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 ca…

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 …

4 CONTRAINDICATIONS None. None

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.

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).

8.2 Lactation Risk Summary Capsaicin is negligibly absorbed systemically by the mother following topical administration of QUTENZA, and breastfeeding is not expected to result in exposure of the infant to QUTENZA [see Clinical Pharmacology ( 12.3 )] . There are no data on the effects of capsaicin on milk production. To minimize potential direct exposure of QUTENZA to the breastfed infant, avoid applying QUTENZA directly to the nipple and areola. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for QUTENZA and any potential adverse effects on the breastfed infant from QUTENZA or from the underlying maternal condition.

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 i…