseline, considering both the KS lesions and dermal toxicity at the lesion site, in at least 50% of the index lesions and maintained for at least 3 weeks. Patients were also asked about their satisfaction with the treatment.

In Study 1, a total of 268 patients were entered from centers in the U.S. and Canada. Patients were treated topically three to four times a day with either Panretin® gel or a matching vehicle gel for a minimum of 12 weeks, followed by an open-label phase in patients who had not yet progressed on Panretin® gel. Responses during the double-blind phase are shown in Table 1. Responses to Panretin® gel were seen in both previously untreated patients and in patients with prior systemic and/or topical KS treatment. A total of 72 patients responded to Panretin( gel during the randomized or crossover portions of the study. At a median duration of monitoring of 16 weeks, only 15% of the 72 patients had relapsed. Panretin( gel would not be expected to affect development of new lesions in untreated areas and these were seen in about 50% of patients, at similar rates in treated and untreated patients, responders and non-responders. The patients' assessment of their overall satisfaction with the drug effect on all treated lesions significantly favored Panretin® gel.

Study 2 was an international study with a planned enrollment of 270 patients. Patients were treated topically twice a day with Panretin® gel or a matching vehicle for 12 weeks. The study was stopped early because of positive interim results in the initial 82 patient data set. Results of the study are shown in Table 1. Responses to Panretin® gel were seen both in previously untreated patients and in patients with prior systemic and/or topical KS treatment.

TABLE 1: Summary of Tumor Responses
	STUDY 1		STUDY 2
	Panretin® Gel N=134	Vehicle Gel N=134	Panretin® Gel N=36	Vehicle Gel N=46
Modified ACTG Response (index lesions)	34% PR 1% CR	16% PR p=0.0012	36% PR	7% PR
Physician's Global/Subjective Assessment (all treated lesions)	19% PR	4% PR p=0.00014	47% PR	11% PR
Beneficial Response Photographs (index lesions only)	15%	4% p=0.0026	19%	2%

In the clinical trials, responses were seen as early as two (2) weeks; most patients, however, required four (4) to eight (8) weeks of treatment, and some patients did not experience significant improvement until 14 or more weeks of treatment. The cumulative percentage of patients who achieved a response was less than 1% at 2 weeks, 10% at 4 weeks, and 28% at 8 weeks.

In both studies, responses occurred in patients with a wide range of baseline CD4+ lymphocyte counts, including patients with CD4+ lymphocyte counts less than 50 cells/mm3. Nearly all patients received concomitant combination antiretroviral therapy.

Photographs of patients revealed a substantial erythematous and edematous response in some cases, leading to a cosmetically mixed outcome even in apparent responders. Nonetheless, in Study 1 it appeared that a cosmetically satisfactory result occurred at about the same rate as the Physician's Global response rate and in both studies such a response was more frequent than in the vehicle control.

INDICATIONS AND USAGE

Panretin® gel is indicated for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma. Panretin® gel is not indicated when systemic anti-KS therapy is required (e.g., more than 10 new KS lesions in the prior month, symptomatic lymphedema, symptomatic pulmonary KS, or symptomatic visceral involvement). There is no experience to date using Panretin® gel with systemic anti-KS treatment.

CONTRAINDICATIONS

Panretin® gel is contraindicated in patients with a known hypersensitivity to retinoids or to any of the ingredients of the product.

WARNINGS

Pregnancy

Panretin® gel could cause fetal harm if significant absorption were to occur in a pregnant woman. 9-cis-Retinoic acid has been shown to be teratogenic in rabbits and mice. An increased incidence of fused sternebrae and limb and craniofacial defects occurred in rabbits given oral doses of 0.5 mg/kg/day (about five times the estimated daily human topical dose on a mg/m2 basis, assuming complete systemic absorption of 9-cis-retinoic acid, when Panretin® gel is administered as a 60 g tube over 1 month in a 60 kg human) during the period of organogenesis. Limb and craniofacial defects also occurred in mice given a single oral dose of 50 mg/kg on day eleven of gestation (about 127 times the estimated daily human topical dose on a mg/m2 basis). Oral 9-cis-retinoic acid was also embryocidal, as indicated by early resorptions and post-implantation loss when it was given during the period of organogenesis to rabbits at doses of 1.5 mg/kg/day (about 15 times the estimated daily human topical dose on a mg/m2 basis) and to rats at doses of 5 mg/kg/day (about 25 times the estimated daily human topical dose on a mg/m2 basis). Animal reproduction studies with topical 9-cis-retinoic acid have not been conducted. It is not known whether topical Panretin® gel can modulate endogenous 9-cis-retinoic acid levels in a pregnant woman nor whether systemic exposure is increased by application to ulcerated lesions or by duration of treatment. There are no adequate and well-controlled studies in pregnant women. If Panretin® gel is used during pregnancy, or if the patient becomes pregnant while taking it, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS

Panretin® gel is indicated for topical treatment of Kaposi's sarcoma. Patients with cutaneous T-cell lymphoma were less tolerant of topical Panretin® gel; five of seven patients had 6 episodes of treatment-limiting toxicities—grade 3 dermal irritation—with Panretin® gel (0.01% or 0.05%).

Information for Patients

Please see accompanying "Patient's Instructions for Use"

Photosensitivity

Retinoids as a class have been associated with photosensitivity. There were no reports of photosensitivity associated with the use of Panretin® gel in the clinical studies. Nonetheless, because in vitro data indicate that 9-cis-retinoic acid may have a weak photosensitizing effect, patients should be advised to minimize exposure of treated areas to sunlight and sunlamps during the use of Panretin® gel.

Drug Interactions

Patients who are applying Panretin® gel should not concurrently use products that contain DEET (N,N-diethyl-m-toluamide), a common component of insect repellent products. Animal toxicology studies showed increased DEET toxicity when DEET was included as part of the formulation.

Although there was no clinical evidence in the vehicle-controlled studies of drug interactions with systemic antiretroviral agents, including protease inhibitors, macrolide antibiotics, and azole antifungals, the effect of Panretin® gel on the steady-state concentrations of these drugs is not known. No drug interaction data are available on concomitant administration of Panretin® gel and systemic anti-KS agents.

Drug/Laboratory Test Interactions

No interference with laboratory tests has been observed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to assess the carcinogenic potential of 9-cis-retinoic acid have not been conducted. 9-cis-Retinoic acid was not mutagenic in vitro (bacterial assays, Chinese hamster ovary cell HGPRT mutation assay) and was not clastogenic in vitro (chromosome aberration test in human lymphocytes) nor in vivo (mouse micronucleus test).

Pregnancy Category D

(see "Warnings" section)

Nursing Mothers

It is not known whether alitretinoin or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions from Panretin® gel in nursing infants, mothers should discontinue nursing prior to using the drug.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Inadequate information is available to assess safety and efficacy in patients age 65 years or older.

ADVERSE REACTIONS

The safety of Panretin® gel has been assessed in clinical studies of 385 patients with AIDS-related KS. Adverse events associated with the use of Panretin® gel in patients with AIDS-related KS occurred almost exclusively at the site of application. The dermal toxicity begins as erythema; with continued application of Panretin® gel, erythema may increase and edema may develop. Dermal toxicity may become treatment-limiting, with intense erythema, edema, and vesiculation. Usually, however, adverse events are mild to moderate in severity; they led to withdrawal from the study in only 7% of the patients. Severe local (application site) skin adverse events occurred in about 10% of patients in the U.S. study (versus 0% in the vehicle control). Table 2 lists the adverse events that occurred at the application site with an incidence of at least 5% during the double-blind phase in the Panretin® gel-treated group and in the vehicle control group in either of the two controlled studies. Adverse events were reported at other sites but generally were similar in the two groups.

TABLE 2: Adverse Events with an Incidence of at Least 5% at the Application Site in Either Controlled Study in Patients Receiving Panretin® Gel or Vehicle Control
Includes Investigator terms: 1 Erythema, scaling, irritation, redness, rash, dermatitis 2 Burning, pain 3 Itching, pruritus 4 Flaking, peeling, desquamation, exfoliation 5 Excoriation, cracking, scab, crusting, drainage, eschar, fissure or oozing 6 Stinging, tingling 7 Edema, swelling, inflammation
Adverse Event Term	Study 1		Study 2
	Panretin® Gel N=134 Pts. %	Vehicle Gel N=134 Pts. %	Panretin® Gel N=36 Pts. %	Vehicle Gel N=46 Pts. %
Rash1	77	11	25	4
Pain2	34	7	0	4
Pruritus3	11	4	8	4
Exfoliative dermatitis4	9	2	3	0
Skin disorder5	8	1	0	0
Paresthesia6	3	0	22	7
Edema7	8	3	3	0

OVERDOSAGE

There has been no experience with acute overdose of Panretin® gel in humans. Systemic toxicity following acute overdosage with topical application of Panretin® gel is unlikely because of limited systemic plasma levels observed with normal therapeutic doses. There is no specific antidote for overdosage.

DOSAGE AND ADMINISTRATION

Panretin® gel should initially be applied two (2) times a day to cutaneous KS lesions. The application frequency can be gradually increased to three (3) or four (4) times a day according to individual lesion tolerance. If application site toxicity occurs, the application frequency can be reduced. Should severe irritation occur, application of drug can be temporarily discontinued for a few days until the symptoms subside.

Sufficient gel should be applied to cover the lesion with a generous coating. The gel should be allowed to dry for three to five minutes before covering with clothing. Because unaffected skin may become irritated, application of the gel to normal skin surrounding the lesions should be avoided. In addition, do not apply the gel on or near mucosal surfaces of the body.

A response of KS lesions may be seen as soon as two weeks after initiation of therapy but most patients require longer application. With continued application, further benefit may be attained. Some patients have required over 14 weeks to respond. In clinical trials, Panretin® gel was applied for up to 96 weeks. Panretin® gel should be continued as long as the patient is deriving benefit.

Occlusive dressings should not be used with Panretin® gel.

How Supplied

Panretin® gel is available in tubes containing 60 grams, (60 mg active ingredient alitretinion). NDC 62856-601-22

Store at 25° C (77° F); excursions permitted to 15-30° C (59-86° F) [see USP Controlled Room Temperature].