QUTENZA

QUTENZA (capsaicin) 8% topical system contains capsaicin in a localized dermal delivery system. The capsaicin in QUTENZA is a synthetic equivalent of the naturally occurring compound found in chili peppers. Capsaicin is soluble in alcohol, acetone, and ethyl acetate and very slightly soluble in water. QUTENZA is a single-use topical system stored in a foil pouch. Each QUTENZA is 14 cm x 20 cm (280 cm 2 ) and consists of a polyester backing film coated with a drug-containing silicone adhesive mixture and covered with a removable polyester release liner. The backing film is imprinted with “capsaicin 8%”. Each QUTENZA contains a total of 179 mg of capsaicin (8% in adhesive, 80 mg per gram of adhesive) or 640 micrograms (mcg) of capsaicin per square cm of topical system. The empirical formula is C 18 H 27 NO 3 , with a molecular weight of 305.42. The chemical compound capsaicin [(E)-8-methyl-N-vanillyl-6-nonenamide] is an activating ligand for transient receptor potential vanilloid 1 receptor (TRPV1) and it has the following structure: FIGURE 1: Structural Formula of Capsaicin QUTENZA contains the following inactive ingredients: diethylene glycol monoethyl ether, dimethicone, ethyl cellulose, polyester film, silicone adhesive, and white ink. QUTENZA is supplied with a Cleansing Gel which is used to remove residual capsaicin from the skin after treatment. Cleansing Gel consists of the following ingredients: butylated hydroxyanisole, carbomer copolymer, edetate disodium, polyethylene glycol, purified water, and sodium hydroxide. Structural Formula of Capsaicin

QUTENZA is indicated in adults for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and for neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet. QUTENZA is a TRPV1 channel agonist indicated for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet. ( 1 )

Only physicians or health care professionals are to administer QUTENZA. ( 2.1 ) Administer QUTENZA in a well-ventilated treatment area. ( 2.1 ) Wear nitrile (not latex) gloves when handling QUTENZA and when cleaning treatment areas. ( 2.1 ) Use of a face mask and protective glasses is advisable for healthcare professionals. ( 2.1 ) Do not use QUTENZA on broken skin. ( 2.1 ) PHN: Apply up to four topical systems for 60 minutes. ( 2.2 ) DPN: Apply up to four topical systems for 30 minutes on the feet. ( 2.2 ) Repeat every 3 months or as warranted by the return of pain (not more frequently than every three months). ( 2.2 ) See Dosage and Administration, Instructions for Use, for detailed instructions on QUTENZA administration. ( 2.3 ) 2.1 Important Dosage and Administration Instructions Do not dispense QUTENZA to patients for self-administration or handling. Only physicians or healthcare professionals are to administer and handle QUTENZA. Unintended exposure to capsaicin can cause severe irritation of eyes, mucous membranes, respiratory tract, and skin in healthcare professionals, patients and others [see Warnings and Precautions ( 5.1 )] . Because unintended exposure to capsaicin can cause severe irritation of eyes, mucous membranes, respiratory tract, and skin, when administering QUTENZA, it is important to follow these procedures: − Administer QUTENZA in a well-ventilated treatment area. − Wear only nitrile gloves when handling QUTENZA or any item that makes contact with QUTENZA, and when cleaning capsaicin residue from the skin. Do not use latex gloves as they do not provide adequate protection. − Use of a face mask and protective glasses is advisable for healthcare professionals. − Keep QUTENZA in the sealed pouch until immediately before use. − Use QUTENZA only on dry, intact (unbroken) skin. − In patients treated for neuropathic pain associated with diabetic peripheral neuropathy, a careful examination of the feet should be undertaken prior to each application of QUTENZA to detect skin lesions related to underlying neuropathy or vascular insufficiency. [see Warnings and Precautions ( 5.4 )] . − During administration, avoid unnecessary contact with any items in the room, including items that the patient may later have contact with, such as horizontal surfaces and bedsheets. − Aerosolization of capsaicin can occur upon rapid removal of QUTENZA. Therefore, remove QUTENZA gently and slowly by rolling the adhesive side inward [see Warnings and Precautions ( 5.1 )] . − Immediately after use, clean all areas that had contact with QUTENZA and properly dispose of QUTENZA, associated packaging, Cleansing Gel, gloves, and other treatment materials in accordance with local biomedical waste procedures. − If QUTENZA is cut, ensure unused pieces are properly disposed of. 2.2 Dosing The recommended dose of QUTENZA for neuropathic pain associated with postherpetic neuralgia is a single, 60-minute application of up to four topical systems. The recommended dose of QUTENZA for neuropathic pain associated with diabetic peripheral neuropathy is a single, 30-minute application on the feet of up to four topical systems. Treatment with QUTENZA may be repeated every three months or as warranted by the return of pain (not more frequently than every three months). 2.3 Instructions for Use USE IN NEUROPATHIC PAIN ASSOCIATED WITH POSTHERPETIC NEURALGIA (60-MINUTE APPLICATION TIME) Prepare Administer QUTENZA in a well-ventilated treatment area. Put on nitrile (not latex) gloves. Use of a face mask and protective glasses is advisable for healthcare professionals. Inspect the pouch. Do not use if the pouch has been torn or damaged. Identify The treatment area (painful area including areas of hypersensitivity and allodynia) must be identified by a physician or healthcare professional and marked on the skin. If necessary, clip hair (do not shave) in and around the identified treatment area to promote QUTENZA adherence. QUTENZA can be cut to match the size and shape of the treatment area. Gently wash the treatment area with mild soap and water, and dry thoroughly. Anesthetize (optional) The treatment area may be pretreated with a topical anesthetic to potentially reduce discomfort associated with the application of QUTENZA. Apply topical anesthetic to the entire treatment area and surrounding 1 to 2 cm, and keep the local anesthetic in place until the skin is anesthetized prior to the application of QUTENZA. Remove the topical anesthetic with a dry wipe. Gently wash the treatment area with mild soap and water, and dry thoroughly. Apply Tear open the pouch along the three dashed lines and remove QUTENZA. Inspect QUTENZA and identify the outer surface backing layer with the printing on one side and the capsaicin-containing adhesive on the other side. The adhesive side of QUTENZA is covered by a clear, unprinted, diagonally cut release liner. Cut QUTENZA before removing the protective release liner. Ensure that unused pieces do not make contact with other objects and are disposed of appropriately. The diagonal cut in the release liner is to aid in its removal. Peel a small section of the release liner back and place the adhesive side of QUTENZA on the treatment area. While you slowly peel back the release liner from under the QUTENZA with one hand, use your other hand to smooth QUTENZA down onto the skin. Once QUTENZA is applied, leave in place for 60 minutes (PHN). To ensure QUTENZA maintains contact with the treatment area, a dressing, such as rolled gauze, may be used. Remove the nitrile gloves after the application. Instruct the patient not to touch QUTENZA or the treatment area. Remove Put on nitrile (not latex) gloves. Remove QUTENZA by gently and slowly rolling inward. Cleanse After removal of QUTENZA, generously apply Cleansing Gel to the treatment area and leave on for at least one minute. Remove Cleansing Gel with a dry wipe and gently wash the area with mild soap and water. Dry thoroughly. Dispose of all treatment materials as described [see Dosage and Administration ( 2.1 )] . Inform the patient that the treated area may be sensitive for a few days to heat (e.g., hot showers/baths, direct sunlight, vigorous exercise). USE IN NEUROPATHIC PAIN ASSOCIATED WITH DIABETIC PERIPHERAL NEUROPATHY (30-MINUTE APPLICATION TIME ON THE FEET) Prepare Administer QUTENZA in a well-ventilated treatment area. Put on nitrile (not latex) gloves. Use of a face mask and protective glasses is advisable for healthcare professionals. Inspect the pouch. Do not use if the pouch has been torn or damaged. Identify The treatment area (painful area including areas of hypersensitivity and allodynia) must be identified by a physician or healthcare professional and marked on the skin. Examine the feet prior to application of QUTENZA to detect skin lesions related to underlying neuropathy or vascular insufficiency. If necessary, clip hair (do not shave) in and around the identified treatment area to promote QUTENZA adherence. QUTENZA can be cut to match the size and shape of the treatment area. Gently wash the treatment area with mild soap and water, and dry thoroughly. Anesthetize (optional) The treatment area may be pretreated with a topical anesthetic to potentially reduce discomfort associated with the application of QUTENZA. Apply topical anesthetic to the entire treatment area and surrounding 1 to 2 cm, and keep the local anesthetic in place until the skin is anesthetized prior to the application of QUTENZA. Remove the topical anesthetic with a dry wipe. Gently wash the treatment area with mild soap and water, and dry thoroughly. Apply Tear open the pouch along the three dashed lines and remove QUTENZA. Inspect QUTENZA and identify the outer surface backing layer with the printing on one side and the capsaicin-containing adhesive on the other side. The adhesive side of QUTENZA is covered by a clear, unprinted, diagonally cut release liner. Cut QUTENZA before removing the protective release liner. Ensure that unused pieces do not make contact with other objects and are disposed of appropriately. The diagonal cut in the release liner is to aid in its removal. Peel a small section of the release liner back and place the adhesive side of QUTENZA on the treatment area. While you slowly peel back the release liner from under the QUTENZA with one hand, use your other hand to smooth QUTENZA down onto the skin. QUTENZA can be wrapped around the dorsal, lateral, and plantar surfaces of each foot to completely cover the treatment area. Once QUTENZA is applied, leave in place for 30 minutes on the feet (DPN). To ensure QUTENZA maintains contact with the treatment area, a dressing, such as rolled gauze, may be used. Remove the nitrile gloves after the application. Instruct the patient not to touch QUTENZA or the treatment area. Remove Put on nitrile (not latex) gloves. Remove QUTENZA by gently and slowly rolling inward. Cleanse After removal of QUTENZA, generously apply Cleansing Gel to the treatment area and leave on for at least one minute. Remove Cleansing Gel with a dry wipe and gently wash the area with mild soap and water. Dry thoroughly. Dispose of all treatment materials as described [see Dosage and Administration ( 2.1 )] . Inform the patient that the treated area may be sensitive for a few days to heat (e.g., hot showers/baths, direct sunlight, vigorous exercise). Figure 2.3-1 Figure 2.3-2 Figure 2.3-3 Figure 2.3-4 Figure 2.3-5 Figure 2.3-6 Figure 2.3-7 Figure 2.3-8 Figure 2.3-9 Figure 2.3-10

None. None

The following serious adverse reactions are discussed elsewhere in the labeling: Severe Irritation Due to Accidental Exposure of Eyes, Skin, Respiratory Tract, and Mucous Membranes [see Warning and Precautions ( 5.1 )] Application-Associated Pain [see Warnings and Precautions ( 5.2 )] Increase in Blood Pressure [see Warnings and Precautions ( 5.3 )] Sensory Function Reduction [see Warning and Precautions ( 5.4 )] Severe Application Site Burns ​[see Warning and Precautions ( 5.5 )] The most common adverse reactions (≥5% and greater than control) in all controlled clinical trials are application site erythema, application site pain, and application site pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Averitas Pharma at 1-877-900-6479 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 to rates in the clinical trials of other drugs and may not reflect the rates observed in clinical practice. Across all controlled and uncontrolled clinical trials, 2848 patients have received QUTENZA. A total of 924 patients received more than one treatment application and 732 patients were followed for 48 weeks or longer. A total of 590 DPN patients and 1112 PHN patients have received QUTENZA across all controlled and uncontrolled clinical trials. Among patients treated with QUTENZA, 1% discontinued prematurely due to an adverse event. Most Common Adverse Reactions in all Controlled Clinical Trials In all controlled clinical trials, adverse reactions occurring in ≥5% of patients in the QUTENZA group and at an incidence at least 1% greater than in the control group were application site erythema, application site pain, and application site pruritus. The majority of application site reactions were transient and self-limited. Transient increases in pain were commonly observed on the day of treatment in patients treated with QUTENZA. Pain increases occurring during QUTENZA application usually began to resolve after QUTENZA removal. On average, pain scores returned to baseline by the end of the treatment day and then remained at or below baseline levels. A majority of QUTENZA-treated patients in clinical trials had adverse reactions with a maximum intensity of "mild" or "moderate". Postherpetic Neuralgia (PHN) Table 1 summarizes all adverse reactions, regardless of causality, occurring in >1% of patients with PHN in the QUTENZA group for which the incidence was at least 1% greater than in the control group. TABLE 1: Adverse Reaction Incidence (%) in Controlled Double-blind Trials in Postherpetic Neuralgia (Events in >1% of QUTENZA-treated Patients and at Least 1% Greater in the QUTENZA Group than in the Control Group) Body System Preferred Term QUTENZA 60 minutes (N=622) % Control 60 minutes (N=495) % General Disorders and Administration Site Conditions Application site erythema 63 54 Application site pain 42 21 Application site pruritus 6 4 Application site papules 6 3 Application site edema 4 1 Application site swelling 2 1 Application site dryness 2 1 Infections and Infestations Nasopharyngitis 4 2 Bronchitis 2 1 Sinusitis 3 1 Gastrointestinal Disorders Nausea 5 2 Vomiting 3 1 Skin and Subcutaneous Tissue Disorder Pruritus 2 < 1 Vascular Disorders Hypertension 2 1 Less common adverse reactions (<1%) with QUTENZA observed during PHN clinical trials included: palpitations, tachycardia, eye pruritus, application site reactions (such as urticaria, paresthesia, dermatitis, hyperesthesia). Neuropathic Pain Associated with Diabetic Peripheral Neuropathy (DPN) Table 2 summarizes all adverse reactions, regardless of causality, occurring in >1% of patients with DPN in the QUTENZA group for which the incidence was at least 1% greater than in the control group. TABLE 2: Adverse Reaction Incidence (%) in Double-blind Controlled Trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy (Events in >1% of QUTENZA-treated Patients and at Least 1% Greater in the QUTENZA Group than in the Control Group) Body System Preferred Term QUTENZA 30 minutes (N=186) % Control 30 minutes (N=183) % General Disorders and Administration Site Conditions Application site reactions Burning sensation 14 3 Application site pain 10 2 Erythema 2 0 Injury, Poisoning and Procedural Complications Excoriation 2 0 Musculoskeletal and Connective Tissue Disorders Pain in extremity 11 6 Nervous System Disorders Headache 3 2 Respiratory, Thoracic and Mediastinal Disorders Upper respiratory symptoms Upper respiratory tract infection 4 < 1 Cough 2 < 1 Vascular Disorders Hypertension 2 < 1 Less common adverse reactions (<1%) with QUTENZA observed during DPN clinical trials included: dizziness, dysesthesia, blister. 6.2 Postmarketing Experience Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of QUTENZA: deep partial-thickness (second-degree) and full-thickness (third-degree) burns and scarring; accidental exposure (including eye pain, cough, eye and throat irritation) ​[see Warnings and Precautions ( 5.1 , 5.5 )].

No clinical drug interaction studies have been performed. Data from in vitro cytochrome P450 inhibition and induction studies show that capsaicin does not inhibit or induce liver cytochrome P450 enzymes at concentrations which far exceed those measured in blood samples. Therefore, interactions with systemic medicinal products are unlikely.