Afamelanotide is a melanocortin-1 receptor (MC1-R) agonist approved to increase pain-free light exposure in patients with a history of phototoxic reactions from erythropoietic protoporphyria (EPP). EPP is a rare disorder caused by mutations leading to impaired activity of ferrochelatase, an enzyme involved in heme production. The decrease in ferrochelatase activity leads to an accumulation of protoporphyrin IX (PPIX). When light reaches the skin, it can react with PPIX causing intense skin pain and skin changes, such as redness and thickening. Afamelanotide increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources. Afamelanotide was evaluated in 2 parallel group clinical trials involving 167 adult patients with EPP. In the first trial (n = 93), the primary endpoint was the total number of hours over 180 days spent in direct sunlight between 10 a.m. and 6 p.m. on days with no pain. The median number of hours with no pain was 64 hours for patients receiving afamelanotide and 41 hours for patients taking placebo. The second trial (n = 74 patients) looked at the total number of hours over 270 days spent in direct sunlight between 10 a.m. and 3 p.m. during which patients experienced no pain when "most of the day" was spent outside in direct sunlight. The median number of hours with no pain was 6 hours for patients receiving afamelanotide and 0.75 hours for patients taking placebo. Afamelanotide may cause skin darkening; a full body skin examination is recommended for patients twice a year.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
Subcutaneous Administration
Insertion:
-Wear sterile gloves and use aseptic technique to minimize any chance of infection.
-Remove the carton containing afamelanotide from the refrigerator to allow the product to gradually warm up to ambient temperature.
-Open the implant vial just before the time of insertion by removing the seal and stopper from the glass vial. Under aseptic conditions, use blunt forceps to remove the implant and place it on a sterile gauze.
-The patient should lay in a comfortable reclined supine position. Identify the insertion site 3 to 4 cm above the anterior supra-iliac crest and disinfect the skin.
-Anesthetize the area of insertion if deemed necessary.
-While pinching the skin of the insertion site, insert the cannula with the bevel facing upwards (away from the abdomen) at a 30 to 45 degree angle into the subcutaneous layer. Advance the cannula 2 cm into the subcutaneous layer.
-Remove the stylet (obturator) from the cannula maintaining aseptic precautions.
-Load the implant into the cannula.
-Using the stylet (obturator) gently push the implant down the full length of the cannula's shaft.
-Apply pressure to the site of the implant while removing the stylet (obturator) and the cannula. Verify that no implant or implant portion remains in the cannula.
-Confirm placement of the implant by palpating the skin overlying the implant.
-Cover the incision site with dressing and leave the dressing in place for 24 hours.
-Monitor the patient for 30 minutes after the implant administration.
During clinical trials, implant site reactions, defined as implant site bruising, discoloration, erythema, hemorrhage, hypertrophy, irritation, nodule, pain, pruritus, swelling, injection site bruising and erythema, and expelled implant, occurred in 21% of patients receiving afamelanotide vs. 10% of patients receiving vehicle implants. The most common implant site reaction in the afamelanotide group was implant site discoloration (10%). Skin hyperpigmentation (4% afamelanotide vs. 0% vehicle implant) and skin irritation (2% afamelanotide vs. 0% vehicle implant) were also reported.
Nausea was reported in 19% of patients receiving afamelanotide compared to 14% of patients receiving vehicle implants during clinical trials.
During clinical trials, oropharyngeal pain (7% afamelanotide vs. 5% vehicle implant), cough (6% afamelanotide vs. 3% vehicle implant) and respiratory tract infection (4% afamelanotide vs. 3% vehicle implant) were reported.
Neurologic adverse reactions reported in patients receiving afamelanotide treatment during clinical trials include fatigue (6% afamelanotide vs. 3% vehicle implant), dizziness (6% afamelanotide vs. 3% vehicle implant), and somnolence (drowsiness) (2% afamelanotide vs. 1% vehicle implant).
Other adverse reactions reported in patients receiving afamelanotide treatment during clinical trials include melanocytic nevus (4% afamelanotide vs. 2% vehicle implant) and non-acute porphyria (2% afamelanotide vs. 0% vehicle implant).
Administration of the afamelanotide implant requires an experienced clinician, specifically a healthcare professional experienced in the subcutaneous implantation procedure and who has completed the training program prior to administration.
Afamelanotide may lead to generalized increased skin hyperpigmentation and darkening of pre-existing nevi and ephelides. A full body skin examination is recommended twice yearly to monitor pre-existing and new skin pigmentary lesions.
There are no available data regarding afamelanotide use during pregnancy to inform a drug-associated risk. Animal data did not reveal evidence of harm to the fetus when administered at doses up to 12 times the maximum recommended human dose (MRHD).
There are no data on the presence of afamelanotide in human milk, the effects on a breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For use in erythropoietic protoporphyria (EPP) to increase pain free light exposure in patients with a history of phototoxic reactions:
Subcutaneous implant dosage:
Adults: 1 implant (16 mg) inserted subcutaneously above the anterior supra-iliac crest every 2 months. Patients need to maintain sun and light protection measures during treatment to prevent phototoxic reactions related to EPP.
Maximum Dosage Limits:
-Adults
One (16 mg) subcutaneous implant every 2 months
-Geriatric
One (16 mg) subcutaneous implant every 2 months
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Afamelanotide products.
Afamelanotide is a synthetic tridecapeptide and a structural analog of alpha-melanocyte stimulating hormone (alpha-MSH). Afamelanotide is a melanocortin receptor agonist and binds predominantly to MC1-R. Afamelanotide increases production of eumelanin in the skin independently of exposure to sunlight or artificial UV light sources.
Afamelanotide is administered by a subcutaneous insertion of an implant containing afamelanotide. High variability was observed in the plasma concentrations of afamelanotide following a single subcutaneous implant in 12 healthy volunteers. The mean Cmax was 3.7 +/- 1.3 ng/mL, AUC was 138.9 +/- 42.6 hr x ng/mL, median Tmax was 36 hours, and the apparent half-life was 15 hours. Afamelanotide may undergo hydrolysis, however, its metabolic profile has not been fully characterized.
Affected cytochrome P450 isoenzymes: None
No pharmacokinetic-based drug interaction studies were conducted with afamelanotide implants.