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VALCHLOR
(mechlorethamine) Gel
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.
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.
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]. 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.
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].
Patients or caregivers should follow these instructions when applying VALCHLOR:
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).
VALCHLOR is supplied in 60g tubes of 0.016% w/w mechlorethamine as a clear gel [NDC 42427-002-60].
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
REFERENCES
1 OSHA Hazardous Drugs. OSHA. [Accessed July 3, 2013, from http://www.osha.gov/SLTC/hazardousdrugs]
Manufactured for: Ceptaris Therapeutics, Inc., Malvern, PA 19355. Revised: August 2013
The following adverse reactions are described in greater detail in other sections:
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 valchlor 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 [see Clinical Studies]. In these trials, 3136 and 1232 COPD patients were exposed to valchlor 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 valchlor 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 valchlortreated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of valchlor 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 valchlor-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 valchlor group in 8 controlled COPD clinical trials.
Table 1: Adverse Reactions Reported by ≥
2% of Patients Treated with valchlor 500 mcg daily and Greater Than Placebo
| Adverse Reactions (Preferred Term) | Treatment | |
| valchlor (N=4438) n (%) |
Placebo (N=4192) n (%) |
|
| Diarrhea | 420 (9.5) | 113 (2.7) |
| Weight decreased | 331 (7.5) | 89 (2.1) |
| Nausea | 209 (4.7) | 60 (1.4) |
| Headache | 195 (4.4) | 87 (2.1) |
| Back pain | 142 (3.2) | 92 (2.2) |
| Influenza | 124 (2.8) | 112 (2.7) |
| Insomnia | 105 (2.4) | 41 (1.0) |
| Dizziness | 92 (2.1) | 45 (1.1) |
| Decreased appetite | 91 (2.1) | 15 (0.4) |
Adverse reactions that occurred in the valchlor 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
The following adverse reactions have been identified from spontaneous reports of valchlor 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 valchlor. 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 valchlor exposure: hypersensitivity reactions including angioedema, urticaria, and rash.
A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 [see CLINICAL PHARMACOLOGY].
Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of valchlor. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with valchlor is not recommended [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY
The co-administration of valchlor (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit. [see CLINICAL PHARMACOLOGY].
The co-administration of valchlor (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully against benefit [see CLINICAL PHARMACOLOGY].
Included as part of the PRECAUTIONS section.
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.
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].
The most common adverse reaction was dermatitis, which occurred in 56% of the patients [see ADVERSE REACTIONS]. 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].
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.
Based on its mechanism of action, case reports in humans, and findings in animals, VALCHLOR 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 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].
Alcohol-based products, including VALCHLOR, are flammable. Follow recommended application instructions [see DOSAGE AND ADMINISTRATION].
See FDA-approved patient labeling (Medication Guide)
Advise patients of the following and provide a copy of the Medication Guide.
Apply a thin film of VALCHLOR once daily to affected areas of the skin [see DOSAGE AND ADMINISTRATION].
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].
Patients and caregivers should follow these instructions when applying VALCHLOR [see DOSAGE AND ADMINISTRATION]:
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 60 days [see HOW SUPPLIED/Storage and Handling].
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.
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].
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].
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 and WARNINGS AND PRECAUTIONS].
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].
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].
Advise women of the potential hazard to a fetus and to avoid pregnancy while using VALCHLOR [see WARNINGS AND PRECAUTIONS].
Advise women to discontinue nursing due to the potential for topical or systemic exposure to VALCHLOR [see Use In Specific Populations].
Mechlorethamine is a probable carcinogen in humans. There are reports of non-melanoma skin cancer with the use of topical mechlorethamine in patients [see WARNINGS AND PRECAUTIONS]. 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 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.
Pregnancy Category D [see WARNINGS AND PRECAUTIONS]
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 [see WARNINGS AND PRECAUTIONS].
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.
It is not known if mechlorethamine is excreted in human milk. Due to the potential for topical or systemic exposure to VALCHLOR 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.
Safety and effectiveness in pediatric patients have not been established.
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.
No information provided.
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.
Mechlorethamine, also known as nitrogen mustard, is an alkylating agent which inhibits rapidly proliferating cells.
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.
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.
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 (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.
Table 2: Efficacy in Patients with Mycosis Fungoides-Type CTCL
| Response Rates | VALCHLOR N=119 |
Comparator N=123 |
| CAILS Overall Response (CR+PR), % (N) | 60% | 48% |
| Complete Response (CR) | 14% | 11% |
| Partial Response (PR) | 45% | 37% |
| SWAT Overall Response (CR+PR), %(N) | 50% | 46% |
| Complete Response (CR) | 7% | 3% |
| Partial Response (PR) | 43% | 43% |
VALCHLOR™
(val-klor)
(mechlorethamine) Gel
Important information: VALCHOR is for use on skin only. Do not get VALCHLOR near or in your eyes, mouth, or nose.
What is the most important information I should know about VALCHLOR?
Keep VALCHLOR away from your eyes, mouth, and nose.
Get medical help right away if VALCHLOR gets in your eyes, mouth, or nose. Talk with your healthcare provider before using VALCHLOR about how to get medical help.
What is VALCHLOR?
VALCHLOR is a prescription medicine used on the skin to treat people with Stage 1A and 1B mycosis fungoides-type cutaneous T-cell lymphoma who have received previous skin treatment.
It is not known if VALCHLOR is safe and effective in children.
Who should not use VALCHLOR?
Do not use VALCHLOR if you are severely allergic to mechlorethamine. Tell your healthcare provider if you have had an allergic reaction to mechlorethamine.
What should I tell my healthcare provider before using VALCHLOR?
Before using VALCHLOR, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take including prescription and over-thecounter medicines, vitamins, and herbal supplements.
How should I use VALCHLOR?
What should I avoid while using VALCHLOR?
VALCHLOR is flammable. Avoid fire, flame, and smoking until VALCHLOR has dried.
What are the possible side effects of VALCHLOR?
See “What is the most important information I should know about VALCHLOR?”
VALCHLOR can cause serious side effects, including:
The most common side effects of VALCHLOR include: redness, swelling, itching, skin ulcers or blisters, skin infection, and darkening of areas of your skin.
These are not all the possible side effects of VALCHLOR.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088.
How should I store VALCHLOR?
General information about the safe and effective use of VALCHLOR.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about VALCHLOR that is written for health professionals. Do not use VALCHLOR for a condition for which it was not prescribed. Do not give VALCHLOR to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about VALCHLOR. If you would like more information about VALCHLOR, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about VALCHLOR that is written for health professionals.
What are the ingredients in VALCHLOR?
Active ingredient: mechlorethamine
Inactive ingredients: diethylene glycol monoethyl ether, propylene glycol, isopropyl alcohol, glycerin, lactic acid, hydroxypropylcellulose, sodium chloride, menthol, edetate disodium, butylated hydroxytoluene
