Qutenza

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION 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

4 CONTRAINDICATIONS None. None

5 WARNINGS AND PRECAUTIONS Severe Irritation with Unintended Capsaicin Exposure: Capsaicin can cause severe irritation of eyes, mucous membranes, respiratory tract, and skin to the healthcare professional, patients, and others. (See Full Prescribing Information for detailed instructions on how to manage this risk. ( 2.1 , 5.1 ) Application-Associated Pain: Patients may experience substantial procedural pain and burning upon application of QUTENZA and following removal of QUTENZA. Prepare to treat acute pain during and following the application procedure with local cooling and/or appropriate analgesic medication. ( 5.2 ) Increase in Blood Pressure: Transient increases in blood pressure may occur with QUTENZA treatment. Monitor blood pressure during and following the treatment procedure. ( 5.3 ) Sensory Function: Reductions in sensory function, which were generally minor and temporary, have been reported following administration of QUTENZA. Assess for signs of sensory deterioration or loss prior to each application of QUTENZA. If sensory loss occurs, treatment should be reconsidered. ( 5.4 ) Severe Application Site Burns: Full-thickness (third-degree) and deep partial-thickness (second-degree) burns have been reported following administration of QUTENZA. Ensure that dosage and administration recommendations are followed. ( 5.5 ) 5.1 Severe Irritation with Unintended Capsaicin Exposure Unintended exposure to capsaicin can cause severe irritation of eyes, mucous membranes, respiratory tract, and skin in healthcare professionals, patients, and others. Ensure that the recommended procedures and protective measures are used when administering QUTENZA [see Dosage and Administration ( 2.1 )] . Eye and Mucous Membrane Exposure • For healthcare professionals: ○ Wear nitrile gloves when administering QUTENZA and avoid unnecessary contact with items in the room, including items that the patient may later have contact with, such as horizontal surfaces and bedsheets. ○ Use of a face mask and protective glasses is advisable. • Do not apply QUTENZA to the patient’s face, eyes, mouth, nose, or scalp to avoid risk of exposure to eyes or mucous membranes. • Accidental exposure to the eyes and mucous membranes can occur from touching QUTENZA or items exposed to capsaicin and then touching the eyes and mucous membranes. • If irritation of eyes or mucous membranes occurs, flush eyes and mucous membranes with cool water. Remove the affected individual (healthcare professional or patient) from the vicinity of QUTENZA. Respiratory Tract Exposure Aerosolization of capsaicin can occur upon rapid removal of QUTENZA. Therefore, remove QUTENZA gently and slowly by rolling the adhesive side inward [see Dosage and Administration ( 2.1 , 2.3 )] . Inhalation of airborne capsaicin can result in coughing or sneezing. Administer QUTENZA in a well-ventilated treatment area. Provide supportive medical care if shortness of breath develops. If irritation of airways occurs, remove the affected individual (healthcare professional or patient) from the vicinity of QUTENZA. If respiratory irritation worsens or does not resolve, do not re-expose the affected healthcare professional or patient to QUTENZA [see Adverse Reactions ( 6.2 )] . Skin Exposure If skin not intended to be treated is exposed to QUTENZA, apply Cleansing Gel for one minute and wipe off with dry gauze. After the Cleansing Gel has been wiped off, wash the area with soap and water. Thoroughly 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 [see Dosage and Administration ( 2.1 , 2.3 )] . 5.2 Application-Associated Pain Even following use of a local anesthetic prior to administration of QUTENZA, patients may experience substantial procedural pain and burning upon application of QUTENZA and following removal of QUTENZA. Prepare to treat acute pain during and following the application procedure with local cooling and/or appropriate analgesic medication. 5.3 Increase in Blood Pressure In clinical trials, transient increases in blood pressure occurred during or shortly after exposure to QUTENZA. The changes averaged less than 10 mm Hg, although some patients had greater increases and these changes lasted for approximately two hours after QUTENZA removal. Increases in blood pressure were unrelated to the pretreatment blood pressure but were related to treatment-related increases in pain. Monitor blood pressure periodically during and following the treatment procedure and provide adequate support for treatment-related pain. Patients with unstable or poorly controlled hypertension, or a recent history of cardiovascular or cerebrovascular events, may be at an increased risk of adverse cardiovascular effects. Consider these factors prior to initiating QUTENZA treatment. 5.4 Sensory Function Reductions in sensory function have been reported following administration of QUTENZA. Decreases in sensory functions are generally minor and temporary (including to thermal and other harmful stimuli). All patients with pre-existing sensory deficits should be clinically assessed for signs of sensory deterioration or loss prior to each application of QUTENZA. If sensory deterioration or loss is detected or pre-existing sensory deficit worsens, continued use of QUTENZA treatment should be reconsidered. 5.5 Severe Application Site Burns Cases of full-thickness (third-degree) and deep partial-thickness (second-degree) burns have been reported following administration of QUTENZA. Cases of full-thickness (third-degree) burns, requiring hospitalization and skin grafting have been reported in patients who received QUTENZA for an unapproved indication and/or frequency of dosing at an application site where there had been prior skin trauma ​[see Adverse Reactions ( 6.2 )]. ​Ensure that dosage and administration recommendations are followed ​[see Dosage and Administration ( 2 )]. ​

7 DRUG INTERACTIONS 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.

6 ADVERSE REACTIONS 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 )].

8.1 Pregnancy Risk Summary Capsaicin is negligibly absorbed systemically following topical administration of QUTENZA, and maternal use is not expected to result in the fetal exposure to QUTENZA. In animal reproductive studies, no evidence of malformations were observed when capsaicin was administered daily by the topical route to pregnant rats and rabbits during the period of organogenesis at doses of up to 11- and 37-times, respectively, the maximum recommended human dose (MRHD) of QUTENZA at 716 mg capsaicin per day (4 topical systems containing 179 mg/topical system). In a peri- and postnatal development study, no adverse effects were observed when capsaicin was administered daily by the topical route to rats during implantation to weaning at doses of up to 11-times the MRHD (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data There was no evidence of fetal malformations in embryofetal developmental toxicological studies conducted in pregnant rats and rabbits in which QUTENZA (rats) or capsaicin liquid (rabbits) were applied once daily for a 3-hour duration during the period of fetal organogenesis at doses up to 11-times (rat, 32 mg QUTENZA /day) and 37-times (rabbit, 260 mg capsaicin/day) the MRHD based on a C max exposure comparison. In a peri- and postnatal reproduction toxicology study, pregnant female rats were treated with QUTENZA at doses up to 32 mg QUTENZA/rat/day applied once daily for a 3-hour duration during gestation and lactation (from Gestation Day 7 through Lactation Day 20). Analyses of milk samples on Day 14 of the lactation period demonstrated measurable levels of capsaicin in the dam's milk at all dose levels. There were no effects on survival, growth, learning and memory tests (passive avoidance and water maze), sexual maturation, mating, pregnancy, and fetal development in the offspring of mothers treated with capsaicin up to 32 mg QUTENZA /rat/day (11-times the MRHD based on C max exposure).