VALCHLOR（MECHLORETHAMINE HYDROCHLORIDEGEL TOPICAL是第一个也是唯一获批的外用配方氮芥制剂，每天涂抹一次 Valchlor（mechlorethamine，氮芥）凝胶是由CeptarisTherapeutics公司研发的一种注射用化疗药物，日前获得FDA批准通过，这种药物可以直接通过皮下注射药物mechlorethamine以治疗阿利贝尔氏病（T细胞淋巴瘤的一种）。 CeptarisTherapeutics公司是一家私营专业制药公司，于8月26日获美国FDA批准其罕用药Valchlor（mechlorethamine，氮芥）凝胶用于局部治疗先前接受过皮肤治疗IA和IB阶段蕈样肉芽肿型皮肤T细胞淋巴瘤（CTCL）的患者。Valchlor是第一个也是唯一获得FDA批准的外用配方氮芥制剂。局部应用于皮肤，每天涂抹一次。 氮芥是一种化疗药，先前获准用于静脉注射治疗蕈样肉芽肿，最常见类型的CTCL。（美国）国家综合癌症网络（NCCN）目前推荐外用氮芥制剂用于治疗早期CTCL，在Valchlor获准前，尚没有获得FDA批准的外用氮芥制剂产品，只有药房配制的非标准化复合油质软膏或水质外用制剂。药房自配的复合制剂无需FDA审查批准，因此没有经过一个审查。 斯坦福大学医学院皮肤淋巴瘤多学科诊所主任、皮肤科和皮肤淋巴瘤研究教授PeterHaasJr指出：“本品获准是患者的福音。现在我们有充分对照的临床试验证据支持Valchlor在大多数先前作过治疗的IA和IB阶段CTCL患者有临床意义的应答。” HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VALCHLOR™ safely and effectively. See full prescribing information for VALCHLOR. VALCHLOR (mechlorethamine) gel, for topical use Initial U.S. Approval: 1949 INDICATIONS AND USAGE VALCHLOR is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy (1). DOSAGE AND ADMINISTRATION For topical dermatological use only (2.1). Apply a thin film once daily to affected areas of the skin (2.1, 2.2). DOSAGE FORMS AND STRENGTHS Gel: 0.016% w/w of mechlorethamine (equivalent to 0.02% mechlorethamine HCl) in 60g tubes (3) CONTRAINDICATIONS Severe hypersensitivity to mechlorethamine (4) WARNINGS AND PRECAUTIONS Mucosal or eye injury: VALCHLOR exposure to mucous membranes, especially of the eyes, can cause mucosal injury which may be severe. Eye injury may lead to blindness. Immediately irrigate for at least 15 minutes followed by immediate medical consultation (5.1). Secondary exposure to VALCHLOR: individuals other than the patient must avoid skin contact with VALCHLOR (2.2, 5.2). Dermatitis: Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections. Stop treatment or reduce dose frequency (2.1, 5.3). Non-melanoma skin cancer: Monitor patients during and after treatment (5.4). Embryo-fetal toxicity: Can cause fetal harm. Advise women of potential hazard to a fetus (5.5, 8.1). Flammable gel: VALCHLOR is an alcohol-based gel. Avoid fire, flame, and smoking until the gel has dried (2.2, 5.6). ADVERSE REACTIONS The most common adverse reactions (≥5%) are dermatitis, pruritus, bacterial skin infection, skin ulceration or blistering, and hyperpigmentation (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Ceptaris Therapeutics, Inc. at 1-855-4-VALCHLOR (1-855-482-5245) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS Nursing Mothers: Discontinue drug or nursing (5.2, 8.3). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 8/2013 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE VALCHLOR is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing and Dose Modification For Topical Dermatological Use Only Apply a thin film of VALCHLOR gel once daily to affected areas of the skin. Stop treatment with VALCHLOR for any grade of skin ulceration, blistering, or moderately-severe or severe dermatitis (i.e., marked skin redness with edema) [see Warnings and Precautions (5.3)]. Upon improvement, treatment with VALCHLOR can be restarted at a reduced frequency of once every 3 days. If reintroduction of treatment is tolerated for at least one week, the frequency of application can be increased to every other day for at least one week and then to once daily application if tolerated. 2.2 Application Instructions VALCHLOR is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 Patients must wash hands thoroughly with soap and water after handling or applying VALCHLOR. Caregivers must wear disposable nitrile gloves when applying VALCHLOR to patients and wash hands thoroughly with soap and water after removal of gloves. If there is accidental skin exposure to VALCHLOR, caregivers must immediately wash exposed areas thoroughly with soap and water for at least 15 minutes and remove contaminated clothing [see Warnings and Precautions (5.2)]. Patients or caregivers should follow these instructions when applying VALCHLOR: Apply immediately or within 30 minutes after removal from the refrigerator. Return VALCHLOR to the refrigerator immediately after each use. Apply to completely dry skin at least 4 hours before or 30 minutes after showering or washing. Allow treated areas to dry for 5 to 10 minutes after application before covering with clothing. Emollients (moisturizers) may be applied to the treated areas 2 hours before or 2 hours after application. Do not use occlusive dressings on areas of the skin where VALCHLOR was applied. Avoid fire, flame, and smoking until VALCHLOR has dried [see Warnings and Precautions (5.6)]. 3 DOSAGE FORMS AND STRENGTHS The active ingredient in VALCHLOR is mechlorethamine. Each tube of VALCHLOR contains 60g of 0.016% w/w mechlorethamine clear gel (equivalent to 0.02% mechlorethamine HCl).  4 CONTRAINDICATIONS The use of VALCHLOR is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine. 5 WARNINGS AND PRECAUTIONS 5.1 Mucosal or Eye Injury Exposure of the eyes to mechlorethamine causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. Advise patients that if eye exposure occurs, (1) immediately irrigate for at least 15 minutes with copious amounts of water, normal saline, or a balanced salt ophthalmic irrigating solution and (2) obtain immediate medical care (including ophthalmologic consultation). Exposure of mucous membranes such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, which may be severe. Should mucosal contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, followed by immediate medical consultation. 5.2 Secondary Exposure to VALCHLOR Avoid direct skin contact with VALCHLOR in individuals other than the patient. Risks of secondary exposure include dermatitis, mucosal injury, and secondary cancers. Follow recommended application instructions to prevent secondary exposure [see Dosage and Administration (2.2)]. 5.3 Dermatitis The most common adverse reaction was dermatitis, which occurred in 56% of the patients [see Adverse Reactions (6.1)]. Dermatitis was moderately severe or severe in 23% of patients. Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections. The face, genitalia, anus, and intertriginous skin are at increased risk of dermatitis. Follow dose modification instructions for dermatitis [see Dosage and Administration (2.1)]. 5.4 Non-Melanoma Skin Cancer Four percent (4%, 11/255) of patients developed a non-melanoma skin cancer during the clinical trial or during one year of post-treatment follow-up: 2% (3/128) of patients receiving VALCHLOR, and 6% (8/127) of patients receiving the mechlorethamine ointment comparator. Some of these non-melanoma skin cancers occurred in patients who had received prior therapies known to cause non-melanoma skin cancer. Monitor patients for non-melanoma skin cancers during and after treatment with VALCHLOR. Non-melanoma skin cancer may occur on any area of the skin, including untreated areas. 5.5 Embryo-fetal Toxicity Based on its mechanism of action, case reports in humans, and findings in animals, VALCHLOR can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations in pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic and embryo-lethal after a single subcutaneous administration to animals. Advise women to avoid becoming pregnant while using VALCHLOR. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 5.6 Flammable Gel Alcohol-based products, including VALCHLOR, are flammable. Follow recommended application instructions [see Dosage and Administration (2.2)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the prescribing information: Mucosal or eye injury [see Warnings and Precautions (5.1)] Secondary exposure to VALCHLOR [see Warnings and Precautions (5.2)] Dermatitis [see Warnings and Precautions (5.3)] Non-melanoma skin cancer [see Warnings and Precautions (5.4)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. 6.1 Clinical Trials Experience In a randomized, observer-blinded, controlled trial, VALCHLOR 0.016% (equivalent to 0.02% mechlorethamine HCl) was compared to an Aquaphor®-based mechlorethamine HCl 0.02% ointment (Comparator) [see Clinical Studies (14)]. The maximum duration of treatment was 12 months. Sixty-three percent (63%) of patients in the VALCHLOR arm and 67% in the comparator arm completed 12 months of treatment. The body system associated with the most frequent adverse reactions was skin and subcutaneous tissue disorders. The most common adverse reactions (occurring in at least 5% of the patients) are shown in Table 1. Table 1. Most Commonly Reported (≥5%) Cutaneous Adverse Reactions  VALCHLOR N=128 % of patients Comparator N=127 % of patients Any Grade Moderately-Severe or Severe Any Grade Moderately-Severe or Severe Dermatitis 56 23 58 17 Pruritus 20 4 16 2 Bacterial skin infection 11 2 9 2 Skin ulceration or blistering 6 3 5 2 Skin hyperpigmentation 5 0 7 0 In the clinical trial, moderately-severe to severe skin-related adverse events were managed with treatment reduction, suspension, or discontinuation. Discontinuations due to adverse reactions occurred in 22% of patients treated with VALCHLOR and 18% of patients treated with the comparator. Sixty-seven percent (67%) of the discontinuations for adverse reactions occurred within the first 90 days of treatment. Temporary treatment suspension occurred in 34% of patients treated with VALCHLOR and 20% of patients treated with the comparator. Reductions in dosing frequency occurred in 23% of patients treated with VALCHLOR and 12% of patients treated with the comparator. Reductions in hemoglobin, neutrophil count, or platelet count occurred in 13% of patients treated with VALCHLOR and 17% treated with Comparator. 7 DRUG INTERACTIONS No drug interaction studies have been performed with VALCHLOR. Systemic exposure has not been observed with topical administration of VALCHLOR; therefore, systemic drug interactions are not likely. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.5)] Risk Summary Mechlorethamine can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations in pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic in animals after a single subcutaneous administration. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.5)]. Animal Data Mechlorethamine caused fetal malformations in the rat and ferret when given as single subcutaneous injections of 1 mg/kg. Other findings in animals included embryolethality and growth retardation when administered as a single subcutaneous injection. 8.3 Nursing Mothers It is not known if mechlorethamine is excreted in human milk. Due to the potential for topical or systemic exposure to VALCHLOR through exposure to the mother's skin, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use A total of 79 patients age 65 and older (31% of the clinical trial population) were treated with either VALCHLOR or the comparator in the clinical trial. Forty-four percent (44%) of patients age 65 or older treated with VALCHLOR achieved a CAILS response compared to 66% of patients below the age of 65. Seventy percent (70%) of patients age 65 and older experienced cutaneous adverse reactions and 38% discontinued treatment due to adverse reactions, compared to 58% and 14% in patients below the age of 65, respectively. Similar differences in discontinuation rates between age subgroups were observed in the comparator group. 11 DESCRIPTION VALCHLOR is a topical product that contains mechlorethamine HCl, an alkylating drug. Mechlorethamine HCl is a white to off white solid that is very soluble in water and methanol, partially soluble in acetone, and generally not soluble in organic solvents. Mechlorethamine HCl is designated chemically as 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride. The molecular weight is 192.52 and the melting point is 108-111°C. The empirical formula is C5H11Cl2N•HCl, and the structural formula is: CH3N(CH2CH2Cl)2•HCl. Each tube of VALCHLOR contains 60g of a gel containing 0.016% w/w of mechlorethamine (equivalent to 0.02% mechlorethamine HCl) in a base of the following inactive ingredients: diethylene glycol monoethyl ether, propylene glycol, isopropyl alcohol, glycerin, lactic acid, hydroxypropylcellulose, sodium chloride, menthol, edetate disodium, butylated hydroxytoluene. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Mechlorethamine, also known as nitrogen mustard, is an alkylating agent which inhibits rapidly proliferating cells. 12.3 Pharmacokinetics Systemic exposure was undetectable after topical administration of VALCHLOR to patients. Blood samples were analyzed from 16 and 15 patients following treatment with VALCHLOR (mechlorethamine gel 0.016%) and an identical formulation consisting of mechlorethamine 0.032% w/w, respectively. For patients who received mechlorethamine 0.016%, samples were collected to measure mechlorethamine concentrations prior to dosing, on day 1, and at the first month visit. Following the topical administration of mechlorethamine 0.016%, there were no detectable plasma mechlorethamine concentrations observed in any of the patients. Patients who received mechlorethamine 0.032% had no measurable concentrations of mechlorethamine or half-mustard after 2, 4, or 6 months of treatment. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Mechlorethamine is a probable carcinogen in humans. There are reports of non-melanoma skin cancer with the use of topical mechlorethamine in patients [see Warnings and Precautions (5.4)]. Mechlorethamine was carcinogenic in mice when injected intravenously with four doses of 2.4 mg/kg (0.1% solution) at 2-week intervals with observations for up to 2 years. An increased incidence of thymic lymphomas and pulmonary adenomas was observed. Painting mechlorethamine on the skin of mice at a dose of 4 mg/kg for periods of up to 33 weeks resulted in squamous cell tumors in 9 of 33 mice. Mechlorethamine was genotoxic in multiple genetic toxicology studies, which included mutations in the bacterial reverse mutation assay (Ames test) and chromosome aberrations in mammalian cells. Dominant lethal mutations were produced in ICR/Ha Swiss mice. The reproductive effects of VALCHLOR have not been studied; however, published literature indicates that fertility may be impaired by systemically administered mechlorethamine. Mechlorethamine impaired fertility in the rat at a daily dose of 500 mg/kg intravenously for two weeks. Treatment with intravenous mechlorethamine has been associated with delayed catamenia, oligomenorrhea, and temporary or permanent amenorrhea. 13.2 Animal Toxicology and/or Pharmacology Animal studies have shown mechlorethamine to be corrosive to skin and eyes, a powerful vesicant, irritating to the mucous membranes of the respiratory tract, and highly toxic by the oral route. 14 CLINICAL STUDIES The efficacy of VALCHLOR was assessed in a randomized, multicenter, observer-blind, active-controlled, non-inferiority clinical trial of 260 patients with Stage IA, IB, and IIA mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL) who had received at least one prior skin-directed therapy. Qualifying prior therapies included topical corticosteroids, phototherapy, Targretin® gel, and topical nitrogen mustard. Patients were not required to be refractory to or intolerant of prior therapies. Patients were stratified based on Stage (IA vs. IB and IIA) and then randomized to receive VALCHLOR 0.016% (equivalent to 0.02% mechlorethamine HCl) or Aquaphor®-based mechlorethamine HCl 0.02% ointment (Comparator) at 13 centers in the United States. Eighteen patients were excluded from the efficacy analysis due to protocol violations involving randomization at a single site. Study drug was to be applied topically on a daily basis for 12 months. Concomitant use of topical corticosteroids was not permitted during the study. Dosing could be suspended or continued with reduced frequency for dermatitis. The mean daily usage of VALCHLOR gel was 2.8 g (1 to 2 tubes per month). The maximum daily usage was 10.5 g (5 to 6 tubes per month). Patients were evaluated for a response on a monthly basis for the first 6 months and then every 2 months for the last 6 months using the Composite Assessment of Index Lesion Severity (CAILS) score. The CAILS score is obtained by adding the severity score of each of the following categories for up to 5 index lesions: erythema, scaling, plaque elevation, and surface area. Severity was graded from 0 (none) to 8 (severe) for erythema and scaling; 0 to 3 for plaque elevation; and 0 to 9 for surface area. A response was defined as greater than or equal to 50% reduction in baseline CAILS score which was confirmed at the next visit at least 4 weeks later. A complete response was defined as a confirmed CAILS score of 0. Non-inferiority was considered to have been demonstrated if the lower bound of the 95% confidence interval (CI) around the ratio of response rates (VALCHLOR/Comparator) was greater than or equal to 0.75. Patients were also evaluated using the Severity Weighted Assessment Tool (SWAT). The SWAT score is derived by measuring each involved area as a percentage of total body surface area (%BSA) and multiplying it by a severity weighting factor (1=patch, 2=plaque, 3=tumor or ulcer). A response was defined as greater than or equal to 50% reduction in baseline SWAT score which was confirmed at the next visit at least 4 weeks later. The baseline demographics and disease characteristics were balanced between treatment arms. The median age was 57 years in the VALCHLOR arm and 58 years in the comparator arm. The majority of the patients were male (60% in VALCHLOR arm, 59% in Comparator arm) and white (75% in both treatment arms). The median number of prior therapies was 2 in both treatment arms. The most common prior therapy was topical corticosteroids (used in 86% of patients in both treatment arms). The median body surface area (BSA) involvement at baseline was 8.5% (range 1%, 61%) in the VALCHLOR arm and 9% (range 1%, 76%) in the comparator arm. Sixty percent (60%) of the patients on the VALCHLOR arm and 48% of patients on the comparator arm achieved a response based on the CAILS score. VALCHLOR was non-inferior to the comparator based on a CAILS overall response rate ratio of 1.24 (95% CI 0.98, 1.58). Complete responses constituted a minority of the CAILS or SWAT overall responses (Table 2). The onset of CAILS overall response for both treatment arms showed a wide range from 1 to 11 months. Table 2. Efficacy in Patients with Mycosis Fungoides-Type Cutaneous T-Cell Lymphoma (MF-CTCL) Response Rates VALCHLOR N=119 Comparator N=123 CAILS Overall Response (CR+PR), % (N)     Complete Response (CR)     Partial Response (PR) 60% 14% 45% 48% 11% 37% SWAT Overall Response (CR+PR), %(N)     Complete Response (CR)     Partial Response (PR) 50% 7% 43% 46% 3% 43% 15 REFERENCES 1 OSHA Hazardous Drugs. OSHA. [Accessed July 3, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16 HOW SUPPLIED/STORAGE AND HANDLING VALCHLOR is supplied in 60g tubes of 0.016% w/w mechlorethamine as a clear gel [NDC 42427-002-60]. Prior to dispensing, store in the freezer at -13°F to 5°F (-25°C to -15°C). Advise patients that refrigerated storage is required once dispensed. VALCHLOR is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=706bd420-2f32-11e0-aaee-0002a5d5c51b