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)].

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 case reports in humans, findings in animal reproduction studies, its mechanism of action, and genotoxicity findings, mechlorethamine may cause fetal harm. 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)].

6.1 Clinical Trials Experience

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.

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.

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.

8.1 Pregnancy

Risk Summary

Based on case reports in humans, findings in animal reproduction studies, its mechanism of action, and genotoxicity findings, mechlorethamine may cause fetal harm.

Available published case reports in pregnant women receiving intravenous mechlorethamine demonstrate that mechlorethamine can cause major birth defects when a pregnant woman is systemically exposed. In animal reproduction studies, subcutaneous administration of mechlorethamine to pregnant rats and ferrets during organogenesis resulted in embryo‐fetal mortality, alterations to growth, and structural abnormalities. Based on limited available data with VALCHLOR use in pregnant women, if VALCHLOR is used during pregnancy or if the patient becomes pregnant while taking this drug, patient should be advised of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data
The limited available data with VALCHLOR use in pregnant women does not show evidence of congenital malformation in newborns. Cases of newborns with congenital malformations have been reported in women who received systemic mechlorethamine during pregnancy.

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 embryo lethality and growth retardation when administered as a single subcutaneous injection.

8.2 Lactation

Risk Summary

There are no data on the presence of mechlorethamine or its metabolites in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Because of the potential for topical or systemic exposure to VALCHLOR through exposure to the mother's skin and the potential for serious adverse reactions in the breastfed child from mechlorethamine, advise patients not to breastfeed during treatment with VALCHLOR.

8.3 Females and Males of Reproductive Potential

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment with VALCHLOR. A barrier method of contraception should be used to avoid direct exposure of reproductive organs to VALCHLOR.

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with VALCHLOR [ see Nonclinical Toxicology (13.1)]. A barrier method of contraception should be used to avoid direct exposure of reproductive organs to VALCHLOR.

Infertility

Based on animal data, mechlorethamine may impair fertility in males and females [see Nonclinical Toxicology (13.1)]. The reversibility of the effect on fertility is unknown.

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.

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 male rats at a daily dose of 0.25 to 0.5 mg/kg when given intravenously every two weeks for up to 12 doses. When mechlorethamine was administered intraperitoneally to male and female mice for 4 consecutive days at a dose of 0.5 mg/kg the pregnancy rate decreased (from 80% to 12.5%) when treated males were paired with treated females. 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.

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