Nuceiva

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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  This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NUCEIVA 100 Units powder for solution for injection 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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 PARTICULARS 
 
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 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. 



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• 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 (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. 
 



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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. 



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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. 
 



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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 



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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. 
 



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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, 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 Appendix V. 
 
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 PROPERTIES 
 
5.1  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 



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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 
the Primary 
Efficacy 
Endpoint  

Placebo BOTOX NUCEIVA 

Absolute Difference 

BOTOX   
Vs. 

Placebo 

NUCEIVA    
Vs. Placebo 

NUCEIVA    
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 
 



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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 
 
 
 
Baseline GLS Category at Rest  

NUCEIVA (N=245) 
GLS=0 at Day 30 at 

Maximum Contraction 
GLS=1 at Day 30 at 

Maximum Contraction 
≤1 (i.e., none or mild)   

Number   61/103 40/103 
Percentage 59.2% 38.8% 

>1 (i.e., moderate or severe)   
Number 15/138 93/138 
Percentage  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. No beneficial effect was 
demonstrated on psychological wellbeing but broadly favourable patient reported cosmetic outcomes 
were recorded.  
  
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. 
 



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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 PARTICULARS 
 
6.1 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 
 
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 



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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. 
 
Amount of solvent added (sodium chloride 9 mg/ml 
(0.9%) solution for injection) to a 100 Unit vial 

Resulting dose (Units per 0.1 mL) 

2.5 mL 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 (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% 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 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 

plenty of water. 
 
• If splashed into the eyes, rinse eyes thoroughly with plenty of water or with an eye wash 

solution. 
 



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If the injector injures himself (cuts, pricks himself), proceed as above and take the appropriate medical 
steps.  

These instructions for use, handling, and disposal should be strictly followed. 

7. MARKETING AUTHORISATION HOLDER
Evolus Pharma Ltd 
70 Sir John Rogerson’s Quay 
Dublin 2  
Ireland 

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1364/001 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: September 27, 2019 

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.  



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ANNEX II 

 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 



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A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

Name and address of the manufacturer(s) of the biological active substance(s)  

Daewoong Pharmaceutical Co. Limited 
35-14 Jeyakgongdan 4-gil 
Hyangnam-eup 
Hwaseong-si 
Gyeonggi-do  
18623 
KOREA, REPUBLIC OF 
 
Name and address of the manufacturer(s) responsible for batch release 

Baggerman Farmanet N.V. 
Barrierweg 3G 
5622 CL Eindhoven 
NETHERLANDS 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

 

• Periodic safety update reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 

The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

• Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 



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• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 

• Obligation to conduct post-authorisation measures 
 

The MAH shall complete, within the stated timeframe, the below measures: 

 
Description Due date 
Introduction of an in vitro method as a replacement for the potency assay of the 
Nuceiva finished product. 

September 2021 

 

  



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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



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A. LABELLING 
  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NUCEIVA 100 Units powder for solution for injection  
botulinum toxin type A 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 100 Units botulinum toxin type A 
After reconstitution each 0.1 mL of the solution contains 4 Units 
 
 
3. LIST OF EXCIPIENTS 
 
Human albumin, sodium chloride 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for injection 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
Intramuscular use 
Single use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
Read the leaflet for the shelf life of the reconstituted medicine  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator  
 
 



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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Evolus Pharma Limited 
70 Sir John Rogerson’s Quay 
Dublin 2  
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1364/001 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
NUCEIVA 100 Units powder for solution for injection  
botulinum toxin type A 
IM 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
100 Units  
 
 
6. OTHER 
 
 
  



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B. PACKAGE LEAFLET 



23 

Package leaflet: Information for the user 
 

NUCEIVA 100 Units powder for solution for injection  
botulinum toxin type A 

 
 
Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you have any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What NUCEIVA is and what it is used for  
2. What you need to know before NUCEIVA is used 
3. How to use NUCEIVA  
4. Possible side effects  
5. How to store NUCEIVA  
6. Contents of the pack and other information 
 
1. What NUCEIVA is and what it is used for 
 
NUCEIVA contains the active substance botulinum toxin type A. 
It prevents muscles from contracting, leading to a temporary paralysis. It works by blocking the nerve 
impulses to the muscles in which it has been injected. 
 
NUCEIVA is used for the temporary improvement in the appearance of vertical lines between the 
eyebrows. It is used in adults less than 65 years of age in whom those facial lines have an important 
psychological impact. 
 
2. What you need to know before NUCEIVA is used 
 
NUCEIVA must not be used: 
- if you are allergic to botulinum toxin type A or any of the other ingredients of this medicine 

(listed in section 6); 
- if you have myasthenia gravis or Eaton Lambert syndrome (chronic diseases affecting the 

muscles); 
- if you have an infection or inflammation at the proposed injection sites. 
 
Warnings and precautions  
Side effects possibly related to the spread of botulinum toxin from the site of injection can occur very 
rarely (e.g. muscle weakness, difficulty in swallowing or food or liquid entering the airways). Patients 
receiving recommended doses may have exaggerated muscle weakness. 
 
Visit your doctor immediately if you find it difficult to swallow, to speak or to breathe after treatment.  
 
- NUCEIVA is not recommended in patients who have had problems swallowing (dysphagia) and 

breathing. 
- Too frequent or excessive dosing may lead to antibody formation. Antibody formation can stop 

botulinum toxin type A from working even for other uses. To prevent this, there must be a gap 
of at least three months between doses. 

- Very rarely, an allergic reaction can occur after the injection of botulinum toxin. 
- Drooping of the eyelid may occur after treatment. 



24 

 
Please tell your doctor if: 
- you had problems with previous botulinum toxin injections; 
- you see no significant improvement of your lines one month after your first course of treatment; 
- you suffer from certain diseases affecting your nervous system (such as amyotrophic lateral 

sclerosis or motor neuropathy); 
- you have inflammation at the proposed injection site(s); 
- the muscles to be injected are weak or wasted; 
- you have a bleeding disorder as injection may lead to bruising. 
 
Children and adolescents 
The use of NUCEIVA is not recommended in individuals under 18 years. 
 
Other medicines and NUCEIVA 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  
 
The use of botulinum toxin is not recommended in association with aminoglycoside antibiotics, 
spectinomycin or other medicines that interfere with nerve impulses to the muscle. 
 
Tell your doctor if you have recently been injected with a medicine containing botulinum toxin (the 
active substance of NUCEIVA), as this may increase the effect of NUCEIVA excessively. 
 
Pregnancy and breast-feeding  
 
If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby ask 
your doctor for advice before you receive this medicine. 
 
The use of NUCEIVA is not recommended during pregnancy and in women able to have children who 
are not using contraception.  
 
NUCEIVA is not recommended in breast-feeding women. 
 
Driving and using machines 
 
Muscle weakness, dizziness, and visual disturbance with this medicine could make driving or the use 
of machines dangerous. Do not drive or use machinery until such effects have cleared. 
 
NUCEIVA contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per dose; this means it is essentially 
‘sodium- free’. 
 
3. How to use NUCEIVA 
 
Unit doses for NUCEIVA are not interchangeable with those used for other preparations of botulinum 
toxin. 
 
NUCEIVA should only be injected by physicians with appropriate qualifications and expertise in the 
treatment of glabellar lines at maximum frown. 
 
The usual dose of NUCEIVA is 20 Units. You will be injected with the recommended volume of 
0.1 millilitre (ml) (4 Units) of NUCEIVA into each of 5 injection sites. 
 
Improvement of severity of the lines between the eyebrows generally occurs within a few days of 
treatment.   
 
The interval between treatments will be decided by your doctor. 



25 

 
How NUCEIVA is injected  
 
NUCEIVA is injected into your muscles (intramuscularly), directly into the affected area above and 
between the eyebrows. 
 
If you have any further questions on the use of this product, ask your doctor or pharmacist. 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
In general, side effects occur within the first few days after injection and are temporary. Most side 
effects are of mild to moderate severity. 
 
If you have any difficulty in breathing, swallowing or speaking after receiving NUCEIVA contact 
your doctor immediately.  
 
If you get hives, swelling, including swelling of the face or throat, wheezing, feeling faint or shortness 
of breath, contact your doctor immediately. 
 
The chance of having a side effect is described by the following categories: 
 

Common 
 
(May affect up to 1 
in 10 people) 

Headache, muscle imbalance resulting in elevated or asymmetrical eyebrows, 
eyelid drooping, injection site bruise 

Uncommon  
 
(May affect up to 1 
in 100 people) 

Sensory disturbance, head discomfort, dry eye, eyelid swelling, eye swelling, 
muscle twitching, injection site: redness, pain, tingling 
 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V.  By reporting side effects, you can help provide more information on the safety 
of this medicine. 
 
5. How to store NUCEIVA 
 
Keep out of the sight and reach of children. 
 
Unopened vial 
 
Do not use NUCEIVA after the expiry date which is stated on the vial and the carton after EXP. 
 
 
6. Contents of the pack and other information 
 
What NUCEIVA contains  
- The active substance is: 100 Units botulinum toxin type A. 
- The other ingredients are human albumin and sodium chloride.  
 



26 

What NUCEIVA looks like and contents of the pack 
NUCEIVA is presented as a white powder for solution for injection in a transparent glass vial.  
Each pack contains 1 vial. 
 
Marketing Authorisation Holder  
Evolus Pharma Limited 
70 Sir John Rogerson’s Quay 
Dublin 2  
Ireland 
 
Manufacturers 
Baggerman Farmanet N.V. 
Barrierweg 3G 
5622 CL Eindhoven 
The Netherlands  
 
For any information about this medicine, please contact the the Marketing Authorisation Holder 
 
This leaflet was last revised in{month YYYY}. 
 
------------------------------------------------------------------------------------------------------------------------ 
 
 
THE FOLLOWING INFORMATION IS INTENDED FOR MEDICAL OR HEALTHCARE 
PROFESSIONALS ONLY: 
 
Botulinum toxin units are not interchangeable from one product to another. Doses recommended in 
units are different from other botulinum toxin preparations. 
 
Reconstitution should be performed in accordance with good clinical practice, particularly with respect 
to aseptic technique. NUCEIVA is reconstituted with sodium chloride 9 mg/ml (0.9%) solution for 
injection . 2.5 mL of sodium chloride 9 mg/ml (0.9%) solution for injection is drawn up into a syringe 
in order to obtain a reconstituted solution for injection at a concentration of 4 Units/0.1 mL. 
 
 
 
 

 
The central part of the rubber cap should be cleaned with alcohol. Inject the diluent slowly into the vial 
with a needle through the rubber stopper and gently rotate the vial avoiding bubble formation. The vial 
has to be discarded if the vacuum does not pull the diluent into the vial. Once reconstituted, the 
solution for injection should be visually inspected prior to use to verify it is a clear, colourless solution 
free of particulate matter. 
 
Reconstituted NUCEIVA (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. 
 

Amount of diluent added to 100 Unit vial 
(sodium chloride 9 mg/ml (0.9%) solution for injection) 

2.5 mL 

Resulting dose 
(Units per 0.1 mL) 

4.0 U 



27 

 
 
In order to reduce the complication of eyelid ptosis the following steps should be taken: 
 
- Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow 

depressor complexes. 
- Lateral corrugator injections should be placed at least 1 cm above the bony supraorbital ridge. 
- Ensure the injected volume/dose is accurate and where feasible kept to a minimum. 
 
Procedure to follow for safe disposal of vials, syringes and materials used: 
 
Immediately after use, unused reconstituted NUCEIVA solution for injection in the vial and/or the 
syringe must be inactivated, prior to disposal, with 2 mL of dilute sodium hypochlorite solution at 0.5% 
or 1% available chlorine.  Following inactivation, dispose of in accordance with local requirements. 
Used vials, syringes and materials should not be emptied and must be discarded into appropriate 
containers and disposed of according to local regulations. 
 
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, wash with a solution of sodium hypochlorite and then rinse thoroughly with plenty of 

water. 
 
- If splashed into the eyes, rinse eyes thoroughly with plenty of water or with an eye wash solution. 
 
- If the operator injures himself (cuts, pricks himself), proceed as above and take the appropriate 

medical steps according to the dose injected. 
 
These instructions for use, handling and disposal should be strictly followed. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET