Qutenza

Warnings and Precautions ( 5.2 , 5.5 ) 07/2024

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 …

3 DOSAGE FORMS AND STRENGTHS QUTENZA topical system contains 8% capsaicin (640 mcg per cm 2 ). Each topical system contains a total of 179 mg of capsaicin. Each topical system is 14 cm x 20 cm (280 cm 2 ) and consists of an adhesive side containing the active substance and an outer surface backing layer. The adhesive side is covered with a removable, clear, unprinted, diagonally cut, release liner. The outer surface of the backing layer is imprinted with “capsaicin 8%”. QUTENZA contains 8% capsaicin (640 mcg per cm 2 ). Each topical systems contains a total of 179 mg of capsaicin. ( 3 )

4 CONTRAINDICATIONS None. None

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% 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 …

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 USE IN SPECIFIC POPULATIONS 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. 8.3 Females and Males of Reproductive Potential Infertility In a fertility and reproductive toxicology study, administration of QUTENZA at 13-times the MRHD to male rats for 3 hours/day for 49 days resulted in a statistically significant reduction in the number and percent of motile sperm; however, these reductions did not adversely affect fertility [see Nonclinical Toxicology ( 13.1 )] . As this animal model has a large excess of sperm-generating capacity relative to the threshold necessary for fertilization, the lack of an effect on fertility in this species is of unknown clinical significance for males of reproductive potential treated with the MRHD. 8.4 Pediatric Use The safety and effectiveness of QUTENZA in patients younger than 18 years of age have not been studied. 8.5 Geriatric Use In controlled clinical trials of QUTENZA in neuropathic pain associated with postherpetic neuralgia, 75% of patients were 65 years and older and 43% of patients were 75 ye …

12.1 Mechanism of Action Capsaicin is an agonist for the transient receptor potential vanilloid 1 receptor (TRPV1), which is an ion channel-receptor complex expressed on nociceptive nerve fibers in the skin. Topical administration of capsaicin causes an initial enhanced stimulation of the TRPV1-expressing cutaneous nociceptors that may be associated with painful sensations. This is followed by pain relief thought to be mediated by a reduction in TRPV1-expressing nociceptive nerve endings [see Clinical Pharmacology ( 12.2 )] . Over the course of several months, there may be a gradual re-emergence of painful neuropathy thought to be due to TRPV1 nerve fiber reinnervation of the treated area.

11 DESCRIPTION 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

10 OVERDOSAGE There is no clinical experience with QUTENZA overdose in humans. There is no specific antidote for overdose with capsaicin. In case of suspected overdose, remove QUTENZA gently, apply Cleansing Gel for one minute, wipe off with dry gauze, and gently wash the area with soap and water. Use supportive measures and treat symptoms as clinically warranted.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied QUTENZA (capsaicin) 8% topical system is a single-use topical system stored in a sealed pouch (NDC 72512-920-00). QUTENZA is 14 cm x 20 cm (280 cm 2 ) and consists of an adhesive side containing the active substance and an outer surface backing layer. The adhesive side is covered with a removable, clear, unprinted, diagonally cut, release liner. The outer surface of the backing layer is imprinted with “capsaicin 8%”. Cleansing Gel is provided in a 50 g tube. QUTENZA is available in the following presentations: Carton of one topical system and one 50 g tube of Cleansing Gel (NDC 72512-928-01). Carton of two topical systems and one 50 g tube of Cleansing Gel (NDC 72512-929-01). Carton of four topical systems and three 50 g tubes of Cleansing Gel (NDC 72512-930-01). 16.2 Storage Store carton between 20°C to 25°C (68°F to 77°F). Excursions between 15°C and 30°C (59°F and 86°F) are allowed. Keep QUTENZA in the sealed pouch until immediately before use. 16.3 Handling and Disposal Unintended exposure to capsaicin can cause severe irritation of eyes, skin, respiratory tract, and mucous membranes. Wear nitrile (not latex) gloves while administering QUTENZA. Use of a face mask and protective glasses is advisable. Immediately after use, dispose of used and unused QUTENZA, QUTENZA clippings, associated packaging, Cleansing Gel, and all other potentially contaminated treatment supplies in accordance with local biomedical waste procedures [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.1 )] .