Summary of medicine characteristics - Nuceiva
1. NAME OF THE MEDICINAL PRODUCT
NUCEIVA 50 Units powder for solution for injection
NUCEIVA 100 Units powder for solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 50 Units botulinum toxin type A produced by Clostridium botulinum.
Each vial contains 100 Units botulinum toxin type A produced by Clostridium botulinum.
After reconstitution each 0.1 mL of the solution contains 4 Units.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder for solution for injection.
White powder.
4. CLINICAL PARTICULARS4.1 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 physicians 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 patients
There are limited clinical data with NUCEIVA in patients older than 65 years (see section 5.1).
NUCEIVA 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 NUCEIVA 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 product
For instructions for use, precaution before manipulating or administering the product, handling and disposal of the vials, see section 6.6.
Care should be taken to ensure that NUCEIVA 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 ; 100 Units/2.5 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.
Figure 1: Injection Points
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 NUCEIVA. 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 pronouced weakness or atrophy.
Care should be taken to ensure that NUCEIVA 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 NUCEIVA 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 NUCEIVA 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.
It is mandatory that NUCEIVA is used for one single patient treatment only during a single session.
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). NUCEIVA is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding
There is no information on whether NUCEIVA is excreted in human breast milk. NUCEIVA should not be used during breast-feeding.
Fertility
The effect of NUCEIVA 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 undesirable effects that may occur following treatment with NUCEIVA 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 effects during treatment are headache, occurring in 9.0% of patients, followed by eyelid ptosis, occurring in 1.0% 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 undesirable effects that have been reported following administration of NUCEIVA 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 the national reporting system listed in
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 NUCEIVA 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.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Muscle relaxants, other muscle relaxants, peripherally acting agents, ATC code: M03AX01.
Mechanism of action
Botulinum toxin type A (Clostridium botulinum neurotoxin) blocks peripheral acetylcholine release at presynaptic cholinergic nerve terminals by cleaving SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within the nerve endings, thereby leading to denervation of the muscle and a flaccid paralysis.
After injection, there is an initial rapid high-affinity binding of toxin to specific cell surface receptors. This is followed by transfer of the toxin across the plasma membrane by receptor-mediated endocytosis. Finally, the toxin is released into the cytosol with progressive inhibition of acetylcholine release. Clinical signs are manifest within 2–3 days,with peak effect seen within 4 weeks of injection.
Recovery after intramuscular injection takes place normally within 12 weeks of injection as nerve terminals sprout and reconnect with the endplates.
Clinical efficacy and safety
Glabellar lines
540 patients with moderate to severe glabellar lines seen at maximum frown who felt their glabellar lines had an important psychological impact (on mood, anxiety/or depressive symptoms) have been included in the European/Canadian clinical study.
NUCEIVA injections significantly reduced the severity of glabellar lines by 1 point or greater at maximum frown for up to 139 days, as measured by the investigator assessment of glabellar line severity at maximum frown.
Table 2 – Primary Efficacy Endpoint – Glabellar Line Scale Score of 0 (none) or 1 (mild) at Day 30 by Investigator Assessment at Maximum Contraction, PP Population
| Responders for | Absolute Difference | ||||
| me primary Efficacy Endpoint | Placebo | BOTOX | NUCEIVA | BOTOX Vs. Placebo | NUCEIVA NUCEIVA Vs. Placebo Vs. BOTOX |
| Number | 2/48 | 202/244 | 205/235 | |||
| Percentage | 4.2% | 82.8% | 87.2% | 78.6% | 83.1% | 4.4% |
| (% CI) | (0.0, 9.8) | (78.1, 87.5) | (83.0, 91.5) | (66.5, 85.5) | (70.3, 89.4) | (-1.9, 10.8) |
| PValue | <0.001 | <0.001 |
Glabellar Line Scale (GLS); 0=no lines, 1=mild, 2=moderate, 3=severe
Two days after injection, 12.2% (6/49) of placebo, 57.0% (139/244) Botox treated patients and 54.2% (130/240) of NUCEIVA were considered by investigators as treatment responders (none or mild severity at maximum frown).
Table 3 – Exploratory Efficacy Endpoint – Glabellar Line Scale Score of 0 (none) or 1 (mild) at Day 30 by Investigator Assessment at Maximum Contraction for NUCEIVA Treated Subjects, by Baseline GLS Score at Maximum Contraction, ITT Population
| Baseline GLS Score at Maximum Contraction | NUCEIVA (N=245) | |
| GLS=0 at Day 30 at Maximum Contraction | GLS=1 at Day 30 at Maximum Contraction | |
| 2 (Moderate) Number | 35/62 | 25/62 |
| Percentage | 56.5% | 40.3% |
| 3 (Severe) Number | 41/179 | 108/179 |
| Percentage | 22.9% | 60.3% |
Glabellar Line Scale (GLS); 0=no lines, 1=mild, 2=moderate, 3=severe. Denominators are based on the number of subjects with the specified baseline severity at maximum contraction who had both baseline and Day 30 GLS scores at maximum contraction by investigator assessment
Table 4 – Exploratory Efficacy Endpoint – Glabellar Line Scale Score of 0 (none) or 1 (mild) at Day 30 by Investigator Assessment at Maximum Contraction for NUCEIVA Treated Subjects, by Baseline GLS Categories at Rest, ITT Population
| NUCEIVA (N=245) GLS=0 at Day 30 at GLS=1 at Day 30 at | |
| Baseline GLS Category at Rest | Maximum Contraction Maximum Contraction |
<1 (i.e., none or mild)
| Number Percentage | 61/103 40/103 59.2% 38.8% |
| >1 (i.e., moderate or severe) Number Percentage | 15/138 93/138 10.9% 67.4% |
Glabellar Line Scale (GLS); 0=no lines, 1=mild, 2=moderate, 3=severe. Denominators are based on the number of subjects with the specified baseline severity at rest who also had both baseline and Day 30 GLS scores at maximum contraction by investigator assessment
NUCEIVA injections also reduced the severity of glabellar lines at rest, an exploratory endpoint.
Table 5 – Exploratory Efficacy Endpoint – Glabellar Line Scale Score >/= 2 points better at day 30 by Investigator Assessment At Rest, PP Population
| Responders for the Exploratory Efficacy Endpoint | Placebo | BOTOX | NUCEIVA | Absolute Difference | ||
| BOTOX Vs. Placebo | NUCEIVA Vs. Placebo | NUCEIVA Vs. BOTOX | ||||
| Number | 0/27 | 36/149 | 32/133 | |||
| Percentage | 0% | 24.2% | 24.1% | 24.2% | 24.1% | –0.1% |
| (% CI) | (0.0, 12.8) | (17.5, 31.8) | (17.1, 32.2) | (11.4, 32.3) | (11.3, 32.4) | (-10.1, 9.9) |
| PValue | 0.003 | 0.003 | 0.984 | |||
There are limited phase 3 clinical data with NUCEIVA in patients older than 65 years.
Duration of response in the phase 3 study was 139 days, based on a 1 point GLS improvement.
A total of 922 patients participated in two 1 year open label uncontrolled studies, and over the course of these studies, the average patient received 3 treatments.
The psychological impact of glabellar lines was confirmed at study entry and although a beneficial effect could not be demonstrated on psychological wellbeing, significant effects on patient reported outcomes were demonstrated as compared to placebo. Further, the effects of NUCEIVA on psychological wellbeing and patient reported outcomes were comparable to BOTOX, the active control used in the pivotal study.
5.2 Pharmacokinetic properties
NUCEIVA has not been detected in the peripheral blood following intramuscular injection at the recommended dose.
Absorption, distribution, biotransformation and elimination (ADME) studies on the active substance have not been performed due to the nature of this product.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of acute and repeat dose toxicity.
Reproduction toxicity
The potential impact of NUCEIVA on fertility has not been investigated in animals. In pregnant rats, daily intramuscular injections of 0.5, 1, or 4 Units/kg during the period of organogenesis (from gestation days 6 to 16), did not induce significant test article-related toxicological effects on the dams and on embryo-fetal development. Effects on peri-/postnatal development have not been evaluated.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Human albumin
Sodium chloride
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
Unopened vial
50 Units
30 months
100 Units
30 months
Reconstituted solution
Chemical and physical in-use stability has been demonstrated for 72 hours at 2 – 8°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2° to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Vial (Type I glass) fitted with a stopper (chlorobutyl rubber) and a seal (aluminium).
Pack size of one.
6.6 Special precautions for disposal and other handling
Reconstitution should be performed in accordance with aseptic technique principles. NUCEIVA is reconstituted with sodium chloride 9 mg/ml (0.9%) solution for injection. As per the dilution table below, the amount of sodium chloride 9 mg/ml (0.9%) solution for injection is drawn up into a syringe in order to obtain a reconstituted solution at a concentration of 4 Units/0.1 mL.
| 50 Unit vial | 100 Unit vial | |
| Amount of solvent added (sodium chloride 9 mg/ml (0.9%) solution for injection) | 1.25 mL | 2.5 mL |
| Resulting dose (Units per 0.1 mL) | 4 Units | 4 Units |
The central part of the rubber cap should be cleaned with alcohol.
The solution is prepared by injecting the solvent slowly into the vial with a needle through the rubber stopper and by gently rotating the vial avoiding bubble formation. The vial has to be discarded if the vacuum does not pull the solvent into the vial. Once reconstituted, the solution should be visually inspected prior to use. Only clear, colorless solution without particles should be used.
Reconstituted NUCEIVA (50 Units/1.25 mL ; 100 Units/2.5 mL) is injected using a sterile 30 gauge needle. Four Units (4 U/ 0.1 mL) are administered in each of the 5 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.
It is mandatory that NUCEIVA is used for one single patient treatment only during a single session.
Procedure to follow for a safe disposal of vials, syringes and materials used:
Immediately after use, and prior to disposal, unused reconstituted NUCEIVA solution in the vial and/or the syringe must be inactivated, with 2 mL of dilute sodium hypochlorite solution at 0.5% or 1% (Javel solution) and should be disposed of in accordance with local requirements.
Used vials, syringes, and materials should not be emptied and must be discarded into appropriate containers and disposed as a Medical Biohazardous Waste in accordance with local requirements.
Recommendations in the event of an accident when handling botulinum toxin:
In the event of an accident when handling the product, whether in the vacuum-dried state or reconstituted, the appropriate measures described below must be initiated immediately.
- • The toxin is very sensitive to heat and certain chemical agents.
- • Any spillage must be wiped up: either with an absorbent material soaked in a solution of sodium
hypochlorite (Javel solution) in the case of the vacuum-dried product, or with a dry absorbent material in the case of the reconstituted product.
- • Contaminated surfaces must be cleaned with an absorbent material soaked in a solution of
sodium hypochlorite (Javel solution) and then dried.
- • If a vial is broken, carefully collect the pieces of glass and wipe up the product as stated above,
avoiding cuts to the skin.
- • If splashed on skin, wash with a solution of sodium hypochlorite and then rinse thoroughly with
7. MARKETING AUTHORISATION HOLDER
Evolus Pharma B.V.
Apollolaan 151
1077 AR Amsterdam
The Netherlands
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/19/1364/001
EU/1/19/1364/002
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: September 27, 2019