PATIENT COUNSELING INFORMATION.

Concomitant Measures Advise patients to maintain sun and light protection measures during treatment with SCENESSE to prevent phototoxic reactions related to EPP. Skin Monitoring Advise patients that darkening of pre-existing nevi and ephelides may occur with use of SCENESSE. full body skin examination is recommended twice yearly to monitor pre-existing and new skin pigmentary lesions. Expelled Implant Advise patients to contact their healthcare provider if the implant is expelled. Dressing removal Advise patients that the dressing can be removed after 24 hours. Insertion Site Care and Monitoring Advise patients to monitor the insertion site after dressing removal and to report any reaction observed at the site to their healthcare provider.

ADVERSE REACTIONS SECTION.

Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 of SCENESSE was evaluated in randomized, multicenter, prospective, vehicle controlled clinical trials (Study CUV029, Study CUV030, and Study CUV039) involving 244 adult subjects with erythropoietic protoporphyria (EPP) without significant liver involvement. Subjects received subcutaneous SCENESSE implants containing 16 mg of afamelanotide every months. total of 125 subjects received SCENESSE and 119 subjects received vehicle implants. Table summarizes the adverse reactions that occurred in more than 2% of subjects. Specific Adverse ReactionsImplant Site Reactions: Implant site reactions were more common in the SCENESSE group (21%) compared to the vehicle group (10%). In the SCENESSE group, the most common implant site reaction was implant site discoloration (10%). To to report suspected adverse reactions, contact FDA at 1-800-332-1088 or www.fda.gov/medwatch.. The most common adverse reactions (incidence 2%) are implant site reaction, nausea, oropharyngeal pain, cough, fatigue, dizziness, skin hyperpigmentation, somnolence, melanocytic nevus, respiratory tract infection, non-acute porphyria, and skin irritation.To report suspected adverse reactions, contact CLINUVEL INC. at 1-888-288-2031 or FDA at 1-800-332-1088 or www.fda.gov/medwatch.. Table 1.

CLINICAL STUDIES SECTION.

Three vehicle-controlled, parallel-group clinical trials of SCENESSE were conducted in subjects with EPP. Of these trials, two trials (Study CUV039, NCT 01605136, and Study CUV029, NCT 00979745) were designed to assess exposure to direct sunlight on days with no phototoxic pain. The two trials differed in the number of days of follow-up, the time windows within day in which time spent outdoors was recorded, and how the amount of time spent in direct sunlight on each day was characterized. The subjects enrolled in these trials were primarily Caucasian (98%), the mean age was 40 years (range 18 to 74 years), and 53% of subjects were male and 47% were female. Study CUV039 enrolled 93 subjects, of whom 48 received SCENESSE (16 mg of afamelanotide administered subcutaneously every months), 45 received vehicle. Subjects received three implants and were followed for 180 days. On each study day, subjects recorded the number of hours spent in direct sunlight between 10 am and pm, the number of hours spent in shade between 10 am and pm, and whether they experienced any phototoxic pain that day. The primary endpoint was the total number of hours over 180 days spent in direct sunlight between 10 am and pm on days with no pain. The median total number of hours over 180 days spent in direct sunlight between 10 am and pm on days with no pain was 64.1 hours for subjects receiving SCENESSE and 40.5 hours for subjects receiving vehicle. Study CUV029 enrolled 74 subjects, of whom 38 received SCENESSE (16 mg of afamelanotide administered subcutaneously every months), 36 received vehicle. Subjects received five implants and were followed for 270 days. On each study day, subjects recorded the number of hours spent outdoors between 10 am and pm, whether most of the day was spent in direct sunlight, shade, or combination of both, and whether they experienced any phototoxic pain that day. The primary endpoint was the total number of hours over 270 days spent outdoors between 10 am and pm on days with no pain for which most of the day was spent in direct sunlight. This analysis does not include sun exposure on days for which subjects reported spending time in combination of both direct sunlight and shade. The median total number of hours over 270 days spent outdoors between 10 am and pm on days with no pain for which most of the day was spent in direct sunlight was 6.0 hours for subjects in the SCENESSE group and 0.75 hours for subjects in the vehicle group.

DESCRIPTION SECTION.

SCENESSE (afamelanotide) implant is controlled-release dosage form for subcutaneous administration. Afamelanotide is melanocortin receptor (MC1-R) agonist. The active ingredient afamelanotide acetate is synthetic peptide containing 13 amino acids with molecular formula C78H111N21O19 oxC2H4O2 (3 <= <= 4). The molecular weight of afamelanotide is 1646.85 (anhydrous free base). Afamelanotide acetate has the following structure: Ac-Ser-Tyr-Ser-Nle-Glu-His-(D)Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2o xCH3COOH. Afamelanotide is white to off-white powder, freely soluble in water. Each SCENESSE implant contains 16 mg of afamelanotide (equivalent to 18 mg of afamelanotide acetate), and 15.3-19.5 mg of poly (DL-lactide-co-glycolide). SCENESSE implant is single, solid white to off-white, bioresorbable and sterile rod approximately 1.7 cm in length and 1.45 mm in diameter. The implant core comprises of the drug substance admixed with poly (DL-lactide-co-glycolide) bioresorbable copolymer.

DOSAGE & ADMINISTRATION SECTION.

Important Dosage and Administration Information. SCENESSE should be administered by health care professional. All healthcare professionals should be proficient in the subcutaneous implantation procedure and have completed the training program provided by CLINUVEL prior to administration of the SCENESSE implant [see Dosage and Administration (2.2)]. Additional information, including video, is available at http://www.clinuvel.com/US-HCP. The additional information has not been evaluated or approved by the FDA. single SCENESSE implant is inserted subcutaneously above the anterior supra-iliac crest every months. Use the SFM Implantation Cannula to implant SCENESSE. Contact CLINUVEL INC. for other implantation devices that have been determined by the manufacturer to be suitable for implantation of SCENESSE. Maintain sun and light protection measures during treatment with SCENESSE to prevent phototoxic reactions related to EPP. SCENESSE should be administered by healthcare professional who is proficient in the subcutaneous implantation procedure and has completed training prior to administration. Insert single implant, containing 16 mg of afamelanotide, using an SFM Implantation Cannula or other implantation devices that have been determined by the manufacturer to be suitable for implantation of SCENESSE. Administer SCENESSE subcutaneously every months.

HEALTH CARE PROVIDER LETTER SECTION.

Month/Day/YearIMPORTANT PRESCRIBING INFORMATIONRe: Temporary changes to approved packaging and labeling of SCENESSE(R) (afamelanotide) implant.Dear Health Care Provider,CLINUVEL, INC. is issuing this letter to inform you of temporary changes to the approved packaging and labeling of SCENESSE(R). This means that the appearance of SCENESSE(R) packaging will differ from that approved by the United States Food and Drug Administration (FDA). To meet U.S. demand, CLINUVEL, INC. is releasing batches ML1803 and ML1901 with the temporary changes to the packaging and labelling with the knowledge of the FDA. summary of these changes is outlined below. CLINUVEL will communicate updates to you on its ability to provide SCENESSE(R) in its final U.S. approved packaging.CLINUVEL, INC. is the holder of the approved New Drug Application (NDA) for the medication SCENESSE(R) (afamelanotide) implant. SCENESSE(R) was approved by the U.S. FDA in October 2019 to increase pain-free light exposure in adult patients with history of phototoxicity reactions from erythropoietic protoporphyria (EPP).Summary of the temporary changes to packaging and labeling of SCENESSE(R)SCENESSE(R) will be supplied in single vial contained within clear plastic pouch (transparent, zip-top bag), accompanied with the U.S. approved Prescribing Information, rather than in cardboard carton. Both the pouch and label will feature the following information that is included in the approved labelDetails on the contents of the packaging and ingredients:Each implant contains 16 mg of afamelanotide (equivalent to 18 mg of afamelanotide acetate) and 15.3-19.5mg of poly(DL-lactide-co-glycolide) bioresorbable copolymersNDC number The statement See Prescribing Information for dosage and administration information The statement Rx only; for subcutaneous use only The lot number and expiration date of the SCENESSE(R) implant Storage details Manufacturers name The pouch and vial will not feature product identifier or any colored text or company logo. The pouch will also not feature barcode.The vial should not be removed from the plastic pouch until the product is ready to be administered to patient.Availability of SCENESSE(R)SCENESSE(R) is only available to healthcare professionals trained to administer SCENESSE(R) and should only be administered to adult patients with confirmed diagnosis of EPP.SCENESSE(R) is only available by direct order from CLINUVEL and cannot be obtained through third party distributors or wholesalers.Reporting adverse events and further informationA copy of the full prescribing information for SCENESSE(R) has been appended to this letter.Health Care Providers are expected to report all adverse events experienced by EPP patients receiving SCENESSE(R) to CLINUVEL via email at safetyclinuvel.com or by calling CLINUVEL, INC. on 1(650) 733 2827. Adverse events or quality problems experienced with the use of this product may also be reported to the FDAs MedWatch Adverse Event Reporting Program either online, by regular mail, or by fax:Complete and submit the report Online: www.fda.gov/medwatch/report.htm Regular mail or Fax: Download form www.fda.gov/MedWatch/getforms.htm or call 1-800-332-1088 to request reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178 (1-800-332-0178). If you have any questions, you can call CLINUVEL, INC on 1-650-733-2827.Yours sincerely,Linda TengDirector, Clinical ComplianceCLINUVEL INC.

USE IN SPECIFIC POPULATIONS SECTION.

Pregnancy. Risk SummaryThere are no data on SCENESSE use in pregnant women to evaluate for any drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcome. In animal reproductive and development toxicity studies, no adverse developmental effects were observed with afamelanotide administration during the period of organogenesis to pregnant rats at subcutaneous doses up to 12 times the maximum recommended human dose (MRHD) (see Data). All pregnancies have background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 In embryofetal development studies in Sprague Dawley and Lister Hooded rats, afamelanotide was administered subcutaneously to pregnant rats at doses of 0.2, 2, or 20 mg/kg/day throughout the period of organogenesis. No adverse embryofetal developmental effects were observed at doses up to 20 mg/kg/day (12 times the MRHD, based on body surface area comparison). In pre- and post-natal development study in Sprague Dawley rats, afamelanotide was administered subcutaneously at doses of 0.2, 2, or 20 mg/kg/day during the period of organogenesis through lactation. No treatment-related effects were observed at doses up to 20 mg/kg/day (12 times the MRHD, based on body surface area comparison).