LEDAGA

LEDAGA 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.

Dosing and Dose Modification

For Topical Dermatological Use Only

Apply a thin film of LEDAGA gel once daily to affected areas of the skin.

Stop treatment with LEDAGA for any grade of skin ulceration, blistering, or moderately-severe or severe dermatitis (i.e., marked skin redness with edema). Upon improvement, treatment with LEDAGA 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.

Application Instructions

LEDAGA 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 LEDAGA.

Caregivers must wear disposable nitrile gloves when applying LEDAGA to patients and wash hands thoroughly with soap and water after removal of gloves. If there is accidental skin exposure to LEDAGA, caregivers must immediately wash exposed areas thoroughly with soap and water for at least 15 minutes and remove contaminated clothing.

Patients or caregivers should follow these instructions when applying LEDAGA:

• Apply immediately or within 30 minutes after removal from the refrigerator. Return LEDAGA 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 LEDAGA was applied.
• Avoid fire, flame, and smoking until LEDAGA has dried.

The use of LEDAGA is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

Secondary Exposure to LEDAGA

Avoid direct skin contact with LEDAGA 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.

Dermatitis

The most common adverse reaction was dermatitis, which occurred in 56% of the patients. 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.

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 LEDAGA, 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 LEDAGA. Non-melanoma skin cancer may occur on any area of the skin, including untreated areas.

Embryo-fetal Toxicity

Based on its mechanism of action, case reports in humans, and findings in animals, LEDAGA 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 LEDAGA. 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.

Flammable Gel

Alcohol-based products, including LEDAGA, are flammable. Follow recommended application instructions.

Patient Counseling Information

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 LEDAGA

Apply a thin film of LEDAGA once daily to affected areas of the skin.

Patients must wash hands thoroughly with soap and water after handling or applying LEDAGA. Caregivers must wear disposable nitrile gloves when applying LEDAGA to patients and wash hands thoroughly with soap and water after removal of gloves. If there is accidental skin exposure to LEDAGA, caregivers must immediately wash exposed areas thoroughly with soap and water and remove contaminated clothing.

Patients and caregivers should follow these instructions when applying LEDAGA :

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

Instructions for Patients and Caregivers for Storage of LEDAGA

Store LEDAGA refrigerated at temperatures between 36°F - 46°F (2°C - 8°C). Advise patients that adherence to the recommended storage condition will ensure LEDAGA will work as expected. Patients should consult a pharmacist prior to using LEDAGA that has been left at room temperature for longer than one hour per day. Unused product should be discarded after 60 days.

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

Unused LEDAGA, 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.

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.

Secondary Exposure to LEDAGA

Avoid direct skin contact with LEDAGA in individuals other than the patient. Risks of secondary exposure include dermatitis, mucosal injury, and secondary cancers. Caregivers who help apply LEDAGA to patients must wear disposable nitrile gloves when handling LEDAGA. 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.

Dermatitis

If patients experience skin irritation after applying LEDAGA, 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.

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 LEDAGA. Non-melanoma skin cancer may occur at multiple areas, including areas not directly treated with LEDAGA.

Embryo-fetal Toxicity

Advise women of the potential hazard to a fetus and to avoid pregnancy while using LEDAGA.

Nursing Mothers

Advise women to discontinue nursing due to the potential for topical or systemic exposure to LEDAGA.

Nonclinical Toxicology

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. 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 LEDAGA 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.

Use In Specific Populations

Pregnancy

Pregnancy Category D

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.

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.

Nursing Mothers

It is not known if mechlorethamine is excreted in human milk. Due to the potential for topical or systemic exposure to LEDAGA 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

A total of 79 patients age 65 and older (31% of the clinical trial population) were treated with either LEDAGA or the comparator in the clinical trial. Forty-four percent (44%) of patients age 65 or older treated with LEDAGA 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.

The following adverse reactions are described in greater detail in other sections:

• Psychiatric Events Including Suicidality
• Weight Decrease

Adverse Reactions in Clinical Studies

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described below reflect exposure of 4438 patients to LEDAGA 500 mcg once daily in four 1- year placebo-controlled trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials. In these trials, 3136 and 1232 COPD patients were exposed to LEDAGA 500 mcg once daily for 6 months and 1-year, respectively.

The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV₁) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with LEDAGA reported an adverse reaction compared with 65.3% treated with placebo.

The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for LEDAGAtreated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of LEDAGA were diarrhea (2.4%) and nausea (1.6%).

Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in LEDAGA-treated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure.

Table 1 summarizes the adverse reactions reported by ≥ 2% of patients in the LEDAGA group in 8 controlled COPD clinical trials.

Table 1: Adverse Reactions Reported by ≥ 2% of Patients Treated with LEDAGA 500 mcg daily and Greater Than Placebo

Adverse reactions that occurred in the LEDAGA group at a frequency of 1 to 2% where rates exceeded that in the placebo group include:

Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting

Infections and infestations - rhinitis, sinusitis, urinary tract infection,

Musculoskeletal and connective tissue disorders - muscle spasms

Nervous system disorders - tremor

Psychiatric disorders - anxiety, depression

Postmarketing Experience

The following adverse reactions have been identified from spontaneous reports of LEDAGA received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to LEDAGA. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to LEDAGA exposure: hypersensitivity reactions including angioedema, urticaria, and rash.

No information provided.

Systemic exposure was undetectable after topical administration of LEDAGA to patients. Blood samples were analyzed from 16 and 15 patients following treatment with LEDAGA (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.