4.1. Therapeutic indications

NUCEIVA is indicated for the temporary improvement in the appearance of moderate to severe vertical lines between the eyebrows seen at maximum frown (glabellar lines), when the severity of the above facial lines has an important psychological impact in adults below 65 years of age.

4.2. Posology and method of administration

NUCEIVA should only be administered by healthcare practitioners with appropriate qualifications and expertise in the treatment of glabellar lines and the use of required equipment.

Posology

The recommended injection per muscle site is 4 U/0.1 mL. Five injection sites (see Figure 1): 2 injections in each corrugator muscle (inferior medial and superior medial aspect) and 1 injection in the procerus muscle for a total dose of 20 Units.

Botulinum toxin units are not interchangeable from one product to another. Doses recommended are different from other botulinum toxin preparations.

In the absence of adverse reactions during the initial treatment, an additional course of treatment can be performed subject to a minimum interval of 3 months between the initial and repeat treatment.

In the event of treatment failure (no visible improvement of glabellar lines at maximum frown) one month after the first course of treatment, the following approaches may be considered:

• Examination of the causes of failure, e.g. inappropriate injection technique, incorrect muscles injected, and formation of botulinum toxin-neutralising antibodies.

• Re-evaluation of the appropriateness of treatment with botulinum toxin type A. The efficacy and safety of repeat injections beyond 12 months has not been evaluated.

Elderly

There are limited clinical data with this medicine in patients older than 65 years (see section 5.1). This medicine is not recommended for use in patients over 65 years of age.

No specific dose adjustment is required for use in the elderly.

Paediatric population

There is no relevant use of this medicine in the paediatric population.

Method of administration

Intramuscular use.

Once reconstituted, NUCEIVA should only be used to treat a single patient, during a single session.

Precaution to be taken before manipulating or administering the medicinal product

For instructions for use, precaution before manipulating or administering the medicinalproduct, handling and disposal of the vials, see section 6.6.

Care should be taken to ensure that this medicine is not injected into a blood vessel when it is injected in the vertical lines between the eyebrows seen at maximum frown (also known as glabellar lines) (see section 4.4).

Physical manipulation (such as rubbing) of the injection site in the immediate post-administration period should be avoided.

Administration instructions for Glabellar Lines seen at maximum frown

Reconstituted NUCEIVA (50 Units/1.25 mL) is injected using a sterile 30 gauge needle.

In order to reduce the complication of eyelid ptosis the following steps should be taken:

• Two injections should be administered in each corrugator muscle (inferior medial and superior medial aspect) and 1 injection in the procerus muscle for a total dose of 20 Units.

• Injection near the levator palpebrae superioris should be avoided, particularly in patients with larger brow depressor complexes.

• Lateral corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Generalised disorders of muscle activity (e.g. myasthenia gravis or Eaton Lambert Syndrome)

Infection or inflammation at the proposed injection sites.

4.4. Special warnings and precautions for use

General

The anatomy and anatomical land marks of procerus corrugator supercilli muscles and the surrounding vasucular and nervous structures in the glabellar region must be understood prior to administration of this medicine. Injection into vulnerable anatomical structures, such as nerves and blood vessels, must be avoided.

Localised pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling/oedema, erythema, localised infection, bleeding and/or bruising have been associated with the injection. Needle-related pain and/or anxiety have resulted in vasovagal responses, including transient symptomatic hypotension and syncope.

Caution should be taken when the targeted muscle shows pronounced weakness or atrophy.

Care should be taken to ensure that this medicine is not injected into a blood vessel when it is injected in the glabellar lines seen at maximum frown (see section 4.2).

There is a risk of eyelid ptosis following treatment (see section 4.2).

Caution should be taken if complications have resulted with previous botulinum toxin injections.

Bleeding disorders

Caution should be exercised when this medicine is used in patients with bleeding disorders as injection may lead to bruising.

Local and distant spread of toxin effect

Adverse reactions possibly related to the spread of toxin distant from the site of administration have been reported very rarely with botulinum toxin (see section 4.8). Swallowing and breathing difficulties are serious and can result in death. Injection of this medicine is not recommended in patients with a history of dysphagia and aspiration.

Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.

Pre-existing neuromuscular disorders

Patients with unrecognised neuromuscular disorders may be at increased risk of clinically significant systemic effects, including severe dysphagia and respiratory compromise from typical doses of botulinum toxin type A. In some of these cases, dysphagia has lasted several months and required placement of a gastric feeding tube (see section 4.3).

Caution should also be exercised when botulinum toxin type A is used for treatment of patients with amyotrophic lateral sclerosis or with peripheral neuromuscular disorders.

Hypersensitivity reactions

An anaphylactic reaction may occur very rarely after injection of botulinum toxin. Epinephrine (adrenaline) or any other anti-anaphylactic measures should therefore be available.

Antibody formation

Antibodies to botulinum toxin type A may develop during treatment with botulinum toxin. Some of the antibodies formed are neutralising which may lead to treatment failure of botulinum toxin type A.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Theoretically, the effect of botulinum toxin may be potentiated by aminoglycoside antibiotics, spectinomycin, or other medicinal products that interfere with neuromuscular transmission (e.g. neuromuscular blocking medicinal products).

The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of botulinum toxin type A in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). This medicine is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

There is no information on whether botulinum toxin type A is excreted in human breast milk. This medicine should not be used during breast-feeding.

Fertility

The effect of this medicine on human fertility is unknown. However, another botulinum toxin type A has been shown to impair the fertility of male and female animals.

4.7. Effects on ability to drive and use machines

NUCEIVA has a minor or moderate influence on the ability to drive and use machines. There is a potential risk for asthenia, muscle weakness, dizziness and visual disturbance, which could affect driving and the operation of machinery.

4.8. Undesirable effects

Summary of the safety profile

Serious adverse reactions that may occur following treatment with this medicine include eyelid ptosis, an immune response, distant spread of toxin, development or exacerbation of a neuromuscular disorder, and hypersensitivity reactions. The most commonly reported adverse reactions during treatment are headache, occurring in 9% of patients, followed by eyelid ptosis, occurring in 1% of patients.

Tabulated list of adverse reactions

Table 1 The NUCEIVA related adverse reactions are classified by System Organ Class and frequency defined as follows: 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).

System organ class

Preferred term

Frequency

Infections and infestations

Upper respiratory tract infection

Rare

Psychiatric disorders

Depression

Rare

Nervous system disorders

Headache

Common

Dizziness, migraine, muscle tone disorder, speech disorder

Uncommon

Dysaesthesia, head discomfort, hypoaesthesia, paraesthesia, sensory disturbance

Rare

Eye disorders

Eyelid ptosis

Common

Asthopenia, blepharospasm, brow ptosis, eyelid oedema, eye swelling, vision blurred

Uncommon

Diplopia, dry eye, eyelid sensory disorder

Rare

Ear and labyrinth disorders

Vertigo

Rare

Vascular disorders

Flushing

Rare

Respiratory, thoracic and mediastinal disorders

Epistaxis

Rare

Gastrointestinal disorders

Diarrhea

Rare

Skin and subcutaneous tissue disorders

Pruritis

Uncommon

Dermal cyst, erythema, photosensitivity reaction, skin mass, skin tightness

Rare

Musculoskeletal and connective tissue disorders

Muscle twitching, musculoskeletal pain, myalgia, neck pain

Rare

General disorders and administration site conditions

Application site bruising, influenza like illness, injection site bruising, injection site pain, injection site swelling

Common

Injection site: erythema, injection site paresthesia, injection site pruritis, pain, tenderness

Rare

Investigations

Intraocular pressure test

Rare

Injury, poisoning and procedural complications

Contusion

Uncommon

Post-procedural swelling, procedural headache

Rare

Note: Of the 1659 subjects treated with NUCEIVA, rare events occurred in 1 subject only. Uncommon events occurred in between 2 and 7 subjects.

Description of selected adverse reactions

Application related adverse reactions

Application related adverse reactions that have been reported following administration of this medicine are uncommon events individually, common when added together. These include application and injection site bruising, injection site pain and injection site swelling. Rarely occurring injection site events that have been reported include erythema, paraesthesia, pruritis, pain and tenderness.

Undesirable effects of the substance class botulinum toxin type A

Muscle atrophy

Muscle atrophy is expected after repeated botulinum treatment secondary to the flaccid paralysis of the treated muscles.

Toxin spread

Adverse reactions possibly related to the spread of toxin distant from the site of administration have been reported very rarely with botulinum toxin (e.g. muscle weakness, breathing difficulties, dysphagia or constipation) (see section 4.4).

Hypersensitivity reactions

An anaphylactic reaction may occur very rarely after injection of botulinum toxin. Epinephrine (adrenaline) or any other anti-anaphylactic measures should therefore be available.

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

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms of overdose

Signs of overdose may not be apparent immediately post-injection. Should accidental injection or ingestion occur, the patient should be medically monitored for several days for signs and symptoms of

general weakness or muscle paralysis. Admission to hospital should be considered in patients presenting with symptoms of botulinum toxin type A poisoning (generalised weakness, ptosis, diplopia, swallowing and speech disorders, or paresis of the respiratory muscles).

Too frequent or excessive dosing may enhance the risk of antibody formation. Antibody formation may lead to treatment failure.

Overdose of this medicine depends upon dose, site of injection, and underlying tissue properties. No cases of systemic toxicity resulting from accidental injection of botulinum toxin type A have been observed. Excessive doses may produce local or distant generalised and profound neuromuscular paralysis. No cases of ingestion of botulinum toxin type A have been reported.

Management of overdose

In the event of overdose the patient should be medically monitored for symptoms of excessive muscle weakness or muscle paralysis. Symptomatic treatment should be instigated if necessary.