Botox

Package leaflet: Information for the user

BOTOX 100 Allergan Units, powder for solution for injection, 200 Allergan Units, powder for solution for injection

botulinum toxin type A
Read this leaflet carefully before using this medicine because it contains important information for you

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet

1. What BOTOX is and what it is used for
2. What you need to know before using BOTOX
3. How to use BOTOX
4. Possible side effects
5. How to store BOTOX
6. Contents of the pack and other information

1. What BOTOX is and what it is used for

BOTOX is a muscle-relaxing medicine used to treat a number of conditions in the body.
It contains the active substance botulinum toxin type A and is injected either into muscles, into the bladder wall, or subcutaneously.
It works by partially blocking nerve impulses to each muscle into which it is injected, thereby reducing excessive muscle contractions.
When injected subcutaneously, BOTOX acts on the sweat glands to reduce the amount of sweat produced.
When injected into the bladder wall, BOTOX acts on the bladder muscles to reduce urine leakage (urinary incontinence). In the case of chronic migraine, it is believed that BOTOX can block pain signals, indirectly preventing the development of migraine. However, the exact mechanism of action of BOTOX in chronic migraine has not been fully elucidated.

1. BOTOX can be injected directly into muscles and is used to treat the following conditions:

• Persistent muscle spasms in the legs of children aged 2 years and older with cerebral palsy who are able to walk, to control foot deformity caused by persistent leg muscle spasms
• Persistent muscle spasms in the wrist and hand in adult patients who have had a stroke
• Persistent muscle spasms in the ankle in adult patients who have had a stroke
• Persistent muscle spasms in the eyelids and face in adult patients
• Persistent muscle spasms in the neck and shoulders in adult patients

2. BOTOX is used to reduce the symptoms of chronic migraine in adults who experience headaches on 15 or more days per month, with at least 8 of those days involving migraine, and who have not responded adequately to other anti-migraine medications used for prophylaxis.
   Chronic migraine is a disorder affecting the nervous system. Patients typically experience head pain, often accompanied by increased sensitivity to light, loud sounds, or perfumes/odors, as well as nausea and/or vomiting. These headaches occur on 15 or more days per month.

3. When injected into the bladder wall, BOTOX acts on the bladder muscles to reduce urine leakage (urinary incontinence) and is used to manage the following conditions in adults:

• Overactive bladder with urinary incontinence – sudden urge to empty the bladder and need to urinate more frequently than normal – when other medications (called anticholinergics) have not been effective
• Urinary incontinence due to bladder disorders associated with spinal cord injury or multiple sclerosis

4. In adults, BOTOX can be injected subcutaneously and acts on the sweat glands to reduce excessive sweating of the armpits that interferes with normal daily activities, when other topical treatments have not been effective.

2. What you should know before using BOTOX

Do not use BOTOX

• if you are allergic (hypersensitive) to botulinum toxin type A or to any of the excipients of this medicine (listed in section 6)
• if you have an infection at the proposed injection site
• if you are being treated for urinary incontinence and develop a urinary tract infection or experience sudden inability to empty your bladder (and you do not regularly use a catheter)
• if you are being treated for urinary incontinence and do not intend to use a catheter, if required.

Warnings and precautions
Talk to your doctor or pharmacist before using BOTOX if:

• you have ever had difficulty swallowing or accidental aspiration of food or liquids into the lungs, especially if you are being treated for persistent muscle spasms in the neck and shoulders
• you are over 65 years old and have other serious medical conditions
• you suffer from any other muscle disorder or chronic muscle disease (such as myasthenia gravis or Lambert-Eaton syndrome)
• you suffer from certain neurological disorders (such as amyotrophic lateral sclerosis or motor neuropathy)
• there is significant muscle weakness or loss of muscle tone at the site where the doctor intends to inject
• you have had any surgery or injury that may have altered the muscle to be injected
• you have previously experienced problems with injections (such as fainting)
• you have inflammation in the muscles or in the skin area where the doctor intends to inject
• you suffer from cardiovascular conditions (diseases of the heart or blood vessels)
• you suffer from or have suffered from seizures
• you have an eye condition called glaucoma (high pressure in the eye) of the closed-angle type, or have been told you are at risk of developing this type of glaucoma
• you are about to be treated for overactive bladder with urinary incontinence and you are a man showing signs and symptoms of urinary obstruction, such as difficulty passing urine, weak or interrupted urine flow.

After being treated with BOTOX
You, or your caregiver, must contact your doctor and seek immediate medical attention if any of the following occur:

• difficulty breathing, swallowing, or speaking
• hives, swelling including swelling of the face or throat, wheezing, feeling faint, or shortness of breath (possible symptoms of a severe allergic reaction).

General precautions
As with any injection, the procedure may lead to infection, pain, swelling, abnormal skin sensations (e.g., tingling or numbness), reduced skin sensation, soreness, redness, bleeding/bruising at the injection site, and low blood pressure or fainting; this may result from pain and/or anxiety associated with the injection.
Adverse effects possibly related to the spread of the toxin away from the injection site have been reported with botulinum toxin (e.g., muscle weakness, difficulty swallowing, or accidental aspiration of food or liquid into the airways). These adverse reactions can range from mild to severe, may require treatment, and in some cases may be fatal. This is a particular risk for patients with underlying conditions that make them susceptible to these symptoms.
Severe and/or immediate allergic reactions have been reported, with symptoms possibly including hives, facial or throat swelling, shortness of breath, wheezing, and fainting. Delayed allergic reactions (serum sickness) have also been reported, which may include symptoms such as fever, joint pain, and skin rash.
Cardiovascular system-related adverse effects, including irregular heartbeat and heart attacks, have also been observed in patients treated with BOTOX, sometimes with fatal outcomes. However, some of these patients had pre-existing cardiac risk factors.
Seizures have been reported in adults and children treated with BOTOX, particularly in patients already predisposed to seizures. It is not known whether BOTOX is the cause of these seizures. Seizures reported in children have mostly occurred in patients with cerebral palsy treated for persistent muscle spasms in the legs.
If you are treated with BOTOX too frequently or at too high a dose, you may experience muscle weakness and adverse effects related to toxin spread, or your body may start producing antibodies that could reduce the effectiveness of BOTOX.
When BOTOX is used to treat a condition not listed in this leaflet, it may cause serious reactions, particularly in patients who already have difficulty swallowing or are significantly weakened.
If you have not engaged in much physical activity for a long time before receiving BOTOX treatment, any physical activity should be resumed gradually after treatment.
It is unlikely that this medicine will improve joint mobility when the surrounding muscle has lost its ability to stretch.
BOTOX should not be used to treat persistent muscle spasms in the ankle in adults after stroke if no improvement in function (e.g., walking) or symptoms (e.g., pain) is expected, or if it does not assist in patient care. If the stroke occurred more than 2 years ago or if the ankle muscle spasm is less severe, improvement in activities such as walking may be limited. Additionally, for patients at higher risk of falling, your doctor will assess whether treatment is appropriate.
BOTOX should only be used to treat post-stroke ankle muscle spasms after evaluation by a doctor experienced in managing post-stroke rehabilitation.
When BOTOX is used to treat persistent muscle spasms of the eyelid, it may reduce blinking, which could damage the eye surface. To prevent this, treatment with eye drops, ointments, soft contact lenses, or even protective devices to cover the eye may be necessary. Your doctor will advise you if this is needed.
When BOTOX is used to control urinary leakage, your doctor will administer antibiotics before and after treatment to prevent urinary tract infections.
Your doctor will schedule a follow-up visit approximately 2 weeks after the injection, especially if you did not use a catheter before the injection. At that visit, you will be asked to urinate, and the total volume of residual urine in the bladder will be measured by ultrasound. Your doctor will decide whether you need to return for the same test within the following 12 weeks. Contact your doctor immediately if at any time you are unable to urinate, as you may need to start using a catheter. In patients with urinary incontinence due to bladder disorders associated with spinal cord injury or multiple sclerosis, about one-third of those who did not use a catheter before treatment may need to use one after treatment. In patients with urinary incontinence due to overactive bladder, about 6 out of 100 patients may need to use a catheter after treatment.

Other medicines and BOTOX
Tell your doctor or pharmacist if:

• you are taking antibiotics (used to treat infections), anticholinesterase drugs, or muscle relaxants. Some of these medicines can increase the effect of BOTOX.
• you have recently received treatment with a medicine containing botulinum toxin (the active substance in BOTOX), as this could greatly increase the effect of BOTOX.
• you are using any antiplatelet agents (aspirin-like products) and/or anticoagulants (blood thinners).

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

Pregnancy and breastfeeding
BOTOX should not be used during pregnancy or in women of childbearing potential who are not using contraception, unless clearly needed. BOTOX is not recommended for use in women who are breastfeeding.
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before using this medicine.

Driving and using machines
BOTOX may cause dizziness, drowsiness, fatigue, or vision problems. If you experience any of these effects, do not drive or operate machinery. If in doubt, ask your doctor.

BOTOX contains sodium
This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e., essentially 'sodium-free'.

3. How to use BOTOX

BOTOX must be injected only by physicians with specific expertise and experience in the use of this medicine.
BOTOX should be prescribed for chronic migraine only if you have been diagnosed with this condition by a neurologist, a specialist in this field. BOTOX must be administered under the supervision of a neurologist. BOTOX is not used for acute migraine, chronic tension-type headaches, or in patients with medication-overuse headaches.

Method and route of administration
BOTOX is injected into muscles (intramuscularly), into the bladder wall using a specific instrument (cystoscope) for bladder injection, or into the skin (intradermally). It is injected directly into the affected area; usually, the physician will inject BOTOX at multiple sites within each affected area.

General dosing information

• The number of injections per muscle and the dose vary depending on the indication. However, your doctor will decide how much to administer, how often, and into which muscle(s) to inject BOTOX. Physicians are advised to use the lowest effective dose.
• Dosing for elderly patients is the same as for adults.

The dosage of BOTOX and the duration of its effect vary depending on the disorder being treated. Details for each disorder are provided below.
The safety and efficacy of BOTOX have been established in children and adolescents from 2 years of age onwards for the treatment of foot deformity caused by muscle spasms in the legs associated with Cerebral Palsy.

Foot deformity caused by muscle spasms in the legs of children affected by Cerebral Palsy

2 years

Limited information is available regarding the use of BOTOX in the following conditions in children/adolescents within the age ranges listed in the table below. No dosage recommendations can be made for these indications.

Persistent muscle spasms in the eyelids and face	12 years
Persistent muscle spasms in the neck and shoulders	12 years
Excessive underarm sweating	12 years (limited experience in adolescents aged 12–17 years)
Neurogenic overactivity of the detrusor muscle in pediatric age	5–17 years
Overactive bladder in pediatric age	12–17 years

Dosage

Indication	Maximum dose (Units per affected area)		Minimum time between treatments
	Initial treatment	Subsequent treatments
Chronic lower limb muscle spasms in children with cerebral palsy	4 Units/kg (hemiplegia) 6 Units/kg (diplegia)	4 Units/kg (hemiplegia) 6 Units/kg (diplegia)	3 months*
Chronic muscle spasms in the wrist and hand in post-stroke patients	The exact dose and number of injection sites per hand/wrist are individually adjusted according to patient needs, up to a maximum of 240 Units	The exact dose and number of injection sites are individually adjusted according to patient needs, up to a maximum of 240 Units	12 weeks
Chronic muscle spasms in the ankle in post-stroke patients	Your doctor will perform multiple injections into the affected muscles. The total dose is 300 Units divided among 3 muscles per treatment session	The total dose is 300 Units divided among 3 muscles per treatment session	12 weeks
Chronic muscle spasms of the eyelids and face	1.25–2.5 Units per injection site. Up to 25 Units per eye for eye spasms.	Up to 100 Units for eye spasms.	3 months for eye spasms.
Chronic muscle spasms of the neck and shoulders	200 Units. No more than 50 Units should be injected at each site.	Up to 300 Units	10 weeks
Headaches in adults with chronic migraine	155 to 195 Units. No more than 5 Units should be injected at each site.	155 to 195 Units	12 weeks
Overactive bladder with urinary incontinence	100 Units	100 Units	3 months
Urinary incontinence due to neurogenic detrusor overactivity associated with spinal cord injury or multiple sclerosis in adults	200 Units	200 Units	3 months
Excessive underarm sweating	50 Units per armpit	50 Units per armpit	16 weeks

*The physician may determine a dosing regimen that justifies treatments up to 6 months apart.

Onset of improvement and duration of effect

For persistent leg muscle spasms in children with cerebral palsy, improvement is generally observed within the first 2 weeks after injection.

For persistent wrist and hand muscle spasms in patients who have suffered a stroke, improvement is generally observed within the first 2 weeks after injection. Maximum effect is usually seen between 4 and 6 weeks after treatment.

For persistent ankle muscle spasms in patients who have suffered a stroke, when the effect begins to wear off, treatment may be repeated, but no more frequently than once every 12 weeks.

For persistent eyelid and facial muscle spasms, improvement is generally observed within 3 days after injection. Maximum effect is usually seen 1 to 2 weeks after treatment.

For persistent neck and shoulder muscle spasms, improvement is generally observed within 2 weeks after injection. Maximum effect is usually seen approximately 6 weeks after treatment.

For urinary incontinence due to overactive bladder, improvement is generally observed within 2 weeks after injection. The effect generally lasts about 6–7 months after injection.

For urinary incontinence due to bladder disorders associated with spinal cord injury or multiple sclerosis, improvement is generally observed within 2 weeks after injection. The effect generally lasts about 8–9 months after injection.

For excessive underarm sweating, improvement is generally observed within the first week after injection.

The effect usually lasts on average 7.5 months after the first injection, and approximately 1 in 4 patients still shows treatment effect after one year.

If you receive more BOTOX than you should

Signs of BOTOX overdose may not appear for several days after injection. If you have ingested BOTOX or it has been accidentally injected, you must contact your doctor, who may monitor you for several weeks.

If you have received an excessive dose of BOTOX, you may experience one or more of the following symptoms, and in such case you should contact your doctor immediately. The doctor will assess whether hospitalization is necessary:

• muscle weakness, which may be localized or distant from the injection site
• difficulty breathing, swallowing, or speaking due to muscle paralysis
• food or liquids accidentally entering the lungs, which may cause pneumonia (lung infection) due to muscle paralysis
• drooping eyelids, double vision
• general weakness.

If you have any doubts about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
In general, side effects occur within the first few days of treatment. These usually last only a short time but may persist for several months and, in rare cases, even longer.
Contact your doctor immediately if:

• you have any difficulty breathing, swallowing, or speaking after receiving BOTOX
• you develop hives, swelling including swelling of the face or throat, wheezing, feeling faint, or shortness of breath.

Side effects are classified into the following categories depending on how often they occur:

Very common	may affect more than 1 in 10 people
Common	may affect up to 1 in 10 people
Uncommon	may affect up to 1 in 100 people
Rare	may affect up to 1 in 1,000 people
Very rare	may affect up to 1 in 10,000 people
Not known	cannot be estimated from the available data

Below are listed the adverse effects that vary depending on the part of the body where BOTOX is injected. If you experience any adverse effect, including those not listed in this leaflet, contact your doctor or pharmacist.
Injections in the legs in children with cerebral palsy

Very common	Viral infection, ear infection
Common	Somnolence, gait disturbance, numbness or tingling, rash, muscle pain, muscle weakness, pain in extremities such as hands and fingers, urinary incontinence (urine leakage), feeling of general discomfort, injection site pain, feeling of weakness, falls.

There have been rare reports of death following treatment with BOTOX, sometimes associated with aspiration pneumonia in children with severe cerebral palsy.

Injections in the wrist and hand in patients who have had a stroke

Common

Pain in hands and fingers, nausea, swelling of extremities such as hands and feet, fatigue, muscle weakness

Ankle injections in adult patients affected by stroke

Common

Skin rash, joint pain or inflammation, muscle stiffness or soreness, swelling of the extremities such as hands and feet.

Injections in the eyelid and face

Very common	Drooping of the eyelid.
Common	Localized corneal damage (transparent surface covering the front of the eye), difficulty closing the eye completely, dry eyes, light sensitivity, eye irritation, excessive tearing, bruising under the skin, skin irritation, facial swelling.
Uncommon	Dizziness, weakness of facial muscles, relaxation of muscles on one side of the face, inflammation of the cornea (transparent surface covering the front of the eye), abnormal inward or outward movement of the eyelids, double vision, visual disturbances, blurred vision, rash, fatigue.
Rare	Swelling of the eyelid.
Very rare	Ulcer, corneal damage (transparent surface covering the front of the eye).

Injections in the neck and shoulder

Very common	Difficulty in swallowing, muscle weakness, pain
Common	Swelling and irritation of upper airways (rhinitis), nasal congestion or rhinorrhea, cough, sore throat, throat tickle or irritation, dizziness, increased muscle tension (cramps), reduced skin sensitivity, somnolence, headache,
	dry mouth, feeling of nausea, muscle stiffness or soreness, feeling of weakness, influenza-like syndrome, feeling of general malaise.
Uncommon	Double vision, fever, drooping of the eyelid, shortness of breath, change in voice.

Injections in the head and neck for the treatment of headache in patients suffering from
chronic migraine

Common	Headache, migraine, worsening of migraine, facial muscle weakness, skin rash, itching, neck pain, muscle pain, muscle spasm, muscle stiffness, muscle tenderness, muscle weakness, injection site pain.
Uncommon	Difficulty swallowing, skin pain, jaw pain.
Not known	Mefisto sign (elevation of the outer part of the eyebrows).

Injections into the bladder wall for urinary incontinence due to overactive bladder

Very common	Urinary tract infections, painful urination after injection*.
Common	Bacteria in urine, inability to empty the bladder (urinary retention), incomplete bladder emptying, frequent urination during the day, white blood cells in urine, blood in urine after injection**.

This adverse effect may also be related to the injection procedure.
This adverse effect is related only to the injection procedure.
Injections into the bladder wall for urinary incontinence due to overactive bladder in pediatric patients

Common

Urinary tract infections, painful urination after injection*, urethral pain (the duct carrying urine from the urinary bladder to the outside of the body)*, abdominal pain, lower abdominal pain

*This adverse effect is related only to the injection procedure.
Injections into the bladder wall of adult patients for urinary incontinence due to neurogenic
bladder associated with spinal cord injury or multiple sclerosis

Very common

Urinary tract infections, inability to empty the bladder (urinary retention).

Common

Difficulty falling asleep (insomnia), constipation, muscle weakness, muscle spasm, blood in the urine after injections*, painful urination after injections*, swelling in the bladder wall (bladder diverticulum), fatigue, problems with walking (gait disturbances), possible uncontrolled reflex reaction of the body (such as excessive sweating, pounding headache, or increased heart rate) occurring around the time of injections (autonomic dysreflexia)*, falls.

*Some of these common adverse reactions may also be related to the injection procedure.
Injections into the bladder wall of pediatric patients for urinary incontinence due to bladder disorders associated with spina bifida, spinal cord injury, or transverse myelitis

Very common	Bacteria in urine
Common	Urinary tract infection, white blood cells in urine, blood in urine after injection, bladder pain after injection*

*This adverse effect is related only to the injection procedure.
Injections for excessive underarm sweating

Very common	Pain at injection site.
Common	Headache, numbness or tingling, hot flushes, increased sweating in areas other than the armpit, abnormal skin odour, itching, swelling under the skin, hair loss, pain in extremities such as hands and fingers, pain, reactions and swelling, bleeding or burning, and increased sensitivity at injection site, generalized weakness.
Uncommon	Nausea, muscle weakness, feeling of weakness, muscle pain, joint problems.

The following list includes additional adverse reactions reported with the use of BOTOX, used for
any condition, since it has been marketed:

• allergic reaction, including protein or serum injection reactions
• swelling of the deeper layers of the skin
• urticaria, pruritus
• eating disorders, loss of appetite
• nerve damage (brachial plexopathy)
• voice and speech problems
• weakness of facial muscles, drooping of muscles affecting part of the face
• reduced skin sensitivity
• muscle weakness
• chronic muscle disease (myasthenia gravis)
• difficulty in movement of arms and shoulders
• numbness or tingling
• pain/numbness/or weakness originating from the spine
• seizures and fainting
• increased eye pressure
• strabismus (crossed eyes)
• blurred vision
• difficulty seeing clearly
• hearing loss, tinnitus
• sensation of dizziness or spinning (vertigo)
• cardiac problems (including heart attacks)
• aspiration pneumonia (lung inflammation caused by accidental aspiration of food, drinks, saliva, or vomit)
• breathing difficulties, respiratory depression and/or respiratory failure
• abdominal pain, nausea, vomiting
• diarrhea, constipation
• dry mouth
• difficulty in swallowing
• hair loss
• different types of red patchy skin rashes
• excessive sweating
• loss of eyelashes/eyebrows
• muscle pain, loss of innervation to/contraction of the injected muscle
• general feeling of malaise
• fever
• dry eye (associated with injections around the eyes)
• localized muscle contractions/involuntary muscle contractions
• eyelid swelling

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, consult your doctor.
You can also report adverse reactions directly through the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. How to store BOTOX

Keep this medicine out of the sight and reach of children.
The physician must not use BOTOX after the expiry date stated on the label after Exp.
The expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C), or in a freezer (from -5°C to -20°C).
After reconstitution, immediate use of the solution is recommended; however, the product may be
stored for up to 24 hours in a refrigerator (2°C - 8°C).

6. Package contents and other information

What BOTOX contains

• The active substance is: botulinum toxin type A from Clostridium botulinum. Each vial contains 50, 100 or 200 Allergan Units of botulinum toxin type A.
• The other ingredients are human albumin and sodium chloride.

Description of the appearance of BOTOX and contents of the pack
BOTOX powder for solution for injection (powder for injection) is presented as a fine white powder
which may be difficult to see at the bottom of a clear glass vial. Before injection, the product must be reconstituted using sterile 0.9% sodium chloride solution free of preservatives.
Pack sizes may contain 1, 2, 3, 6 or 10 vials.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
AbbVie S.r.l.
S.R. 148 Pontina km 52 snc
04011 Campoverde di Aprilia (LT)
Italy

Manufacturer
Allergan Pharmaceuticals Ireland
Castlebar Road
Westport
County Mayo
Ireland
or
AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany

Other sources of information
To request a copy of this package leaflet in an enlarged print version, please contact the Marketing Authorisation Holder.

The following information is intended for healthcare professionals only:

Refer to the Summary of Product Characteristics for complete prescribing information for BOTOX.
Botulinum toxin units are not interchangeable between products. The recommended doses in Allergan Units differ from those of other botulinum toxin preparations.
BOTOX must be administered only by physicians with appropriate qualifications and expertise in the treatment and use of the necessary equipment.
Diagnosis of chronic migraine and administration of BOTOX must be performed only under the supervision of neurologists experienced in the treatment of chronic migraine.
The safety and efficacy of BOTOX for indications other than those described for the pediatric population in section 4.1 of the Summary of Product Characteristics have not been established.
No dosage recommendations can be made for indications other than focal spasticity associated with cerebral palsy in pediatric patients. The currently available data by therapeutic indication are described in sections 4.2, 4.4, 4.8 and 5.1 of the Summary of Product Characteristics, as shown in the following table.

Blepharospasm / Hemifacial spasm	12 years (see sections 4.4 and 4.8)
Cervical dystonia	12 years (see sections 4.4 and 4.8)
Focal spasticity associated with cerebral palsy in pediatric patients	2 years (see sections 4.2, 4.4 and 4.8)
Primary axillary hyperhidrosis	12 years (limited experience in adolescents aged 12 to 17 years, see sections 4.4, 4.8 and 5.1)
Neurogenic detrusor overactivity in pediatric patients	5–17 years (see sections 4.8 and 5.1)
Overactive bladder in pediatric patients	12–17 years (see sections 4.8 and 5.1)

No specific dose adjustment is required for use in the elderly. The initial dose should be the lowest recommended dose for the specific indication. For repeated injections, it is recommended to administer the lowest effective dose at the longest clinically appropriate interval between treatments. Particular caution should be exercised in elderly patients with significant medical history and those receiving concomitant treatment with other medicinal products.

Optimal regimens regarding dosage and number of injection sites for each muscle have not been established for all indications. In such cases, individual treatment regimens must be established by the physician. Optimal dosage levels should be determined by titration, but the maximum recommended dose must not be exceeded.

As with any pharmacological treatment, the initial dose in a new patient should be the lowest effective dose.

Dosage and method of administration (refer to sections 4.2 and 4.4 of the SmPC for further information).
Focal spasticity associated with cerebral palsy in children:

Muscles	Dose
Medial and lateral heads of the affected gastrocnemius muscle.	Hemiplegia: recommended initial dose of 4 Units/kg body weight in the affected limb. Diplegia: recommended initial dose of 6 Units/kg body weight divided between the affected limbs. The total dose must not exceed 200 Units.

Focal spasticity of the upper and lower limbs associated with stroke:
BOTOX is a treatment for focal spasticity studied only in association with other standard care regimens, and is not intended to replace such therapies. BOTOX is unlikely to be effective in improving range of motion in a joint affected by fixed contracture.
Focal spasticity of the upper limb associated with stroke:

Muscles	Recommended dose; number of sites
Forearm Pronator quadratus	10 - 50 Units; 1 site
Wrist Flexor carpi radialis Flexor carpi ulnaris	15 - 60 Units; 1-2 sites 10 - 50 Units; 1-2 sites
Fingers/hand Flexor digitorum profundus Flexor digitorum superficialis Lumbricals* Interossei*	15 - 50 Units; 1-2 sites 15 - 50 Units; 1-2 sites 5 - 10 Units; 1 site 5 - 10 Units; 1 site
Thumb Adductor pollicis Flexor pollicis longus Flexor pollicis brevis Opponens pollicis	20 Units; 1-2 sites 20 Units; 1-2 sites 5 - 25 Units; 1 site 5 - 25 Units; 1 site

• When injected into the lumbricals and/or interossei, the maximum recommended dose is 50 U per
  hand.
  The recommended dose for the treatment of adults with upper limb spasticity is up to 240 Units
  divided among the affected muscles, as reported in the table above. The maximum dose in a single
  treatment is 240 Units.
  The exact dosage and the number of injection sites should be adjusted according to individual needs,
  depending on the size, number, and location of the involved muscles, the severity of spasticity, any
  local muscle weakness, and the patient's response to previous treatment.
  Focal spasticity of the lower limb associated with cerebral stroke:

Muscles	Recommended dose Total dose; number of sites
Gastrocnemius Medial head Lateral head	75 Units; 3 sites 75 Units; 3 sites
Soleus	75 Units; 3 sites
Posterior tibialis	75 Units; 3 sites

The recommended dose for the treatment of adults with lower limb spasticity involving the
ankle is 300 Units divided among 3 muscles.
Blepharospasm/hemifacial spasm:

Target Muscles

Dose

Medial and lateral regions of the upper eyelid orbicularis oculi muscle and lateral region of the lower eyelid orbicularis oculi muscle. Additional injection sites may be used in the eyebrow area, lateral orbicularis region, and upper face if spasms in these areas interfere with vision. Patients with hemifacial spasm or facial nerve (VII cranial nerve) disorders should be treated similarly to those with unilateral blepharospasm, with additional injections administered as needed into other affected facial muscles (e.g., zygomaticus major, orbicularis oris).

Recommended initial dose: 1.25 - 2.5 Units injected into the medial and lateral regions of the upper eyelid orbicularis oculi muscle and lateral region of the lower eyelid orbicularis oculi muscle. The initial dose should not exceed 25 Units per eye. The total dose should not exceed 100 Units every 12 weeks.

Reduced blinking caused by injection of botulinum toxin into the orbicularis muscle may lead to corneal pathology. A careful assessment of corneal sensitivity should be performed in previously operated eyes, injection into the lower eyelid area should be avoided to prevent ectropion, and effective treatment of epithelial defects should be implemented. This may require the use of eye drops, ophthalmic ointments, soft therapeutic contact lenses, or eye closure by taping or other means.
Cervical dystonia:

Muscles	Dose
Sternocleidomastoid, scapular elevator, scalene, splenius capitis, semispinalis, longissimus and/or trapezius muscle(s).	No more than 50 Units should be administered at each site. No more than 100 Units should be injected into the sternocleidomastoid muscle. No more than a total of 200 Units should be administered in the first treatment cycle, with appropriate dosage adjustments in subsequent cycles based on the initial response. The total dose of 300 Units per single session must not be exceeded.

The list of muscles is not exhaustive, as any muscle involved in controlling head position may be implicated and therefore require treatment.

Chronic Migraine
The recommended dose of reconstituted BOTOX for the treatment of chronic migraine ranges between 155 Units and 195 Units administered intramuscularly using a 30 gauge 0.5 inch needle, with 0.1 ml injections (5 Units) given at 31 to 39 sites. Injections should be distributed across 7 specific head/neck muscle areas, as indicated in the table below. A 1 inch needle may be required in the cervical region for patients with extremely thick neck muscles. Except for the procerus muscle, which requires injection at one site (midline), all other muscles should be treated bilaterally, with half of the injections administered on the left and half on the right side of the head and neck. In cases of predominant pain location(s), additional injections may be administered on one or both sides to up to 3 specific muscle groups (occipital, temporal, and trapezius), up to the maximum dose per muscle as specified in the table below.

	Recommended dose
Head/neck area	Total dosage (number of sites)
Corrugator muscleb	10 Units (2 sites)
Procerus muscle	5 Units (1 site)
Frontal muscleb	20 Units (4 sites)
Temporal muscleb	40 Units (8 sites) up to 50 Units (up to 10 sites)
Occipital muscleb	30 Units (6 sites) up to 40 Units (up to 8 sites)
Cervical paraspinal muscle groupb	20 Units (4 sites)
Trapezius muscleb	30 Units (6 sites) up to 50 Units (up to 10 sites)
Total dose range:	From 155 Units to 195 Units From 31 to 39 sites

1 IM injection site = 0.1 ml = 5 Units of BOTOX
Dose distributed bilaterally
Urinary incontinence due to overactive bladder
The recommended dose is 100 Units of BOTOX, i.e. 0.5 ml (5 Units) injections into 20 sites of the
detrusor muscle, avoiding the trigone and the base.
Urinary incontinence due to neurogenic detrusor overactivity:
The recommended dose is 200 Units of BOTOX, i.e. 1 ml (~6.7 Units) injections into 30 sites of the
detrusor muscle, avoiding the trigone and the base.
Primary axillary hyperhidrosis:

Inoculation sites	Dose
At multiple sites approximately 1-2 cm apart, in the hyperhidrotic area of each axilla.	Doses higher than 50 Units per axilla have not been studied and therefore cannot be recommended.

The patient's medical history and physical examination, along with any additional tests deemed necessary, must be performed in order to exclude potential causes of secondary hyperhidrosis (e.g., hyperthyroidism, pheochromocytoma). This will prevent symptomatic treatment of hyperhidrosis without diagnosis and/or treatment of underlying diseases.

For all indications:

Adverse effects due to the spread of the toxin away from the injection site have been reported, sometimes resulting in death, in some cases associated with dysphagia, pneumonia and/or significant debilitation. The symptoms are related to the mechanism of action of botulinic toxin and have been reported hours to weeks after injection. The risk of such symptoms is probably greater in patients with underlying conditions or comorbidities that may predispose them to these symptoms, including children and adults treated for spasticity, particularly when treated with high doses.

Patients receiving therapeutic doses may also experience exaggerated muscle weakness.

Pneumothorax associated with the injection procedure has been reported following administration of BOTOX near the chest. Care must be taken when injecting near the lungs, particularly in the apical region, or near other vulnerable anatomical structures. Serious adverse reactions, including fatal outcomes, have been reported in patients who received off-label injections of BOTOX directly into the salivary glands, the oro-lingual-pharyngeal region, the esophagus, and the stomach. Some patients had pre-existing dysphagia or significant debilitation.

Rare spontaneous reports of death, sometimes associated with aspiration pneumonia, have been reported in children with severe cerebral palsy following treatment with botulinum toxin, including cases of off-label use (e.g., neck area). Extreme caution must be exercised when treating patients who have significant neurological weakness, dysphagia, or who have recently experienced aspiration pneumonia or pulmonary disease. Treatment in patients with a precarious underlying health status should only be performed if the potential benefit to the patient is considered to outweigh the risks.

Very rarely, an anaphylactic reaction may occur after injection of botulinum toxin. Epinephrine (adrenaline) and other anti-anaphylactic measures must therefore be readily available.

In case of treatment failure after the first treatment session—for example, absence of a significant clinical improvement compared to baseline one month after injection—the following actions should be taken:

• Clinical evaluation, which may include electromyographic examination in a specialized setting, to assess the effect of the toxin on the injected muscle(s);
• Analysis of the causes of failure, such as incorrect selection of muscles to inject, insufficient dose, ineffective injection technique, development of fixed contracture, excessively weak antagonist muscles, or formation of neutralizing antibodies against the toxin;
• Re-evaluation of the appropriateness of treatment with botulinum toxin type A;
• In the absence of adverse events following the first treatment session, initiate a second treatment session as follows: i) adjust the dose, taking into account the analysis of the previous treatment failure; ii) use EMG guidance; and iii) maintain an interval of three months between the two treatment sessions.

In case of treatment failure or reduced effect upon repeated injections, alternative therapeutic approaches should be considered.

Reconstitution of the medicinal product:

If during the same treatment different pack sizes of BOTOX with varying dosage strengths are used,
particular attention must be paid to using the correct amount of diluent to reconstitute the specific number of units per 0.1 ml. The amount of diluent varies between BOTOX 100 Units Allergan and BOTOX 200 Units Allergan. Each syringe must be appropriately labeled.

It is good practice to perform vial reconstitution and syringe preparation over a plasticized absorbent pad to collect any spilled product.

BOTOX must be reconstituted only with sterile 0.9% sodium chloride solution without preservatives for injectable use. The correct volume of diluent should be drawn up using a syringe (see dilution instructions or the table below).

Dilution instructions for the treatment of urinary incontinence due to overactive bladder:

It is recommended to use one 100 Unit vial or two 50 Unit vials for easier reconstitution.

Dilution instructions using two 50 Unit vials	Reconstitute two BOTOX 50 Unit vials each with 5 ml of sterile preservative-free 0.9% sodium chloride solution for injection, and gently mix the contents of the vials. •Withdraw 5 ml from each vial using a single 10 ml syringe.
Dilution instructions using one 100 Unit vial	Reconstitute one 100 Unit vial of BOTOX with 10 ml of sterile preservative-free 0.9% sodium chloride solution for injection and gently mix.
	Withdraw 10 ml from the vial using a 10 ml syringe.
Dilution instructions using one 200 Unit vial	Reconstitute one 200 Unit vial of BOTOX with 8 ml of sterile preservative-free 0.9% sodium chloride solution for injection and gently mix. •Withdraw 4 ml from the vial using a 10 ml syringe. •Complete reconstitution by adding 6 ml of sterile preservative-free 0.9% sodium chloride solution for injection using a 10 ml syringe and gently mix.

This will result in a 10 ml syringe containing a total of 100 Units of reconstituted BOTOX. Use the product immediately after reconstitution in the syringe. Discard any unused sodium chloride solution.
This product is for single use only, and any reconstituted product not used must be discarded.
Dilution instructions for the treatment of urinary incontinence due to neurogenic detrusor overactivity:
It is recommended to use 200 Unit or 100 Unit vials depending on the reconstitution requirements.

Dilution instructions using four 50 Unit vials	Reconstitute each of four 50 Unit vials of BOTOX with 3 ml of sterile preservative-free 0.9% sodium chloride solution for injection, and gently mix the vials. •Withdraw 3 ml from the first vial and 1 ml from the second vial using a 10 ml syringe. •Withdraw 3 ml from the third vial and 1 ml from the fourth vial using a second 10 ml syringe. •Withdraw the remaining 2 ml from the second and fourth vials using a third 10 ml syringe. •Complete reconstitution by adding 6 ml of sterile preservative-free 0.9% sodium chloride solution for injection to each of the three 10 ml syringes and gently mix.
Dilution instructions using two 100 Unit vials	Reconstitute each of two 100 Unit vials of BOTOX with 6 ml of sterile preservative-free 0.9% sodium chloride solution for injection, and gently mix the vials. •Withdraw 4 ml from each vial using two separate 10 ml syringes. •Withdraw the remaining 2 ml from each vial using a third 10 ml syringe. •Complete reconstitution by adding 6 ml of sterile preservative-free 0.9% sodium chloride solution for injection to each of the three 10 ml syringes and gently mix.
Dilution instructions using one 200 Unit vial	Reconstitute one 200 Unit vial of BOTOX with 6 ml of sterile preservative-free 0.9% sodium chloride solution for injection and gently mix the vial. •Withdraw 2 ml from the vial into each of three 10 ml syringes. •Complete reconstitution by adding 8 ml of sterile preservative-free 0.9% sodium chloride solution for injection to each of the 10 ml syringes and gently mix.

Three 10 ml syringes containing a total of 200 Units of reconstituted BOTOX will be obtained. Use immediately after reconstitution in syringe. Dispose of any unused sodium chloride solution.
Dilution table for the BOTOX 50, 100 and 200 Unit Allergan pack for all other indications:

	Vial of 50 Units	Vial of 100 Units	Vial of 200 Units
Resulting Dose (Units per 0.1 ml)	Amount of Diluent Added to a 50-Unit Vial*	Amount of Diluent Added to a 100-Unit Vial*	Amount of Diluent Added to a 200-Unit Vial*
20 Units	0.25 ml	0.5 ml	1 ml
10 Units	0.5 ml	1 ml	2 ml
5 Units	1 ml	2 ml	4 ml
2.5 Units	2 ml	4 ml	8 ml
1.25 Units	4 ml	8 ml	N/A

* 0.9% sodium chloride solution for sterile injectable use, preservative-free
This product is for single use only, and any unused residual solution must be discarded.
Since BOTOX is denatured by foaming or vigorous shaking, the diluent must be injected slowly into the vial. Discard the vial if the vacuum is insufficient to draw the diluent into the vial. Reconstituted BOTOX must be a clear, colorless or slightly yellow solution, free from particles. The reconstituted solution must be visually inspected before use for clarity and absence of particles. Once reconstituted in the vial, BOTOX may be stored in the refrigerator (2°C - 8°C) for up to 24 hours prior to use. If further diluted in a syringe for intradetrusorial injection, it must be used immediately. Potency studies have shown that the product may be stored for up to 5 days at 2-8°C after reconstitution. From a microbiological standpoint, 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 normally should not exceed 24 hours at 2-8°C, unless reconstitution/dilution (etc.) has taken place under controlled and validated aseptic conditions.

Procedure for safe disposal of vials, syringes, and used materials
Medicines must not be disposed of via wastewater or household waste.
For safe disposal, unused vials should be reconstituted with a small amount of water and then autoclaved. Any used vials, syringes, spilled materials, etc., should be autoclaved, or any residual BOTOX should be inactivated using a 0.5% sodium hypochlorite solution for 5 minutes. Consult your pharmacist on how to dispose of medicines you no longer use. These measures will help protect the environment.

Product identification
To ensure you are using AbbVie's BOTOX, check the BOTOX cartons for tamper-evident features and the vial label for a holographic film. To view this film, examine the vial under a desk lamp or fluorescent light. When rotating the vial back and forth between your fingers, colored horizontal rainbow lines and the word "abbvie" will appear within the rainbow lines.
Do not use the product and contact your local AbbVie office for further information if the vial label does not display iridescent horizontal lines or the word "abbvie".

Additionally, BOTOX vial labels contain removable stickers including the batch number and expiration date of the received product. These stickers can be removed and affixed to the patient's medical record for traceability purposes. Note that after removing the sticker, the word "USED" appears on the BOTOX vial label, providing an additional assurance to the user that authentic BOTOX is being used.