Caryolysine

Caryolysine 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.

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.

Dosing and Dose Modification

For Topical Dermatological Use Only

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

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

Caryolysine 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 Caryolysine.

Caregivers must wear disposable nitrile gloves when applying Caryolysine to patients and wash hands thoroughly with soap and water after removal of gloves. If there is accidental skin exposure to Caryolysine, 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 Caryolysine:

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

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). 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.

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.

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.

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

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.

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 Caryolysine

Avoid direct skin contact with Caryolysine 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 Caryolysine, 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 Caryolysine. 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, Caryolysine 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 Caryolysine. 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 Caryolysine, 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 Caryolysine

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

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

Patients and caregivers should follow these instructions when applying Caryolysine :

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

Instructions for Patients and Caregivers for Storage of Caryolysine

Store Caryolysine refrigerated at temperatures between 36°F - 46°F (2°C - 8°C). Advise patients that adherence to the recommended storage condition will ensure Caryolysine will work as expected. Patients should consult a pharmacist prior to using Caryolysine 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 Caryolysine in its original box out of the reach of children and avoid contact with food when storing in the refrigerator.

Unused Caryolysine, 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 Caryolysine

Avoid direct skin contact with Caryolysine in individuals other than the patient. Risks of secondary exposure include dermatitis, mucosal injury, and secondary cancers. Caregivers who help apply Caryolysine to patients must wear disposable nitrile gloves when handling Caryolysine. 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 Caryolysine, 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 Caryolysine. Non-melanoma skin cancer may occur at multiple areas, including areas not directly treated with Caryolysine.

Embryo-fetal Toxicity

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

Nursing Mothers

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

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 Caryolysine 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 Caryolysine 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 Caryolysine or the comparator in the clinical trial. Forty-four percent (44%) of patients age 65 or older treated with Caryolysine 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.

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 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.

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 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.

Embryo-fetal Toxicity

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.

Flammable Gel

Alcohol-based products, including VALCHLOR, 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 Valchlor

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

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.

Patients and 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 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 60 days.

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.

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 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.

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.

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.

Embryo-fetal Toxicity

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

Nursing Mothers

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

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 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.

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 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.

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 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.

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 Caryolysine 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 Caryolysine 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 Caryolysine 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 Caryolysinetreated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of Caryolysine 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 Caryolysine-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 Caryolysine group in 8 controlled COPD clinical trials.

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

Adverse reactions that occurred in the Caryolysine 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 Caryolysine 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 Caryolysine. 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 Caryolysine exposure: hypersensitivity reactions including angioedema, urticaria, and rash.

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 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. 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 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

Postmarketing Experience

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.

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

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.