afamelanotide: prescribing information – dosing, contraindications, interactions, side effects

SCENESSE is indicated for prevention of phototoxicity in adult patients with erythropoietic protoporphyria (EPP).

SCENESSE should only be prescribed by specialist physicians in recognised porphyria centres and administration should be performed by a physician trained and accredited by the marketing authorisation holder to administer the implant.

Posology

One implant is administered every 2 months prior to expected and during increased sunlight exposure.
The overall duration of treatment is at the specialist physician’s discretion (see sections 4.4 and 5.1).

Special populations

For patients with renal or hepatic impairment see sections 4.3 and 5.2.

Elderly population

Due to limited data in treatment of elderly patients, the use of afamelanotide is not recommended (see section 4.4).

Paediatric population

The safety and efficacy of afamelanotide in children and adolescents aged to 17 years have not yet been established.
No data are available.

Method of administration

For subcutaneous use.

Instruction for use

• Take the packed implant out of the refrigerator and allow the medicinal product to warm up to ambient temperature.
• Have the patient sit in a comfortable position or lie on his/her back with the upper part of the body slightly raised.
• Disinfect the skin above the supra-iliac crest.
• Anaesthetise the insertion area if deemed necessary and in consultation with the patient.
• Select a 14 gauge (1.6 mm inner diameter) catheter with needle.
• Mark 1.5 to 2 cm on the catheter shaft using surgical ink.
• Hold the catheter at its base using a sterile technique, pinch and hold the skinfold cranial to, or overlying the patient’s supra-iliac crest with two fingers.
• With the bevel of the needle facing upwards, insert the catheter laterally 1.5 to 2 cm into the subcutaneous layer at a 30 to 45 degree angle to the skin surface in one continuous flowing movement.
• With the catheter in place, aseptically remove the implant from the vial.
• Remove the needle from within the catheter using a sterile technique.
• Transfer the implant to the outlet of the catheter.
• Using a suitable device (such as a stylet) gently push the implant down the full length of the catheter lumen.
• Apply some pressure to the insertion area with your finger while removing the stylet and the catheter.
• Confirm insertion of the implant by palpating the skin with subcutis cranial to/overlying the suprailiac crest until the implant is located. Always verify the presence of the implant, if in doubt of its presence, check whether the implant has remained in the catheter. If the implant has not been administered during the procedural steps described above, discard the implant and administer a new implant. Do not administer a new implant unless it has been unequivocally confirmed that the first one had not been inserted.
• Apply a small pressure dressing to the injection site.
• Observe the patient for 30 minutes to ensure that you will notice if the patient develops an allergic or hypersensitivity reaction (immediate type).

The implant can be surgically removed if needed.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Presence of severe hepatic disease
• Hepatic impairment (see section 5.2)
• Renal impairment (see section 5.2)

Summary of the safety profile

The safety profile is based on pooled data from clinical studies in 425 patients.
The most commonly reported adverse reactions are nausea, experienced by approximately 19% of subjects who received treatment with this medicinal product, headache (20%), and implant site reactions (21%; mainly discolouration, pain, haematoma, erythema). In most cases these adverse reactions are reported to be mild in severity.

Uncommon occurrences of hypersensitivity reactions, including anaphylaxis, have been reported in association with SCENESSE treatment (see section 4.4).

Tabulated list of adverse reactions

The adverse reactions reported during clinical studies conducted with afamelanotide are listed in the table below by MedDRA system organ class and frequency convention.

Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), and rare (≥1/10,000 to <1/1,000).

System Organ Class Very common
Common
Uncommon
Rare
Infections and infestations

Influenza
Upper respiratory tract infection

Cystitis
Folliculitis
Gastrointestinal infection
Gastroenteritis
Candida infection
Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Melanocyte naevus
Haemangioma

Blood and lymphatic system disorders

Leukopenia
Immune system disorders

Hypersensitivity,
Anaphylaxis

Metabolism and nutrition disorders

Decreased appetite
Increased appetite
Hypercholesterola emia

Psychiatric disorders

Depressed mood including depression
Insomnia
Confusional state
Nervous system disorders
Headache

Dizziness
Migraine
Somnolence

Balance disorder
Hyperaesthesia
Lethargy
Paraesthesia
Poor quality sleep
Presyncope

Restless leg syndrome
Syncope
Dysgeusia
Post-traumatic headache

Eye disorders

Dry eye
Eye pain
Ocular hyperaemia
Photophobia
Presbyopia
Eyelid oedema

Ear and labyrinth disorders

Tinnitus

Cardiac disorders

Palpitations
Tachycardia
Vascular disorders

Flushing
Hot flush
Haemorrhage
Haematoma
Hypertension
Diastolic hypertension

Respiratory, thoracic and mediastinal disorders

Sinus congestion

Gastrointestinal disorders
Nausea
Abdominal pain including abdominal discomfort
Diarrhoea
Toothache
Vomiting
Abdominal distension
Defaecation disorders
Dyspepsia
Flatulence
Gastroesophageal reflux disease
Gastritis
Irritable bowel syndrome
Gingival pain
Hypoaesthesia oral
Lip swelling
Bowel movement irregularity
Cheilitis
Gingival discolouration
Lip discolouration
Lip oedema
Tongue discolouration

System Organ Class Very common
Common
Uncommon
Rare
Skin and subcutaneous tissue disorders

Ephelides
Erythema
Pigmentation disorder
Pruritus
Rash including rash vesicular, rash erythematous, rash papular and rash pruritic

Acne
Dermatitis contact
Dry skin
Eczema
Hair colour changes
Hyperhidrosis
Nail pigmentation
Papule
Photosensitivity reaction
Pigmentation lip
Post inflammatory pigmentation change
Pruritus generalised
Skin burning sensation
Skin discolouration
Skin exfoliation
Skin hyperpigmentation
Skin hypopigmentation
Skin irritation
Skin lesion
Seborrhoea
Urticaria
Lichen planus
Vitiligo

Musculoskeletal and connective tissue disorders

Musculoskeletal pain including back pain, arthralgia, pain in extremity and groin pain Joint stiffnes Muscle spasm Musculoskeletal stiffness Muscular weakness Limb discomfort Reproductive system and breast disorders

Breast tenderness
Dysmenorrhoea
Menstruation irregular
Libido decreased
Menorrhagia
Vaginal discharge
General disorders and administration site conditions

Asthenia
Fatigue

Implant site disorders including implant site bruising, implant site discolouration, implant site erythema, implant site haematoma, implant site haemorrhage, implant site hypersensitivity, implant site hypertrophy, implant site induration, implant site irritation, implant site mass, implant site oedema, implant site pain, implant site pruritus, implant site reaction, implant site swelling, implant site urticaria, Chills Feeling hot Hangover Malaise Oedema peripheral Oedema mucosal

System Organ Class Very common
Common
Uncommon
Rare implant site vesicles, implant site warmth

Influenza-like illness including cough, nasal congestion, nasopharyngitis, oropharyngeal pain, rhinitis

Pain
Pyrexia
Investigations

Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood creatine phosphokinase increased
Blood glucose increased
Blood iron decreased
Blood urine present
Hepatic enzyme increased
Liver function test abnormal
Transaminases increased
Blood pressure diastolic increased
Transferrin saturation decreased
Weight increased
Injury, poisoning and procedural complications

Fall
Wound
Procedural nausea
Wound complication
Product issues

Device expulsion

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V

Hypersensitivity

Uncommon occurrences of hypersensitivity reactions, including anaphylaxis, have been reported following administration of SCENESSE. Appropriate medical support measures should be readily available when SCENESSE is administered. If a serious hypersensitivity reaction occurs, appropriate medical treatment should be initiated, the implant should be removed if needed and further treatment with SCENESSE should be discontinued (see section 4.8).

Concomitant disorders not studied

Clinically significant disorders of the gastrointestinal, cardiovascular, respiratory, endocrine (including diabetes, Cushing’s disease, Addison’s disease, Peutz-Jeghers syndrome), neurological (including seizures) and haematological (especially anaemia) systems have not been evaluated.
A careful decision must be made whether to treat patients with any of these conditions with this medicinal product. If such patients are treated they must be monitored after each implant administration, including vital signs, routine haematology, and biochemistry.

Sun protection

It is recommended that sun protection measures routinely adopted by each patient to manage their photosensitivity related to EPP and in accordance with their skin type (Fitzpatrick scale) are maintained during treatment with this medicinal product.

Skin monitoring

Afamelanotide may induce darkening of pre-existing pigmentary lesions due to its pharmacological effect. A regular full body skin examination (every 6 months) is recommended to monitor all pigmentary lesions and other skin abnormalities.
If the skin changes noted are consistent with skin cancer or its precursors, or are ambiguous to the porphyria specialist, dermatology specialist consultation should be sought.
The two total full body skin examinations per year are intended to:
- detect early any skin cancers and their precursors induced by UV-exposure, as EPP patients can be expected to significantly increase their exposure to sunlight and UV light while on treatment with afamelanotide. EPP patients with fair skin may be more likely to request treatment and are more prone to developing UV light-associated skin changes, including cancer;
- detect and monitor changes in pigmentary lesions, thus allowing early detection of melanoma.
Special caution is warranted in patients with an
- individual or family history of melanoma (inclusive of in-situ melanoma, e.g. lentigo maligna) or suspected or confirmed susceptibility to cutaneous melanoma (CMM1, MIM #155600, synonyms: familial atypical mole-malignant melanoma syndrome, FAMMM; dysplastic naevus syndrome, DNS; B-K mole syndrome; CMM2 MIM #155601) and/or an
- individual history of basal cell carcinoma, squamous cell carcinoma (inclusive of carcinoma in situ, e.g. Bowen’s disease), Merkel cell carcinoma, or other malignant or premalignant skin lesions.

Long-term use

Long-term safety data for afamelanotide are limited.
The safety of this medicinal product has not been evaluated in clinical studies of duration longer than 2 years (see section 4.2).

Elderly

Since available data in treatment of the elderly are limited, afamelanotide should not be used in patients over 70 years of age. If such patients are treated they must be monitored after administration of every implant, including vital signs, routine haematology and biochemistry.

No specific interaction studies have been performed with this medicinal product.
Pharmacokinetic data for afamelanotide or any of its metabolites are very limited. As an oligopeptide with a short half-life, afamelanotide is expected to be rapidly hydrolysed into shorter peptide fragments and into its individual amino acids. However, due to the lack of data caution is warranted.

Patients taking substances which reduce coagulation, such as vitamin K antagonists (e.g. warfarin), acetylsalicylic acid and non-steroidal anti-inflammatory drug (NSAIDs) may experience increased bruising or bleeding at the site of implantation.

Women of childbearing potential/contraception in females

Women of childbearing potential have to use effective contraception during treatment with SCENESSE and for a period of three months thereafter.

Pregnancy

There are no or limited amounts of data from the use of afamelanotide in pregnant women.
Animal studies are insufficient with respect to developmental toxicity (see section 5.3). A risk to newborns/infants cannot be excluded.
SCENESSE should not be used during pregnancy and in women of childbearing potential not using effective contraception.

Breast-feeding

It is unknown whether afamelanotide or any of its metabolites are excreted in breast milk.
No clinical data are available on the use of afamelanotide in breastfeeding women.

A risk to newborns/infants cannot be excluded. SCENESSE should not be used during breastfeeding.

Fertility

There are no clinical data on the effects of afamelanotide on fertility. Animal studies have not shown any harmful effect on fertility and reproduction.

Afamelanotide has moderate influence on the ability to drive and use machines, especially within 72 hours of administration. Following administration of this medicinal product, somnolence, fatigue, dizziness, and nausea have been reported. Patients should not drive or use machines in case they are affected by these symptoms.

There are no data available on symptoms or treatment of overdose with afamelanotide.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Emollients and protectives, protectives against UV-radiation for systemic use, ATC code: D02BB02

Mechanism of action

Afamelanotide is a synthetic tridecapeptide and a structural analogue of α-melanocyte stimulating hormone (α-MSH). Afamelanotide is a melanocortin receptor agonist and binds predominantly to the melanocortin-1 receptor (MC1R). Its binding lasts longer than that of α-MSH. This results in part from afamelanotide’s resistance to immediate degradation by serum or proteolytic enzymes (see section 5.2). It presumably undergoes hydrolysis within a short time; its metabolites’ pharmacokinetics and pharmacodynamics are not understood yet.
Afamelanotide is thought to mimic the endogenous compound’s pharmacological activity by activating the synthesis of eumelanin mediated by the MC1R receptor.
Eumelanin contributes to photoprotection through different mechanisms including:
- strong broadband absorption of UV and visible light, where eumelanin acts as a filter
- antioxidant activity through scavenging of free radicals; and
- inactivation of the superoxide anion and increased availability of superoxide dismutase to reduce oxidative stress.

Pharmacodynamic effects

Administration of afamelanotide may, therefore, result in increased production of eumelanin in the skin of the EPP patient independently of exposure to sunlight or artificial UV light. This can be accompanied by a darkening of the skin pigmentation in areas with melanocytes which gradually fades unless a further implant is administered.

Clinical efficacy and safety

From the clinical development programme, there are limited data on dosing 4-6 implants/year.

In the pivotal clinical trial CUV039 a total of three 16 mg SCENESSE implants were administered at a two-month interval. It has been demonstrated that EPP patients receiving afamelanotide had more exposure to direct sunlight (10:00 to 18:00 hours) during a 180 day trial period compared to placebo recipients (p=0.044; afamelanotide arithmetic mean: 115.6 h, median 69.4h; placebo mean 60.6h, median 40.8h).

In the supportive study CUV029 and a Post-Authorization Safety Study (PASS), five or up to six 16 mg SCENESSE implants were administered per year (at a two-month interval). The observed safety profile appears similar to that of the pivotal study CUV039.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with SCENESSE in one or more subsets of the paediatric population in erythropoietic protoporphyria (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

Dose-finding studies have not been conducted.
The pharmacokinetics of afamelanotide have not been fully characterised yet, i.e. distribution, metabolism or excretion are not clear. No pharmacokinetic information is available on any of its metabolites (active or inactive).
Half-life is approximately 30 minutes.
Following subcutaneous administration of the implant, most of the active substance is released within the first 48 hours with over 90% released by day 5. Plasma levels of afamelanotide are maintained

over a number of days. In most clinical studies afamelanotide plasma levels were below the limit of quantitation by day 10. The implant is absorbed by the body within 50 to 60 days after administration.

Data on possible interactions or effects in special populations, e.g. in patients with hepatic or renal impairment are not available.

Paediatric population

No data are available.