Mechlorethamine Hydrochloride

Description

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 C 5 H 11 Cl 2 N

What Is Mechlorethamine Hydrochloride Used For?

1 INDICATIONS AND USAGE VALCHLOR is 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. 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

2 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 ). 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 ) ].

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following clinically significant 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 ) ] 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 Helsinn Therapeutics (U.S.), Inc., at 1-855-482-5245 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 . 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.

Drug Interactions

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.

Contraindications

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. Severe hypersensitivity to mechlorethamine ( 4 )

Pregnancy and Breastfeeding

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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING VALCHLOR is supplied in 60g tubes of 0.016% w/w mechlorethamine as a clear gel [NDC 69639-120-01]. 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