VALCHLOR

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.

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).

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.

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.

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.

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.

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.

¹ OSHA Hazardous Drugs. OSHA. [Accessed July 3, 2013, from www.osha.gov/SLTC/hazardousdrugs/index.html]

VALCHLOR is supplied in 60g tubes of 0.016% w/w mechlorethamine as a clear gel [NDC 66215-016-60].

See FDA-approved patient labeling (Medication Guide)

Advise patients of the following and provide a copy of the Medication Guide.

Instructions for Patients and Caregivers for Application of VALCHLOR:
Apply a thin film of VALCHLOR once daily to affected areas of the skin [see Dosage and Administration (2.1)].

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 and remove contaminated clothing [see Dosage and Administration (2.2)].

Patients and caregivers should follow these instructions when applying VALCHLOR [see Dosage and Administration (2.2)]:

• Apply immediately or within 30 minutes after removal from the refrigerator. Return VALCHLOR to the refrigerator immediately after each use.
• Apply VALCHLOR 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 of VALCHLOR.
• Occlusive (air or water-tight) dressings should not be used on areas of the skin where VALCHLOR was applied.

Instructions for Patients and Caregivers for Storage of VALCHLOR
Store VALCHLOR refrigerated at temperatures between 36°F - 46°F (2°C - 8°C). Advise patients that adherence to the recommended storage condition will ensure VALCHLOR will work as expected. Patients should consult a pharmacist prior to using VALCHLOR that has been left at room temperature for longer than one hour per day. Unused product should be discarded after 90 days [see How Supplied/Storage and Handling (16)].

With clean hands, replace tube in the original box, then place in the refrigerator. Keep VALCHLOR in its original box out of the reach of children and avoid contact with food when storing in the refrigerator.

Unused VALCHLOR, empty tubes, and used application gloves should be discarded in household trash in a manner that prevents accidental application or ingestion by others, including children and pets.

Mucosal or Eye Injury
Exposure of the eyes to mechlorethamine causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible eye injury may occur. Should eye contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, normal saline, or a balanced salt ophthalmic irrigating solution, followed by immediate ophthalmologic consultation [see Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.1)].

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. Caregivers who help apply VALCHLOR to patients must wear disposable nitrile gloves when handling VALCHLOR. If secondary exposure occurs to eyes, mouth, or nose, immediately irrigate the exposed area for at least 15 minutes with copious amounts of water. Thoroughly wash affected areas of the skin with soap and water [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

Dermatitis
If patients experience skin irritation after applying VALCHLOR, such as redness, swelling, inflammation, itchiness, blisters, ulceration, or secondary skin infections, instruct patients to discuss with their physician options for changes in the treatment plan. The face, genitalia, anus, or intertriginous skin (skin folds or creases) are at increased risk of skin irritation [see Warnings and Precautions (5.3)].

Non-Melanoma Skin Cancers
Instruct patients to notify their physician of any new skin lesions and to undergo periodic assessment for signs and symptoms of skin cancer. Non-melanoma skin cancers have been reported in patients receiving the active ingredient in VALCHLOR. Non-melanoma skin cancer may occur at multiple areas, including areas not directly treated with VALCHLOR [see Warnings and Precautions (5.4)].

Embryo-fetal Toxicity
Advise women of the potential hazard to a fetus and to avoid pregnancy while using VALCHLOR [see Warnings and Precautions (5.5)].

Nursing Mothers
Advise women to discontinue nursing due to the potential for topical or systemic exposure to VALCHLOR [see Use in Specific Populations (8.3)].

Manufactured for:
Actelion Pharmaceuticals US, Inc.
South San Francisco, CA 94080, USA

© 2016 Actelion Pharmaceuticals US, Inc. All rights reserved.

ACT20160815

VALCHLOR^®
(mechlorethamine)gel
0.016%

For Topical Use
Dispense with Medication Guide

Before dispensing, store in freezer
After dispensing, store refrigerated

RX Only
NET WT 60 grams

NDC 66215-016-60