Dosage and Administration

Information for Prescribing and Practicing Specialists

According to the European Risk Management Plan For Botulinum Toxin Products
Introduction
This brochure contains important information regarding the use of Azzalure® (botulinum
toxin type A) and includes recommendations stated in the Summary of Product
Characteristics for Azzalure®.
Its purpose is to promote:
• Understanding of the mode of action of Azzalure®
• Understanding of potential adverse events associated with remote distribution of effect
of botulinum toxin and risk factors for serious adverse events
• Awareness that botulinum toxin units are not interchangeable from one product to
another
• Appropriate injection technique
• Appropriate reconstitution, dose and treatment intervals
• Education of patients and their caregivers on the following subjects:
• What causes wrinkles
• Various treatments of wrinkles
• The mode of action of botulinum toxin in the treatment of glabellar lines and the
treatment procedure
• The duration of effect and treatment intervals
• The description of the usual side effects of Azzalure®, signs of spread of the
botulinum toxin to distant sites, description of possible severe adverse reactions
observed with botulinum toxin A and risk factors.
• What the patients should do if they experience any of these symptoms
Treating physicians should have the appropriate qualifications and expertise or training in
the use of botulinum toxin type A.
If more copies of this educational material are required please contact Galderma (UK) Ltd,
Tel: +44 1923 208950, Fax: +44 1923 208998
Azzalure® mode of action
When injected into the target muscle, Azzalure® (botulinum toxin type A) binds to the
presynaptic nerve endings, crosses the pre-synaptic nerve membrane and blocks release
of the neurotransmitter acetylcholine. This results in a reversible, inhibition of
neurotransmission at the neuromuscular junction of the injected muscles (1-5)

Azzalure® effect
After injection in the glabellar muscles (corrugators and procerus), moderate to severe
glabellar wrinkles are reduced. The median time to onset of response is 2 to 3 days
following treatment.
An optimal effect was demonstrated for up to 4 months after injection. Some patients were
still responders at 5 months .
The treatment interval depends on the individual patient’s response after assessment.
Treatment interval should not be more frequent than every 3 months (6-10).

Potential risks associated with the use of Azzalure®

The nature of the potential adverse reactions is consistent with the pharmacological action
of botulinum toxin type A and the injection procedure. It can include injection site reactions,
headaches or clinically detectable effects in the muscles adjacent to the target muscles
injected.
Every effort should be made to avoid injection of excess botulinum toxin (i.e. overdosing)
which can bind to sites outside the target area (11-14) or very rarely lead to remote effect
of botulinum toxin A.
Knowledge of facial anatomy, training on the injection of botulinum toxin A in the glabella,
consideration of the patient’s goal, examination of the patient’s facial mimics and wrinkles
and the use of Azzalure® according to the recommendations in the SmPC, i.e., for dose,
product reconstitution and injection sites, will optimise treatment effect and safety.
The most frequently occurring adverse reactions are headache and injection site reactions.
In general, treatment/injection technique related reactions occur within the week following
the injection and are transient.
Ocular Events
Ocular events, which are usually dose- and technique-related, were found in studies in a
very low number of patients. The incidence of eyelid ptosis ranged from 0% to 2.5% and
tended to decrease with repeated treatments.
Eyelid oedema, dry eye and lacrimation could also result from unwanted spread of
botulinum toxin away from the site of injection. Other possible ocular effects are
asthenopia, secondary muscle twitching, visual disturbance, vision blurred, diplopia and
rarely, eye movement disorder.

Systemic Events

Serious adverse events suspected to be related to the remote distribution of

effects of botulinum toxin outside the target tissue have been reported with
all botulinum toxin preparations, including dysphagia and rare cases of
excessive muscle weakness, or aspiration pneumonia.
There have been very rare reports of adverse events with fatal outcome. In
clinical trials conducted with Azzalure® in the treatment of moderate to
severe glabellar lines, there have been no adverse events (serious or non-
serious) suspected to be related to the remote distribution of effects of
botulinum toxin outside the target tissue.
Patients with:
• underlying neurological disorders
• history of swallowing difficulties
• history of breathing difficulties
• history of aspiration
• concomitant drug treatment interfering directly or indirectly with the neuromuscular
function (e.g. aminoglycosides, curare-like non-depolarising blockers) are at increased
risk of these side effects and should be treated with extreme caution and only if the
benefit of the treatment with botulinum toxin is considered to outweigh the risk.
In order to minimize any risk of serious spread reactions of botulinum toxin, it is essential
that the posology, warnings and precautions are strictly followed as stipulated in the
SmPC.
Patients should be informed about the potential risks associated with the use of botulinum
toxin type A, instructed to recognise early signs of important undesirable effects
(difficulties swallowing, speaking, breathing or excessive muscle weakness, allergic
reaction) and urged to seek urgent medical advice if these symptoms are experienced.
They also should be instructed to inform other health professionals about their use of
botulinum toxin type A when seeking treatment for other conditions.
The development of neutralizing antibodies to botulinum toxin type A that could reduce or
abolish response to repeat administrations is extremely rare in indications requiring low
therapeutic doses. However, to reduce the risk of secondary non-response the treatment
interval should not be less than 3 months.
In the event of treatment failure or diminished effect following repeat injections, alternative
treatment methods should be employed. In case of treatment failure after the first
treatment session, the following approaches may be considered:
• Analysis of the causes of failure, e.g. incorrect muscles injected, injection technique,
and formation of toxin-neutralising antibodies;
• Re-evaluation of the relevance of treatment with botulinum toxin A
Adverse event reporting
Please remember that any adverse event following the use of botulinum toxin products
should be reported to the marketing authorisation holder and/or local regulatory
authorities, in the usual way.

For further information, please contact:

Galderma (UK) Ltd.
Phone: +44 1923 208950
Fax: +44 1923 208998

Healthcare professionals are asked to report any suspected adverse reactions via
HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;
Fax: +353 1 6762517. Website:www.hpra.ie; E-mail:[email protected].

Botulinum toxin units are not interchangeable

The potency of Azzalure® is measured in Speywood units and correlates with the efficacy
in clinical use. The units of Azzalure® are specific to its preparation and are not
interchangeable with units of other preparations of botulinum toxins.

Approved indications for Azzalure® in Ireland

Adults
Azzalure® is indicated for the temporary improvement in the appearance of moderate to
severe glabellar lines (vertical lines between the eyebrows) seen at frown, in adult patients
under 65 years, when the severity of these lines has an important psychological impact on
the patient

Children
There is no relevant indication for the use of Azzalure® in patients under the age of 18. The
safety and effectiveness of Azzalure® in individuals under 18 years of age have not been
demonstrated.
Reconstitution, storage and disposal
Reconstitution should be performed in accordance with good practice rules, particularly
in the respect of asepsis.
Azzalure® has to be reconstituted with a sodium chloride 9 mg/ml (0.9%) solution for
injection.
As per the dilution table below, the requested amount of sodium chloride 9 mg/ml (0.9%)
solution for injection has to be drawn up into a syringe in order to obtain a reconstituted
clear solution at a concentration of 10 U/0.05 ml;

Amount of solvent added (0.9% sodium Resulting dose (Units per 0.05 ml)
chloride solution) to a 125 U vial
0.63 ml 10 U
The accurate measurement of 0.63ml can be achieved using 1ml syringes, graduated in
0.1 ml and 0.01 ml increments.
The stopper of the Azzalure® vial should be cleaned with alcohol and then the solvent
introduced slowly into the vial. The vial should be mixed gently to dissolve the vial’s
contents. This provides a clear solution containing 125 Speywood Units of active substance
at a concentration of 10 Speywood U per 0.05ml of reconstituted solution.
Chemical and physical in-use stability has been demonstrated for 24 hours between
2-8°C. From a microbiological point of view, unless the method of reconstituting precludes
the risks of microbial contamination, the product should be used immediately.
If not used immediately, in-use storage times and conditions are the responsibility of the
user. Azzalure® should not be frozen.
Once reconstituted, Azzalure® should only be used to treat a single patient, during a single
session.

Recommendations for the disposal of contaminated materials

Immediately after use and prior to disposal, unused reconstituted Azzalure® (in the vial
or in the syringe) should be inactivated with 2ml of dilute sodium hypochlorite solution at
0.55 or 1% (bleach).
Used vials, syringes and materials should not be emptied and must be discarded into
appropriate containers and disposed of in accordance with local requirements.
Recommendations should any incident occur during the
handling of botulinum toxin
• Any spills of the product must be wiped up: either using absorbent material impregnated
with a solution of sodium hypochlorite (bleach) in case of the powder, or with dry,
absorbent material in case of reconstituted product.
• The contaminated surfaces should be cleaned using absorbent material impregnated
with a solution of sodium hypochlorite (bleach), then dried.
• If a vial is broken, proceed as mentioned above by carefully collecting the pieces of
broken glass and wiping up the product, avoiding any cuts to the skin.
• If the product comes into contact with the skin, wash the affected area with a solution
of sodium hypochlorite (bleach) then rinse abundantly with water.
• If product enters into contact with the eyes, rinse thoroughly with plenty of water or with
an ophthalmic eyewash solution.
• If product enters into contact with a wound, cut or broken skin, rinse thoroughly with
plenty of water and take the appropriate medical steps according to the dose injected.

Dosage and administration of Azzalure®

• Botulinum toxin units are different depending on the medicinal products. The Speywood
units of Azzalure® are specific to the preparation and are not interchangeable with
other preparations of botulinum toxin.
• Azzalure® should only be administered by physicians with appropriate qualifications
and expertise in this treatment and having the required equipment.
• The dosage regimen recommended in the SmPC should be followed. Treatment should
be repeated as required to prevent recurrence of the symptoms, but no more frequently
than recommended in the SmPC.
Treatment of moderate to severe glabellar lines
with Azzalure®
Administration instructions:
• Remove the make-up and disinfect the skin with a local antiseptic.
• Intramuscular injections should be performed at right angles to the skin using a sterile
29-30 gauge needle.
• The recommended dose is 50 Speywood units (0.25 ml of the reconstituted solution) of
Azzalure® to be divided into 5 injection sites, 10 Speywood units (0.05 ml of the
reconstituted solution) are to be administered intramuscularly into each of the 5 sites:
2 injections into each corrugator muscle and one into the procerus muscle near the
nasofrontal angle as shown below:
1cm

1cm

• The anatomical landmarks can be more readily identified if observed and palpated at
maximal frown. Before injection, place the thumb or index finger firmly below the
orbital rim in order to prevent extravasation below the orbital rim. The needle should
be pointed upward and medially during the injection. In order to reduce the risk of
ptosis, avoid injections near the levator palpebrae superioris muscle, particularly in
patients with larger brow-depressor complexes (depressor supercilii). Injections in the
corrugator muscle must be made into the central part of that muscle, at least 1 cm
above the orbital rim.
• The physician must ensure that he avoids intravascular injection.
Planning of a detailed discussion with the patients
and their caregivers on the benefit/risk ratio, potential
risks and availability of the educational material
for patients
Before starting treatment with Azzalure® the patient must be informed about
• The causes of glabellar lines
• The alternative and complementary treatment options available
• The treatment objectives and expected outcome
• Possible side effects and known risk factors, i.e. the benefit/risk ratio.
• Who to inform and what to do when the patient experiences a side effect to
botulinum toxin

Further information regarding the use and safety

of Azzalure®
For further information, please contact:
Galderma (UK) Ltd.
Phone: +44 1923 208950
Fax: +44 1923 208998
References
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course of tissue distribution. Toxicon 2003;42:461-469.
2. Tang-Liu DD, Aoki KR, Dolly JO, et al. Intramuscular injection of 125I-botulinum neurotoxin-
complex versus 125I botulinum-free neurotoxin: time course of tissue distribution. Toxicon
2003;42:461-469.
3. Poulain B, Popoff M, Molgo J. How do botulinum neurotoxins block neurotransmitter release: from
botulism to the molecular mechanism of action. The Botulinum J 2008;1:14-87.
4. Rogozhin AA, Pang KK, Bukharavea E. Recovery of mouse neuromuscular junctions from single
and repeated injections of botulinum neurotoxin A. J Physiol 2008;586;3163-3182.
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editors. Handbook of Botulinum Toxin Treatment. 2nd Ed. Blackwell Science 2003.
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of botulinum toxin type A for the treatment of glabellar lines: determination of optimal dose.
Dermatol Surg 2007;33(1):S51-9.
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controlled study of efficacy and safety of three doses of botulinum toxin A in the treatment of
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scheduling the next injection. Aesth Surg J 2005;365-376.
9. Rzany B, Ascher B, Fratila A, et al. Efficacy and safety of 3- and 5-injection patterns (30 and 50 U)
of botulinum toxin A (Dysport) for the treatment of wrinkles in the glabella and the central forehead
region. Arch Dermatol 2006;142(3):320-326.
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lines in the upper face: a retrospective study of 103 treatments in 945 patients. Dermatol Surg
2007;33(1):S18-25.
11. Elson ML. Evaluation and treatment of the aging face. In: Evaluation and Treatment of the Aging
Face, Elson M, ed. Springer-Verlag, New York, 1995, 1-9.
12. Borodic, GE, R Ferrante, LB Pearce, et al. Histologic assessment of dose-related diffusion and
muscle fiber response after therapeutic botulinum A toxin injections. Mov Disord, 1994. 9(1):31-9
13. Shaari, CM and I Sanders. Quantifying how location and dose of botulinum toxin injections affect
muscle paralysis. Muscle Nerve, 1993. 16(9):964-9
14. Eleopra R, Tugnoli V, Caniatti L, De Grandis D. Botulinum toxin treatment in the facial muscles of
humans: evidence of an action in untreated near muscles by peripheral diffusion. Neurology
1996;46:1158-1160.
AZZ/026/0415a(1)
Date of preparation: November 2015