Valchlor

Mechlorethamine Hydrochloride


Helsinn Therapeutics (u.s.), Inc.
Human Prescription Drug
NDC 69639-120
Valchlor also known as Mechlorethamine Hydrochloride is a human prescription drug labeled by 'Helsinn Therapeutics (u.s.), Inc.'. National Drug Code (NDC) number for Valchlor is 69639-120. This drug is available in dosage form of Gel. The names of the active, medicinal ingredients in Valchlor drug includes Mechlorethamine - .012 g/60g . The currest status of Valchlor drug is Active.

Drug Information:

Drug NDC: 69639-120
The labeler code and product code segments of the National Drug Code number, separated by a hyphen. Asterisks are no longer used or included within the product code segment to indicate certain configurations of the NDC.
Proprietary Name: Valchlor
Also known as the trade name. It is the name of the product chosen by the labeler.
Product Type: Human Prescription Drug
Indicates the type of product, such as Human Prescription Drug or Human OTC Drug. This data element corresponds to the “Document Type” of the SPL submission for the listing.
Non Proprietary Name: Mechlorethamine Hydrochloride
Also known as the generic name, this is usually the active ingredient(s) of the product.
Labeler Name: Helsinn Therapeutics (u.s.), Inc.
Name of Company corresponding to the labeler code segment of the ProductNDC.
Dosage Form: Gel
The translation of the DosageForm Code submitted by the firm. There is no standard, but values may include terms like `tablet` or `solution for injection`.The complete list of codes and translations can be found www.fda.gov/edrls under Structured Product Labeling Resources.
Status: Active
FDA does not review and approve unfinished products. Therefore, all products in this file are considered unapproved.
Substance Name:MECHLORETHAMINE - .012 g/60g
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.
Route Details:TOPICAL
The translation of the Route Code submitted by the firm, indicating route of administration. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Marketing Information:

An openfda section: An annotation with additional product identifiers, such as NUII and UPC, of the drug product, if available.
Marketing Category: NDA
Product types are broken down into several potential Marketing Categories, such as New Drug Application (NDA), Abbreviated New Drug Application (ANDA), BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.
Marketing Start Date: 08 Nov, 2018
This is the date that the labeler indicates was the start of its marketing of the drug product.
Marketing End Date: 19 Jun, 2026
This is the date the product will no longer be available on the market. If a product is no longer being manufactured, in most cases, the FDA recommends firms use the expiration date of the last lot produced as the EndMarketingDate, to reflect the potential for drug product to remain available after manufacturing has ceased. Products that are the subject of ongoing manufacturing will not ordinarily have any EndMarketingDate. Products with a value in the EndMarketingDate will be removed from the NDC Directory when the EndMarketingDate is reached.
Application Number: NDA202317
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.
Listing Expiration Date: 31 Dec, 2023
This is the date when the listing record will expire if not updated or certified by the firm.

OpenFDA Information:

An openfda section: An annotation with additional product identifiers, such as NUII and UPC, of the drug product, if available.
Manufacturer Name:Helsinn Therapeutics (U.S.), Inc.
Name of manufacturer or company that makes this drug product, corresponding to the labeler code segment of the NDC.
RxCUI:1437711
1437713
The RxNorm Concept Unique Identifier. RxCUI is a unique number that describes a semantic concept about the drug product, including its ingredients, strength, and dose forms.
Original Packager:Yes
Whether or not the drug has been repackaged for distribution.
UPC:0369639120016
UPC stands for Universal Product Code.
NUI:N0000000236
N0000175558
Unique identifier applied to a drug concept within the National Drug File Reference Terminology (NDF-RT).
UNII:50D9XSG0VR
Unique Ingredient Identifier, which is a non-proprietary, free, unique, unambiguous, non-semantic, alphanumeric identifier based on a substance’s molecular structure and/or descriptive information.
Pharmacologic Class MOA:Alkylating Activity [MoA]
Mechanism of action of the drug—molecular, subcellular, or cellular functional activity—of the drug’s established pharmacologic class. Takes the form of the mechanism of action, followed by `[MoA]` (such as `Calcium Channel Antagonists [MoA]` or `Tumor Necrosis Factor Receptor Blocking Activity [MoA]`.
Pharmacologic Class EPC:Alkylating Drug [EPC]
Established pharmacologic class associated with an approved indication of an active moiety (generic drug) that the FDA has determined to be scientifically valid and clinically meaningful. Takes the form of the pharmacologic class, followed by `[EPC]` (such as `Thiazide Diuretic [EPC]` or `Tumor Necrosis Factor Blocker [EPC]`.
Pharmacologic Class:Alkylating Activity [MoA]
Alkylating Drug [EPC]
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

Packaging Information:

Package NDCDescriptionMarketing Start DateMarketing End DateSample Available
69639-120-011 TUBE in 1 CARTON (69639-120-01) / 60 g in 1 TUBE08 Nov, 2018N/ANo
Package NDC number, known as the NDC, identifies the labeler, product, and trade package size. The first segment, the labeler code, is assigned by the FDA. Description tells the size and type of packaging in sentence form. Multilevel packages will have the descriptions concatenated together.

Product Elements:

Valchlor mechlorethamine hydrochloride diethylene glycol monoethyl ether propylene glycol isopropyl alcohol glycerin lactic acid, unspecified form hydroxypropyl cellulose (1600000 wamw) sodium chloride racementhol edetate disodium butylated hydroxytoluene mechlorethamine mechlorethamine clear

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.

Indications and Usage:

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 ).

Warnings and Cautions:

5 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: may cause fetal harm ( 5.5 ). flammable gel: valchlor is an alcohol-based gel. avoid fire, flame, and smoking until the gel has dried ( 2.2 , 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 ) ].

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 ) ].

Dosage Forms and Strength:

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). gel: 0.016% w/w of mechlorethamine (equivalent to 0.02% mechlorethamine hcl) in 60g tubes ( 3 )

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 )

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 obser
ved 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.

Adverse Reactions Table:

Table 1. Most Commonly Reported (≥5%) Cutaneous Adverse Reactions
VALCHLOR N=128 % of patients Comparator N=127 % of patients
Any GradeModerately-Severe or Severe Any GradeModerately-Severe or Severe
Dermatitis56235817
Pruritus204162
Bacterial skin infection11292
Skin ulceration or blistering6352
Skin hyperpigmentation5070

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.

Use in Specific Population:

8 use in specific populations lactation: advise not to breastfeed ( 8.2 ). 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 indicate
d 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.

Use in Pregnancy:

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 de
fect, 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.

Pediatric Use:

8.4 pediatric use safety and effectiveness in pediatric patients have not been established.

Geriatric Use:

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.

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•hcl, and the structural formula is: ch 3 n(ch 2 ch 2 cl) 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.

Clinical Pharmacology:

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.

Mechanism of Action:

12.1 mechanism of action mechlorethamine, also known as nitrogen mustard, is an alkylating agent which inhibits rapidly proliferating cells.

Pharmacokinetics:

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.

Nonclinical Toxicology:

13 nonclinical toxicology 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.

Carcinogenesis and Mutagenesis and Impairment of Fertility:

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 intravenousl
y 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.

Clinical Studies:

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.

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 topi
cal 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) complete response (cr) partial response (pr) 60% 14% 45% 48% 11% 37% swat overall response (cr+pr) complete response (cr) partial response (pr) 50% 7% 43% 46% 3% 43%

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

Information for Patients:

17 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 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 risk to the fetus and to avoid pregnancy while using valchlor. advise males with female partners of reproductive potential to use a barrier method of contraception while using valchlor [ see use in specific populations ( 8.1 , 8.3 ) ]. lactation advise females not to breastfeed during treatment with valchlor [ see use in specific populations ( 8.2 ) ]. manufactured for: helsinn therapeutics, (u.s.), inc., iselin, nj 08830

Package Label Principal Display Panel:

Principal display panel - 60 g tube carton 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 69639-120-01 carton label

Tube label - front tube label front

Tube label - back tube label back


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