Document: Belkyra solution for injection ENG SmPC change

• Belkyra solution for injection SmPC
• Belkyra solution for injection ENG SmPC

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Belkyra 10 mg/ml solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution for injection contains 10 mg deoxycholic acid.

Each vial contains 20 mg of deoxycholic acid in 2 ml solution.

Excipient(s) with known effect

Each mL contains 184 µmol (or 4.23 mg) of sodium from sodium chloride, sodium hydroxide and disodium phosphate anhydrous.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Solution for injection (injection).

A clear, colourless solution, free from visible particles.

The formulation is adjusted to pH 8.3 with hydrochloric acid or sodium hydroxide and has a tonicity compatible with that of biological tissues and fluids at an osmolality of 300 mOsm/kg

4. Clinical particulars

4.1 Therapeutic indications

4.2 Posology and method of administration

Posology

The total volume injected and the number of treatment sessions should be tailored to the individual patient’s submental fat distribution and treatment goals.

Inject 0.2 ml (2 mg) per injection site, 1 cm apart. The maximum dose of 10 ml (100 mg equivalent to 50 injections) should not be exceeded in one treatment session.

Up to a maximum of 6 treatment sessions can be performed. Most patients experience improvement in 2 to 4 treatment sessions.

The time interval between treatment sessions should be at least 4 weeks.

To improve patient comfort during injection, oral analgesics or NSAIDs, topical and/or injectable local anaesthesia (eg, lidocaine) and/or cooling using ice gel packs may be applied to the area of injection at the discretion of the healthcare professional.

Special populations

Renal impairment

No dose adjustment is considered necessary (see section 5.2).

Hepatic impairment

No dose adjustment is considered necessary (see section 5.2).

Elderly (aged 65 years and above)

No dose adjustment is considered necessary. Caution should be exercised in elderly patients (see section 4.4).

Paediatric population

There is no relevant use of Belkyra in children or adolescents.

Method of administration

The product is indicated for subcutaneous administration only.

Belkyra should only be administered by healthcare professionals with appropriate qualifications, expertise and knowledge of the submental anatomy. Safe and effective use of Belkyra depends on appropriate patient selection, which includes knowledge of patient history of prior interventions and their potential to alter the superficial cervical anatomy. Careful consideration should be given to the use of Belkyra in patients with excessive skin laxity, prominent platysmal bands or other conditions for which reduction of submental fat may result in an undesirable outcome.

Belkyra must be used only for one session of injection(s) per patient and the excess of unused product must be properly disposed of.

Belkyra is supplied in ready-to-use, single-use vials. Gently invert the vial several times prior to use. Do not dilute.

Insert the needle perpendicular to the skin for injections with Belkyra.

Needle placement with respect to the mandible is very important as it reduces the potential for injury to the marginal mandibular nerve, a motor branch of the facial nerve. Injury to the nerve presents as an asymmetrical smile due to paresis of lip depressor muscles.

To avoid injury to the marginal mandibular nerve:

• Do not inject above the inferior border of the mandible.

• Do not inject within a region defined by a 1-1.5 cm line below the inferior border (from the angle of the mandible to the mentum).

• Inject Belkyra only within the target submental fat treatment area (see Figures 1 and 3).

Figure 1. Avoid the Marginal Mandibular Nerve Area

Avoid injection into the platysma. Prior to each treatment session, palpate the submental area to ensure sufficient submental fat and to identify subcutaneous fat between the dermis and platysma (pre-platysmal fat) within the target treatment area (Figure 2).

Figure 2. Sagittal View of Platysma Area

Outline the planned treatment area with a surgical pen and apply a 1 cm² injection grid to mark the injection sites (Figures 2 and 3).

Figure 3. Treatment Area and Injection Pattern

Do not inject Belkyra outside the defined parameters.

The solution for injection should be inspected visually prior to use. Only clear, colourless solutions free of visible particles should be used.

4.3 Contraindications

- Hypersensitivity to deoxycholic acid or to any of the excipients listed in section 6.1

- Presence of infection at the proposed injection sites

4.4 Special warnings and precautions for use

To be administered only by subcutaneous route.

Injections in or near vulnerable areas

Do not inject within 1 to 1.5 cm of vulnerable anatomic structures.

Belkyra should not be injected into or in close proximity to the marginal mandibular branch of the facial nerve to avoid the potential for motor neuropraxia, which manifests as an asymmetric smile or facial muscle weakness. In the clinical trials, nerve injury was temporary and all cases resolved.

Care should be taken to avoid inadvertent intradermal or intramuscular injection. Belkyra should be injected mid-way into the preplatysmal subcutaneous fat tissue in the submental area. Do not withdraw the needle from the subcutaneous fat during injection, as this could increase the risk of intradermal exposure and potential skin ulceration.

Avoid injection into salivary glands, the thyroid gland, lymph nodes and muscles.

The safe and effective use forBelkyra outside the SMF area has not been established.

Pre-existing Conditions/Treatments at or Near the Treatment Area

Patients should be screened for other potential causes of submental convexity/fullness (e.g., thyromegaly and cervical lymphadenopathy) prior to use of Belkyra.

Caution should beused whenBelkyra is administered in thepresenceof inflammation or induration at theproposed injection site(s) or in patients with symptoms of dysphagia.

Caution should be used when Belkyrais administeredin patients who have had prior surgical or aesthetic treatment of the submental area. Changes in anatomy/landmarks or the presence of scar tissue may impact the ability to safely administer Belkyra or to obtain the desired result.

Elderly

The clinicalstudiesofBelkyra did not includesufficientnumbers ofpatients aged 65 and overto determinewhether they respond differently thanyounger patients; therefore, caution should be exercised with these patients.

Controlled sodium diet

This medicinal product contains 184 µmol (or 4.23 mg) sodium per mL. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

No clinical druginteraction studieshavebeenconductedwith Belkyra.

4.6 Fertility, pregnancy and lactation

Pregnancy

Reproduction studies have been performed in rats and rabbits at exposures up to 1.8 times (rat) and 12 times (rabbit) the exposure at maximum recommended human dose.While they do not indicate direct or indirect harmful effects with respect to reproductive toxicity, inconclusive findings of missing intermediate lung lobe was noted in rabbits in the embryo-fetal toxicity study (see section 5.3).

There are noadequate and well-controlled studiesin pregnant women. As a precautionary measure, it is preferable to avoid the use of Belkyra during pregnancy.

Breast-feeding

There is no information available on the presence of deoxycholic acid in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because studies in nursing mothers have not been conducted, caution should be exercised when Belkyra is administered to a nursing woman.

Fertility

There are no clinical data on fertility.

Belkyra did not affect general reproductive performance or fertility in male or female rats at doses up to 50 mg/kg, corresponding to approximately 5- and 3-fold exposure margins, respectively, to the maximum human recommended dose (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

The data described in the underlying table reflect undesirable effects reported for Belkyra treated patients (N=1118) who were evaluated in the clinical studies that assessed the use of Belkyra for the treatment of submental fat.

The following side effects have been evaluated in clinical studies with the following frequencies:

• Very common (≥ 1/10)

• Common (≥ 1/100 to <1/10)

• Uncommon (≥ 1/1,000 to <1/100)

• Rare (≥ 1/10,000 to <1/1,000)

• Very rare (<1/10,000)

• Not known (cannot be estimated from the available data).

Reporting of suspected adverse reactions

Reporting 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.

4.9 Overdose

No overdosing with Belkyra in humans has been reported.

Injection of increased volume or decreasing the spacing between injections of Belkyra may be expected to increase risk of local adverse effects. Non-treatment area or systemic adverse reactions were infrequent during clinical studies of doses up to 200 mg.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other dermatological preparations

ATC code: D11AX24

Mechanism of action

Deoxycholic acid is a cytolytic drug, which when injected into localized subcutaneous fat, physically disrupts the cell membrane of adipocytes. The destruction of adipocytes elicits a tissue response in which macrophages are attracted to the area to eliminate cellular debris and lipids, which are then cleared through natural processes. This is followed by the appearance of fibroblasts and observed thickening of fibrous septa suggesting an increase in total collagen (i.e., neocollagenesis).

Clinical efficacy and safety

FourPhase3 randomized,multi-center,double-blind,placebo-controlled trials wereconducted (2 identical studies conducted in the European Union [EU] and 2 identical trials conducted in North America) toevaluateBelkyra forthe treatment of convexity or fullness associated with submental fat (SMF) and the assessment of the associated psychological impact. In all trials the primary endpoints were measured 12 weeks after final treatment. Each Phase 3 trial met its primary efficacy endpoints, and showed improvement in psychological impact versus placebo.

The trials enrolled adults(ages 19 to 65) with moderate or severe convexity or fullness associated with SMF (i.e., grade 2 or 3 on 5-point grading scales, where 0 = absent, 4 = extreme), as judged by both clinician and subject ratings. Patients received up to 4 treatments in the trials conducted in the EU, and up to 6 treatments in the trials conducted in North America, withBelkyra (N=757 for all 4 studies) orplacebo(N=746) at 28-day intervals. Treatment was stopped when the desired response was achieved. Injectionvolume was0.2 ml per injectionsite,spaced 1 cm apart into the SMF tissue, which is also expressed in dose per area as2 mg/cm². For each treatment session a maximum of 100 mg (10 ml) was permitted over the entire treatment area.

The meanagein the trials conducted in the EU was46 years and the mean BMI was 26. Mostpatientswerewomen(75%)andCaucasian(94%). Atbaseline, 68% of the patients hada clinician-rated SMFseverity rating ofmoderate and 32% had a severe SMF rating. For trials conducted in North America, the meanagewas49 years and the mean BMI was 29 kg/m². Mostof thepatients