Consumer medicine information

Botox

Botulinum toxin type A

BRAND INFORMATION

Brand name

Botox

Active ingredient

Botulinum toxin type A

Schedule

1. PRODUCT DESCRIPTION

What is BOTOX® injection?

The injection contains a muscle relaxant obtained from the bacterium Clostridium botulinum.

What is in BOTOX® injection?

Each vial contains either 50 units (U), 100 U or 200 U of Clostridium botulinum toxin type A-haemagglutinin complex as the active ingredient. It also contains human albumin and sodium chloride.

What it looks like

The injection is supplied as a sterile white vacuum-dried powder in a clear glass vial. It is diluted before use with non-preserved, sterile 0.9% w/w sodium chloride injection.

2. WHAT BOTOX® INJECTION IS USED FOR

How BOTOX® injection works

BOTOX® works by temporarily relaxing overactive or spastic (contracting) muscles. BOTOX® can also block signals to the sweat glands thus reducing excessive sweating (hyperhidrosis), and can also block the release of chemicals in the brain associated with the cause of pain (chronic migraine). When injected into the bladder wall, BOTOX® works on the bladder muscle to prevent leakage of urine (urinary incontinence).

It is used to treat medical conditions associated with overactive muscles:

causing excessive eyelid blinking (blepharospasm) in patients twelve years and over
of the face (hemifacial spasm and VIIth nerve disorders) in patients twelve years and over
causing 'lazy eye' or squint (strabismus) in patients twelve years and over
in the throat, causing a strained, strangled sounding voice or breathy voice with voice loss (spasmodic dysphonia)
causing the head to be in an unusual posture or pain in the neck associated with twisting of the head (cervical dystonia)
in children aged two years and older, causing altered and unnatural position or movements in the hand and arm as well as legs, including those muscles that cause abnormal ankle position and walking gait (juvenile cerebral palsy)
in adults, causing focal spasticity in the shoulders, hands, arms or legs (adult focal spasticity).

BOTOX® is also used:

to treat overactive bladder in adults with leakage of urine (urinary incontinence), the sudden urge to empty your bladder and needing to go to the toilet more than usual when another drug (called an anticholinergic) did not help. BOTOX® has been shown to markedly reduce leakage of urine and improve the quality of life of patients suffering from leakage of urine due to overactive bladder
to treat leakage of urine (urinary incontinence) in adults with overactive bladder due to neurologic disease. BOTOX® has been shown to reduce leakage of urine and improve the quality of life of patients suffering from leakage of urine due to neurogenic bladder
to treat headaches occurring in adults with chronic migraine
to treat excessive sweating from the armpit area
to improve the look of vertical frown lines that appear between the eyebrows, lines around the eyes and on the forehead in adults
to temporarily improve the appearance of continuous vertical bands connecting the jaw and neck (platysma muscle) seen at maximum contraction in healthy adults.

Availability

The Department of Health has approved BOTOX® injection for the uses listed above. However, your doctor may use this medicine for another purpose. If you want more information, ask your doctor.

3. WHAT TO BE CAREFUL OF

BOTOX® injection must not be used if:

you are allergic to any of the ingredients listed in section 1 (Product Description)
you have an infection in the muscles where it would normally be injected
you have any muscle disorders in other parts of your body, such as myasthenia gravis or Eaton Lambert Syndrome
you are being treated for leakage of urine and
- have either a sudden onset of urinary tract infection (UTI) or
- have a sudden inability to empty your bladder (and are not regularly using a catheter)
- are not willing and/or able to begin using a catheter, if required
the container is damaged or shows signs of tampering, or if the product does not look quite right

Tell your doctor if:

you have any muscle disorders in other parts of your body, including amyotrophic lateral sclerosis, and motor neuropathy
you are scheduled to have surgery using a general anaesthetic
you are taking anti-platelets (aspirin-like products) and/or anti-coagulants (blood thinners)
you have inflammation or severe weakness in the muscles where BOTOX® would be injected
you have a breathing problem, such as asthma or emphysema
your child who is being treated with BOTOX® for juvenile cerebral palsy has or has had neurological problems, swallowing problems, lung disease or aspiration pneumonia (serious lung infection)
you have swallowing problems
you have bleeding problems
you have had surgery on your face or in your eye
you have drooping eyelids
you have any other change in the way your face normally looks
you have angle closure glaucoma
you have problems with your heart or circulation
you have had seizures
you are pregnant or have the intention of becoming pregnant
you are breastfeeding or planning to start breastfeeding
you are being treated for leakage of urine and
- have chronic urinary tract infection which you take long term antibiotic to treat
- have urinary obstruction. Symptoms and signs include difficulty emptying your bladder and reduced urine flow
you are being treated for leakage of urine due to overactive bladder and have diabetes

In these circumstances it may not be possible to use BOTOX®. Tell your doctor if you have problems swallowing, speaking, or breathing. These problems can happen hours to weeks after an injection of BOTOX® usually because the muscles that you use to breathe and swallow can become weak after the injection.

Swallowing problems may last for several months. People who already have swallowing or breathing problems before receiving BOTOX® have the highest risk of getting these problems.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop. Some medicines and BOTOX® may interfere with each other.

Especially tell your doctor if you:

have received any other botulinum toxin product in the last four months
have recently received an antibiotic by injection, such as gentamycin or tobramycin
take muscle relaxants
take an allergy or cold medicine
take a sleep medicine.

4. HOW TO USE BOTOX® INJECTION

BOTOX® injection should only be administered by a doctor familiar with the required technique. It must be dissolved in sterile saline solution immediately before use and should not be used in higher doses or more frequently than recommended.

When treating paediatric patients, for one or more indications, the maximum cumulative BOTOX® dose in a 3-month period should generally not exceed 8 Units/kg body weight or 300 Units, whichever is lower (refer to indication-specific maximum dosing recommendations).

The usual dosage of BOTOX® is as follows:

For leakage of urine due to overactive bladder

Dosage
Your doctor will give multiple injections into the bladder wall via a specific instrument (cystoscope). The total dose is 100 U of BOTOX®. You may be given a local anaesthetic before the injections (your bladder would be filled with anaesthetic solution for a while and then drained). You may also be given a sedative.

Duration of treatment effect
You will usually see an improvement within 2 weeks after the injection.

Typically, the effect lasts 5-6 months after the injection.

When the effects start to wear off, you can have the treatment again if needed, but not more often than every 3 months.

For leakage of urine due to bladder problems associated with spinal cord injury or multiple sclerosis

Dosage
Your doctor will give multiple injections into the bladder wall via a specific instrument (cystoscope). The total dose is 200 U of BOTOX®. You may be given a local or general anaesthetic before the injections. You may also be given a sedative.

Duration of treatment effect
You will usually see an improvement within 2 weeks after the injection.

Typically, the effect lasts 8-10 months after the injection.

When the effects start to wear off, you can have the treatment again if needed, but not more often than every 3 months.

Blepharospasm, Hemifacial Spasm and VIIth Nerve Disorders

The recommended dose is 1.25 U to 2.5 U (0.05 mL to 0.1 mL) for each muscle injected. The initial effect occurs within 3 days, with the maximum muscle relaxation reached within 1-2 weeks, and lasting approximately 3 months. After this, you should return for a repeat dose. The total maximum dose in a 2 month period should not be more than 200 U.

Strabismus

The volume of BOTOX® injected for the treatment of strabismus or squint should be between 0.05 to 0.15 mL per eye muscle. The muscle relaxation effect begins one to two days after the injection and lasts 2 to 6 weeks. You may need to return for a repeat dose if the effect is inadequate or if the squint recurs. The maximum recommended dose as a single injection for any one muscle is 25 U.

Spasticity in children two years and older

The recommended total dose is up to 8 U/kg injected into the spastic muscles. The maximum total dose is 300 U per treatment session or in a 3 month interval. The initial effect occurs within 2 weeks after injection. The dose is dependent on the size of the spastic muscle and the degree of spasticity. The dose can then be repeated but not more often than every 3 months.

Focal spasticity in Adults

Your doctor will determine the appropriate dose and the number of injection sites based on the number of spastic muscles, the severity of the spasticity and the site and location of the muscles involved. Your doctor may also tailor your dose depending on any muscle weakness that may be present and your response to the injection. Improvement generally occurs within the first 2 weeks after injection, with maximum effect occurring after 4-6 weeks and the effect lasting approximately 3-4 months.

In general, the total maximum dose should not be more than 400 U divided among involved muscles for treating adult upper limb spasticity, and maximum dose of 400 U divided among involved muscles for treating adult lower limb spasticity in any treatment session.

Cervical Dystonia

The recommended dose depends on the type of muscle spasm, the position of the head and neck, whether muscle weakness is present, where pain is felt, your weight and response to the injection. Your doctor will prescribe the proper dose for you. Improvement generally occurs within the first 2 weeks after the injection, with the maximum effect after 6 weeks, and the effect lasting approximately 3-4 months. In general, the total maximum dose in a 2 month period should not be more than 360 U.

Spasmodic Dysphonia

Your doctor will determine the appropriate dose for you at each treatment session. Improvement generally occurs within 2-4 days. The maximum effect is seen within approximately 7 days with the effect lasting approximately 3-4 months.

Chronic Migraine

The recommended dose for treating chronic migraine is 155 U to 195 U administered intramuscularly as 0.1 ml (5 U) injections across 7 specific muscle areas in the head and neck. The dose can then be repeated every 12 weeks, for up to 3 cycles, and then assessment of the need for further treatment should be conducted.

Primary Hyperhidrosis

Recommended dosage is 50 U of BOTOX® (2.0 mL) per armpit, evenly distributed in multiple sites approximately 1-2 cm apart within the armpit area. Injections should be repeated when the effects from the previous injection wear off but not more often than every 4 months.

Frown Lines

The recommended dose of BOTOX® for the treatment of frown lines is 20 U. This is usually injected into the muscles around your eyebrows in 5 different places. The recommended injection volume per muscle site is 0.1 mL. However, the optimum dose levels and number of injections sites per muscles may vary among patients. Improvement in the severity of the lines generally occurs within one week after the injections and has been shown to last for up to 4 months. This will vary between individual people and may depend on the severity of the frown lines.

Crow's Feet

The recommended dose of BOTOX® injection for the treatment of crow's feet lines is 6-18 U per side. This is usually injected into the muscles around your eyes, where most lines are seen when a smile is forced, in 3 different places. Improvement in the severity of the lines generally occurs within one week after the injections and has been shown to last for up to 4 months.

Forehead Lines

The recommended dose of BOTOX® for the treatment of forehead lines is 8-24 U. This is usually injected into the forehead muscle in 4 different places. Improvement in the severity of the lines generally occurs within two weeks after the injections and has been shown to last for up to 6 months.

Continuous vertical bands connecting the jaw and neck (platysma muscle) seen at maximum contraction

BOTOX® is injected directly into the muscle of the affected area at each side of the neck.

The usual dose is either 26, 31, or 36 Units. You will be injected with the recommended volume of 0.05 ml (2 Units) of BOTOX® into 4 sites in the upper segment of platysma muscle, below the jawline on each side. In addition, you will be injected with 0.025 ml (1 Unit) of BOTOX® into 5 sites along each vertical neck band, 1 to 2 vertical neck bands per side. Depending on platysma continuous bands severity, the total dose may be 26 Units (1 band/side), 31 Units (1 band one side, 2 bands other side), or 36 Units (2 bands/side). You cannot receive another platysma treatment sooner than 3 months.

Use in pregnancy

Use of BOTOX® when pregnant or breast-feeding is not recommended. Tell your doctor or pharmacist if you become pregnant while being treated with BOTOX®.

Use in children

The safety and effectiveness of BOTOX® has been established in children/adolescents over the age of two years for the treatment of focal spasticity due to juvenile cerebral palsy.

Limited information is available on the use of BOTOX® in the following conditions in children/adolescents over the age of 12 years. No recommendation on dosage can be made for these indications.

Things to be careful of

Tell your doctor as soon as possible if you do not feel well while being treated with BOTOX® injection.
Be careful to resume activities gradually if you have had little exercise for a long time.
Be careful driving or operating machinery until you know how BOTOX® affects you.

Urinary incontinence due to overactive bladder

You will be seen by your doctor approximately 2 weeks after the injection. You will be asked to pass urine and will then have the volume of urine left in your bladder measured using ultrasound. Your doctor will decide if you need to return for the same test during the next 12 weeks. You must contact your doctor if at any time you find it difficult to pass urine because it is possible that you may need to start using a catheter. In order to avoid urinary tract infections, female patients should pass urine after sexual intercourse.
Please note only a small percentage (12.2%) of patients included in the main clinical trials were male. The improvement seen in male patients following use in BOTOX® is smaller than in female patients and may not be beneficial. No significant reduction in incontinence frequency was seen and a majority of men in the clinical trials felt that their condition was unchanged or worsened after receiving BOTOX®. There are also side effects such as urinary tract infection and inability to empty your bladder (urinary retention) associated with BOTOX® treatment. The decision to receive treatment with BOTOX® should be discussed with your doctor.

Urinary incontinence due to neurogenic bladder

You will be seen by your doctor approximately 2 weeks after the injection, if you were not using a catheter before the injection. You will be asked to pass urine and will then have the volume of urine left in your bladder measured using ultrasound. Your doctor will decide if you need to return for the same test during the next 12 weeks. You must contact your doctor if at any time you find it difficult to pass urine because it is possible that you may need to start using a catheter. In order to avoid urinary tract infections, female patients should pass urine after sexual intercourse.

Overdose

Telephone your doctor or go to casualty at your nearest hospital immediately if you think that you or anyone else may have swallowed or accidentally injected BOTOX® injection, even if there are no signs of discomfort or poisoning. You may need to be watched for several days for signs of muscle weakness or loss of muscle movement.

Tell your doctor if you feel any general weakness, local muscle weakness, difficulty in breathing or swallowing in the weeks following your injection. There is an anti-toxin to the toxin in BOTOX®, but it is only likely to be effective if injected within 30 minutes after the BOTOX® injection. If you have questions or concerns or are not sure about something, please consult your doctor or pharmacist.

5. SIDE EFFECTS

All medicines can have side effects. Sometimes they are serious, most of the time they are not. Some patients may experience unwanted effects with BOTOX® treatment, and may need further medical treatment. Ask your doctor to answer any questions you may have.

If while undergoing treatment with BOTOX® injection you experience any side-effects or symptoms which may be due to this medication (whether or not it is mentioned below) please inform your Doctor as early as possible.

This product contains albumin, an extract of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

Things which may occur

General
Pain, tenderness, inflammation, tingling or numbness, swelling (including swelling of the eyelid following injection), dry mouth, redness of the skin, infection, bleeding and/or bruising at the site of injection, generally feeling unwell and weakness. The following symptoms have been reported on rare occasions: changes in the way the heart beats, chest pain, skin rash and allergic reaction (symptoms: shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin).

In some cases, the effect of botulinum toxin may be observed beyond the site of injection and the following symptoms may occur:

loss of strength and muscle weakness
drooping of the upper eyelid
double or blurred vision
trouble speaking or saying words clearly
constipation
aspiration pneumonia (serious lung infection)
trouble swallowing or breathing, which can be life-threatening.

These symptoms can happen hours to weeks after injection and are more likely to occur in patients treated with high doses or who have underlying conditions that would predispose them to these symptoms.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you experience any of the above symptoms.

Injections in the bladder wall for leakage of urine due to overactive bladder

Very common side effects: urinary tract infection, painful urination after the injection*.

Common side effects: bacteria in the urine, inability to empty your bladder (urinary retention), incomplete emptying of the bladder, frequent daytime urination, blood in the urine after the injection**.

* This side effect may also be related to the injection procedure.

**This side effect is only related to the injection procedure.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Injections in the bladder wall for leakage of urine due to bladder problems associated with spinal cord injury or multiple sclerosis

Very common side effects: urinary tract infection, inability to empty your bladder (urinary retention).

Common side effects: difficulty in sleeping, constipation, muscle weakness, muscle spasm, bulge in the bladder wall, tiredness, problems with walking, fall.

Common side effects related to the injection procedure: blood in the urine after the injection, painful urination after the injection, possible uncontrolled reflex reaction of your body (e.g. profuse sweating, throbbing headache or increase in pulse rate) around the time of the injection.

Blepharospasm, Hemifacial Spasm or VIIth Nerve Disorders
Drooping of the eyelids, irritation or tearing, dry eye, not being able to close the eye, sensitivity to light, dizziness and tiredness. Less common side effects include: inward or outward turning of the eye, inflammation of the eye, double vision, and swelling of the eyelid skin lasting several days.

Strabismus
Drooping of the eyelids, vertical turning of the eye, double vision, bleeding beneath the eye lids and at the front of the eye. Less common side effects include: bleeding behind the eye ball, piercing of the sclera (the tough skin covering part of the eye bulb), dilation of the pupil, loss of awareness of space and past pointing (the inability to place a finger on another part of the body accurately), headache, inability to focus, dizziness, discomfort/irritation of the eye, increased pressure in the eye.

Spasticity in children two years and older
Falling, clumsiness, localised, and/or generalised muscle weakness, localised pain, problems with walking, flu, viral infections, ear infection and pain, bruising and discomfort at the injection site. Less common side effects include: leg cramps, fever, knee or ankle pain, increased frequency of passing urine, joint dislocation and muscle spasms. Seizures, pneumonia, vomiting, bruising, rash, abnormal skin sensations (e.g. tingling or numbness), feeling drowsy or sleepy, generally feeling unwell and running nose were also reported.

Focal spasticity in adults
Most side effects that have been reported in patients being treated for focal spasticity were mild to moderate and got better without needing medical attention. Side effects reported include: nausea, weakness of muscles, pain in extremities such as hands and feet, tiredness and swelling of the extremities such as hands and feet.

Cervical Dystonia
Soreness or bruising where the injection was given, difficulty in swallowing, neck pain, headache, weakness of the neck, dizziness, feeling drowsy or sleepy, dry mouth, nausea, flu-like illness, upper respiratory tract infection, increased muscle tension, muscle stiffness and decreased skin sensation. Less common side effects include: general weakness, fever, shortness of breath, double vision and drooping of the eyelid. Side effects, if they occur, tend to appear in the first week after injection.

However, in rare instances, patients may have serious difficulty in breathing and swallowing that could occur within hours of injection and may persist for weeks after injection and may develop into a more serious condition. Make sure you tell your doctor immediately if you experience any difficulty in swallowing.

Spasmodic Dysphonia
Breathiness, difficulty in swallowing, inhalation of fluid or food particles from the stomach, narrowed air passages causing a harsh sound in breathing and pain were among the more common side effects reported in clinical trials.

Chronic Migraine
Loss of movement on the face, drooping of the eyelids, skin rash, itching, pain at the injection site, neck pain, muscle pain, tenderness or weakness, muscle spasms or tightness. Less common side effects include: pain of skin, pain of jaw and difficulty in swallowing. Mephisto sign (quizzical or Spock's eyebrow, when the outer end of the eyebrow is located above the inner end) has been reported in post-marketing experience.

Headache, including worsening migraine, has been also reported, usually occurring within the first month after treatment; however, these reactions did not always reoccur with following treatments and the overall incidence decreased with repeated treatments.

Primary hyperhidrosis
Increase in sweating in other areas of the body, hot flushes and pain at the injection site.

Frown Lines
Drooping of the eyelids, headache, face pain, redness, swelling at the injection site, bruising, skin tightness, muscle weakness, numbness or a feeling of pins and needles or nausea were among the more common effects reported in clinical trials. Inability to completely close the eyelid and Mephisto sign (quizzical or Spock's eyebrow, when the outer end of the eyebrow is located above the inner end) have been reported in post-marketing experience.

Crow's Feet
Bruising at the injection site, headache, flu-like symptoms and inability to completely close the eyelid.

Forehead Lines
Headache, bruising, drooping of the eyebrows, eyelid swelling, aching/itching forehead, nausea, feeling of tension and flu-like symptoms.

Injections for the temporary improvement in continuous vertical bands connecting the jaw and neck (platysma muscle) seen at maximum contraction

Uncommon:
may affect up to 1 in 100 people

difficulty swallowing
weakness in the lower part of the face.

6. STORAGE AND DISPOSAL

BOTOX® injection should not be used after the date marked on the label (expiry date).
KEEP ALL MEDICINES WHERE YOUNG CHILDREN CANNOT REACH THEM.
BOTOX® injection should be stored in the refrigerator. The injection should be given within 24 hours after being reconstituted and stored in a refrigerator during this time. The injection should be clear, colourless and free from particles. Each vial is intended for use by a single individual patient.

7. FURTHER INFORMATION

If you have any further questions on your BOTOX® treatment or are unsure of the information, please see your doctor, who will be able to assist you.

Supplier

AbbVie Pty Ltd
241 O’Riordan Street
Mascot NSW 2020
Australia

Australian Registration Number

BOTOX® 50 U - AUST R 195530

BOTOX® 100 U - AUST R 67311

BOTOX® 200 U - AUST R 172264

Date of preparation

June 2025

Published by MIMS August 2025

BRAND INFORMATION

Brand name

Botox

Active ingredient

Botulinum toxin type A

Schedule

1 Name of Medicine

Botulinum toxin, type A purified neurotoxin complex.

2 Qualitative and Quantitative Composition

Each vial of Botox injection contains either 50 units (U), 100 units (U) or 200 units (U) of botulinum toxin, type A, as a haemagglutinin complex.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Botox (botulinum toxin type A) purified neurotoxin complex is indicated for the following therapeutic indications:
treatment of overactive bladder with symptoms of urinary incontinence, urgency and frequency, in adult patients who have an inadequate response to or are intolerant of an anticholinergic medication;
treatment of urinary incontinence due to neurogenic detrusor overactivity resulting from a defined neurological illness (such as spinal cord injury or multiple sclerosis) in adult patients who have an inadequate response to or are intolerant of an anticholinergic medication;
prophylaxis of headaches in adults with chronic migraine (headaches on at least 15 days per month of which at least 8 days are with migraine);
treatment of strabismus in patients twelve years and over;
treatment of blepharospasm associated with dystonia, including benign blepharospasm and VIIth nerve disorders (specifically hemifacial spasm) in patients twelve years and over;
treatment of cervical dystonia (spasmodic torticollis);
treatment of focal spasticity of the upper and lower limbs, including dynamic equinus foot deformity, due to juvenile cerebral palsy in patients two years and older;
treatment of severe primary hyperhidrosis of the axillae;
treatment of focal spasticity in adults;
treatment of spasmodic dysphonia.
Botox (botulinum toxin type A) purified neurotoxin complex is indicated for the following cosmetic indications:
temporary improvement in the appearance of upper facial rhytides (glabellar lines, crow's feet and forehead lines) in adults;
temporary improvement in the appearance of platysma continuous bands in healthy in adults.

4.2 Dose and Method of Administration

Route of administration.

Intramuscular injection.
Reconstituted Botox is injected with the purpose of reaching the motor endplate region of the muscle to be treated. May be subcutaneous for blepharospasm. Intradermal for primary hyperhidrosis of the axillae.

General.

Botox should only be given by physicians with the appropriate qualifications and experience in the treatment of patients and the use of required equipment.
The product is for single use in one patient during one session only because the product and diluent do not contain a preservative. Once opened and reconstituted, store in the refrigerator and use within twenty-four hours. Discard any remaining solution. Do not freeze reconstituted Botox.
In general, dosing of Botox should be individualised for each patient and always start with the minimal effective dose. The dosing interval should typically not be more frequent than every three months.
In treating paediatric patients, including when treating for multiple indications, the maximum cumulative dose in a 3-month interval should generally not exceed 8 units/kg body weight or 300 units, whichever is lower (refer to indication-specific maximum dosing recommendations).
If different vial sizes of Botox are being used as part of one injection procedure, care should be taken to use the correct amount of diluent when reconstituting a particular number of units per 0.1 mL. The amount of diluent varies between Botox 100 Allergan Units, Botox 50 Allergan Units and Botox 200 Allergan Units. Each syringe should be labelled accordingly.

Bladder dysfunction.

Overactive bladder.

An intravesical instillation of diluted local anaesthetic with or without sedation may be used prior to injection, per local site practice. If a local anaesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection.
The recommended dose is 100 U of Botox, as 0.5 mL (5 U) injections across 20 sites in the detrusor, which is also the maximum recommended dose.
The recommended dilution is 100 U/10 mL with 0.9% sterile nonpreserved saline solution (see Table 6). Dispose of any unused saline.
Reconstituted Botox (100 U/10 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone and bladder base. The bladder should be instilled with enough saline to achieve adequate visualisation for the injections but overdistension should be avoided.
The injection needle should be filled (primed) with approximately 1 mL of reconstituted Botox prior to the start of injections (depending on the needle length) to remove any air.
The needle should be inserted approximately 2 mm into the detrusor, and 20 injections of 0.5 mL each (total volume of 10 mL) should be spaced approximately 1 cm apart (see Figure 1). For the final injection, approximately 1 mL of sterile non-preserved saline solution should be injected so the full dose is delivered. After the injections are given, the saline used for bladder wall visualisation should not be drained so that patients can demonstrate their ability to void prior to leaving the clinic. The patient should be observed for at least 30 minutes post-injection and until a spontaneous void has occurred.
Clinical improvement may occur within 2 weeks. Patients should be considered for re-injection when the clinical effect of the previous injection has diminished (median duration in Phase 3 clinical studies was 166 days [~ 24 weeks]), but no sooner than 3 months from the prior bladder injection.

Neurogenic detrusor overactivity.

An intravesical instillation of diluted local anaesthetic with or without sedation, or general anaesthesia, may be used prior to injection, per local site practice. If a local anaesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before injection.
The recommended dose is 200 U of Botox.
Reconstitute a 200 U vial of Botox with 6 mL of 0.9% sterile non-preserved saline solution and mix the vial gently. Draw 2 mL from the vial into each of three 10 mL syringes. Complete the reconstitution by adding 8 mL of 0.9% sterile nonpreserved saline solution into each of the 10 mL syringes, and mix gently. This will result in three 10 mL syringes each containing 10 mL (~ 67 U in each), for a total of 200 U of reconstituted Botox. Use immediately after reconstitution in the syringe. Dispose of any unused saline.
Reconstitute two 100 U vials of Botox, each with 6 mL of 0.9% sterile non-preserved saline solution and mix the vials gently. Draw 4 mL from each vial into each of two 10 mL syringes. Draw the remaining 2 mL from each vial into a third 10 mL syringe. Complete the reconstitution by adding 6 mL of 0.9% sterile non-preserved saline solution into each of the 10 mL syringes and mix gently. This will result in three 10 mL syringes each containing 10 mL (~ 67 U in each), for a total of 200 U of reconstituted Botox. Use immediately after reconstitution in the syringe. Dispose of any unused saline.
Reconstituted Botox (200 U/30 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to achieve adequate visualisation for the injections, but overdistension should be avoided.
The injection needle should be filled (primed) with approximately 1 mL of reconstituted Botox prior to the start of injections (depending on the needle length) to remove any air.
The needle should be inserted approximately 2 mm into the detrusor, and 30 injections of 1 mL (~ 6.7 U) each (total volume of 30 mL) should be spaced approximately 1 cm apart (see Figure 1). For the final injection, approximately 1 mL of 0.9% sterile non-preserved saline solution should be injected so the full dose is delivered. After the injections are given, the saline used for bladder wall visualisation should be drained. The patient should be observed for at least 30 minutes post-injection.
Clinical improvement generally occurs within 2 weeks. It is not recommended that patients be retreated pre-emptively, at fixed intervals. Patients should be considered for reinjection when the clinical effect of the previous injection has diminished (median duration in Phase 3 clinical studies was 256-295 days (36-42 weeks) for Botox 200 U), but no sooner than 3 months from the prior bladder injection.
Placebo-controlled data is limited to one cycle so the decision to perform a second treatment should be made only after considering the risks and benefits.

Chronic migraine.

The recommended dose for treating chronic migraine is 155 U to 195 U administered intramuscularly (IM) using a 30 gauge, 0.5 inch needle as 0.1 mL (5 U) injections per each site. Injections should be divided across 7 specific head/neck muscle areas as specified in Table 1. A 1 inch needle may be needed in the neck region for patients with extremely thick neck muscles. With the exception of the procerus muscle, which should be injected at 1 site (midline), all muscles should be injected bilaterally with the minimum dose per muscle as indicated below, with half the number of injections sites administered to the left, and half to the right side of the head and neck. If there is a predominant pain location(s), additional injections to one or both sides may be administered in up to 3 specific muscle groups (occipitalis, temporalis and trapezius), up to the maximum dose per muscle as indicated in Table 1.
The recommended re-treatment schedule is every 12 weeks.
Due to the difficulties in establishing a diagnosis of chronic migraine, patients being considered for prophylaxis of headaches with Botox should be evaluated by a neurologist or pain management specialist prior to receiving treatment with Botox. The use of Botox for prophylaxis of headaches in adults with chronic migraine has been assessed for 3 cycles over 32 weeks. No long-term safety or efficacy data for this indication are available. Patients who do not have an adequate response after 2 treatment cycles should not continue treatment. Patients should not receive more than 3 cycles of treatment prior to an assessment of the need for further treatment.
Recommended injection sites for chronic migraine are shown in Figure 2.

Figure 3 indicates recommended muscle groups for optional additional injections.

Blepharospasm.

An injection of Botox is prepared by drawing into a sterile 1.0 mL tuberculin syringe an amount of the properly diluted toxin (see Table 6) slightly greater than the intended dose. Air bubbles in the syringe barrel are expelled and the syringe is attached to the injection needle, preferably a 1½", 27-30-gauge needle. Injection volume in excess of the intended dose is expelled through the needle into an appropriate waste container to assure patency of the needle and to confirm that there is no syringe needle leakage. A new, sterile needle and syringe should be used to enter the vial on each occasion for dilution or removal of Botox.
For blepharospasm, diluted Botox injection (see Table 6) is injected using a sterile 27-30-gauge needle with or without electromyographic guidance. 1.25 U to 2.5 U (0.05 mL to 0.1 mL volume at each site) injected into the medial and lateral pretarsal orbicularis oculi of the upper lid and into the lateral pretarsal orbicularis oculi of the lower lid is the initial recommended dose. Pretarsal injections are often appropriate and may vary based on the patient's presentation. In the upper lid, maximising the distance of the injection from the levator palpebrae superioris may reduce the complication of ptosis. Avoiding medial lower lid injections, and thereby reducing diffusion into the inferior oblique, may reduce the complication of diplopia. Ecchymosis may occur easily in the soft eyelid tissues. This may be reduced by applying light pressure at the injection site immediately after the injection.
In general, the initial effect of the injections is seen within three days and reaches a peak at one to two weeks post-treatment. Each treatment lasts approximately three months, following which the procedure can be repeated as needed. At repeat treatment sessions, the dose may be increased up to twofold if the response from the initial treatment is considered insufficient, usually defined as an effect that does not last longer than two months. However, there appears to be a minimal increase in benefit from injecting more than 5.0 U per site. Some tolerance may be found when Botox is used in treating blepharospasm if treatments are given any more frequently than every three months. The effect is rarely permanent.
The cumulative dose of Botox in a two-month period should not exceed 200 U.

Strabismus.

Botox is intended for injection into extraocular muscles utilising the electrical activity recorded from the tip of the injection needle as a guide to placement within the target muscle. Injection without surgical exposure or electromyographic guidance should not be attempted. Physicians should be familiar with electromyographic technique.
To prepare the eye for Botox injection, it is recommended that several drops of a local anaesthetic and an ocular decongestant be given several minutes prior to injection.

Note.

The volume of Botox injected for treatment of strabismus should be between 0.05-0.15 mL per muscle.
The initial listed doses of the reconstituted Botox (see Table 6) typically create paralysis of injected muscles beginning one to two days after injection and increasing in intensity during the first week. The paralysis lasts for 2-6 weeks and gradually resolves over a similar time period. Overcorrections lasting over 6 months have been rare. About one half of patients will require subsequent doses because of inadequate paralytic response of the muscle to the initial dose, or because of mechanical factors such as large deviations or restrictions, or because of the lack of binocular motor fusion to stabilise the alignment.

I. Initial doses in units.

Use the lower listed doses for treatment of small deviations. Use the larger doses only for large deviations.
A. For vertical muscles, and for horizontal strabismus of less than 20 prism dioptres: 1.25-2.5 U in any one muscle.
B. For horizontal strabismus of 20 prism dioptres to 50 prism dioptres: 2.5-5.0 U in any one muscle.
C. For persistent sixth nerve palsy of one month or longer duration: 1.25-2.5 U in the medial rectus muscle.

II. Subsequent doses for residual or recurrent strabismus.

A. It is recommended that patients be re-examined 7 to 14 days after each injection to assess the effect of that dose.
B. Patients experiencing adequate paralysis of the target muscle that require subsequent injections should receive a dose comparable to the initial dose.
C. Subsequent doses for patients experiencing incomplete paralysis of the target muscle may be increased up to twofold compared to the previously administered dose.
D. Subsequent injections should not be administered until the effects of the previous dose have dissipated as evidenced by substantial function in the injected and adjacent muscles.
E. The maximum recommended dose as a single injection for any one muscle is 25 U.

VIIth nerve disorders (hemifacial spasm).

Patients with hemifacial spasm or VIIth nerve disorder should be treated as for unilateral blepharospasm. Further injections may be necessary into the corrugator, zygomaticus major, orbicularis oris and/or other facial muscles according to the extent of the spasm. Electromyographical control may be useful to identify small circumoral muscles.
The cumulative dose of Botox in a two month period should not exceed 200 U.

Treatment of focal spasticity of the upper limb and lower limbs, including dynamic equinus foot deformity, due to juvenile cerebral palsy in patients two years and older.

The exact dose and number of injection sites should be tailored to the child's needs based on the size, number and location of muscles involved, the severity of spasticity, presence of local muscle weakness, and the patient's response to previous treatment. In clinical trials the dose per muscle ranged from 0.5-2.0 U/kg bodyweight in the upper limb and 2.0-4.0 U/kg/bodyweight in the lower limb, per treatment session. For the treatment of equinus foot deformity the total dose is up to 4 U/kg or 200 U (whichever is the lesser amount) divided into two sites in each medial and lateral head of the gastrocnemius muscle. In other muscles the dose per muscle ranged from 3.0-8.0 U/kg bodyweight and did not exceed 300 U divided among selected muscles at any treatment session. Following initial injection to the gastrocnemius muscle, further involvement of the anterior or posterior tibialis may need to be considered for additional improvement in the foot position at heel strike and during standing.
A 27- or 30-gauge needle should be used with an appropriate needle length to reach the targeted muscles. For focal spasticity, localisation techniques include electromyography, muscle ultrasound or electrical stimulation.
Clinical improvement generally occurs within the first two weeks after injection. Repeat doses should be administered when the clinical effect of a previous injection diminishes, but typically not more frequently than every three months. The degree of muscle spasticity at the time of reinjection may necessitate alterations in the dose of Botox and muscles to be injected.
Table 2 is intended to give dosing guidelines for injection of Botox in the treatment of focal spasticity in children aged 2 years and older. The maximum cumulative dose should generally not exceed 8.0 U/kg bodyweight and up to a maximum of 300 U divided among selected muscles at any treatment session or in a 3-month interval.

Focal spasticity in adults.

The exact dose and number of injection sites should be tailored to the individual based on the size, number and location of muscles involved, the severity of spasticity, presence of local muscle weakness and the patient response to previous treatment. Clinical trials support a maximum dose of 400 U divided among involved muscles for treating adult upper limb spasticity and a maximum dose of 400 U divided among involved muscles for treating adult lower limb spasticity at any treatment session. Clinical improvement in muscle tone generally occurs within two weeks following treatment with the peak effect seen four to six weeks following treatment. In clinical studies, patients were reinjected at 12 to 16 week intervals. The degree of muscle spasticity at the time of reinjection may necessitate alterations in the dose of Botox and muscles to be injected.
Table 3 is intended to provide dosing guidelines for the injection of Botox in selected muscles evaluated in supporting clinical trials.

A 27- or 30-gauge needle should be used with an appropriate needle length to reach the targeted muscles. For focal spasticity, localisation techniques include electromyography, muscle ultrasound or electrical stimulation.
Multiple injection sites may allow Botox to have more uniform contact with the innervation areas of the muscle and may be especially useful in larger muscles.

Cervical dystonia (spasmodic torticollis).

Dosing must be tailored to the individual patient based on the patient's head and neck position, localisation of pain, muscle hypertrophy, patient's bodyweight and patient response.
Multiple injection sites allow Botox to have more uniform contact with the innervation areas of the dystonic muscle and are especially useful in larger muscles. The optimal number of injection sites is dependent upon the size of the muscle to be chemically denervated. The treatment of cervical dystonia typically may include, but is not limited to, injection of Botox into the sternocleidomastoid, levator scapulae, scalene, splenius capitis, and/or the trapezius muscle(s).
A 25-, 27- or 30-gauge needle should be used for superficial muscles, and a needle of appropriate length should be used for deeper musculature. For cervical dystonia, localisation of the involved muscles with electromyographic guidance may be useful.
Table 4 is intended to provide dosing guidelines for injection of Botox in the treatment of cervical dystonia.

This information is provided as guidance for the initial injection. The extent of muscle hypertrophy and the muscle groups involved in the dystonic posture may change with time necessitating alterations in the dose of toxin and muscles to be injected. The exact dose and sites injected must be individualised for each patient.
Clinical improvement generally occurs within the first two weeks after injection. The maximum clinical benefit generally occurs approximately six weeks postinjection. Treatment intervals of less than two months are not recommended. The duration of therapeutic effect reported in clinical trials showed substantial variation (from 2 to 32 weeks), with a typical duration of approximately 12 to 16 weeks, depending on the patient's individual disease and response.
Table 5 shows the median dose of Botox injected per muscle in a clinical study in which dose was determined by the practitioner based on the presentation of the individual cervical dystonia patient.

In initial controlled clinical trials to establish safety and efficacy for cervical dystonia, doses of Botox ranged from 140 to 280 U. In more recent studies, the doses have ranged from 95 to 360 U (with an approximate mean of 240 U). As with any drug treatment, initial dosing should begin at the lowest effective dose.
In general, a total dose of 360 U every two months should not be exceeded for the treatment of cervical dystonia. The time to retreatment will vary between patients, however data from controlled clinical studies indicates that symptoms may start to re-emerge at approximately 8-10 weeks postinjection (see Clinical trials).
Repeat doses should be administered when the clinical effect of a previous injection diminishes, though usually not more frequently than every two months. Booster injections are not recommended.

Primary hyperhidrosis of the axillae.

For the treatment of hyperhidrosis, 100 U of Botox should be reconstituted with 4.0 mL of 0.9% sterile non-preserved sodium chloride for injection. For each axilla, 50 U of Botox (2.0 mL) should be injected intradermally and evenly distributed in 10-15 sites approximately 1-2 cm apart within the hyperhidrotic area. For the treatment of hyperhidrosis, a 30-gauge needle should be used. The hyperhidrotic area may be defined using standard staining techniques (e.g. Minor's iodine starch test). Each dose is injected to a depth of approximately 2 mm and at a 45 degree angle to the skin surface with the bevel side up to minimise leakage and ensure the injections remain intradermal. Repeat injections for axillary hyperhidrosis should be administered when the effects from the previous injection subside. However, repeat injections at intervals of less than four months are not recommended.

Spasmodic dysphonia.

Patients with spasmodic dysphonia should be treated by physicians skilled in the anatomy and physiology of the larynx and have facilities with nasal endoscopy and also electromyographically guided injections. The procedure should be carried out in a facility equipped to manage potential acute complications such as reflex stridor. The treatment program should be individualised for each patient at each treatment session. Peak effect is generally seen within 7 days following an injection.
Botox (100 U/vial) should be reconstituted with 4.0 to 5.0 mL of 0.9% sterile non-preserved saline solution, giving a final concentration of 2.0-2.5 U per 0.1 mL. It is usual to commence with a standard dose of 1.0-2.5 U in 0.1 mL of Botox to each thyroarytenoid muscle in adductor spasmodic dysphonia and subsequently vary the dose by altering the concentration according to patient requirements and response to therapy. An occasional patient will require 3.0 U per vocal cord and many patients over the years have reduced their dose, down to even 0.2 U per vocal cord. Bilateral injections are generally recommended but an occasional patient will benefit from unilateral injections, sometimes alternating between sides with each subsequent treatment.
In abductor spasmodic dysphonia 2.0-5.0 U of Botox are usually injected unilaterally into one posterior cricoarytenoid muscle via a lateral retrocricoid, supracricoid or transcricoid approach.
The injection is usually performed in the supine position with a small pillow under the shoulders to improve laryngeal exposure. For adductor spasmodic dysphonia, the laryngeal surface landmarks are identified, including the thyroid and cricoid cartilage, and in particular the small gap of the cricothyroid membrane. Identification of the landmarks is a critical part of this procedure and sometimes this can be difficult in individuals with thick necks.
In adductor spasmodic dysphonia the EMG recording needle is advanced in the midline through the cricothyroid membrane, directing the needle rostrally, and approximately 30° laterally towards the intended thyroarytenoid muscle. For a bilateral procedure, the needle is redirected towards the corresponding contralateral muscle. Once within the muscle, EMG insertional activity is audible and placement can be confirmed by having the patient phonate an "e". Having confirmed needle placement, the desired amount of Botox in 0.1 mL is injected.
In all cases of abductor spasmodic dysphonia, endoscopy should be performed prior to each treatment to assess the dynamic activity of each vocal cord and the size of the glottal airway. Typically, the posterior cricoarytenoid (PCA) muscle on the more active side is chosen for therapy. A retrocricoid approach should be used whereby the injection needle, containing 2.0-5.0 U of Botox in 0.1 mL, is directed towards the PCA muscle in a curving fashion at the level of the cricoid cartilage to lie behind the larynx. The larynx may be rotated laterally on the appropriate side to improve access. To confirm needle placement, the patient sniffs sharply to activate the posterior cricoarytenoid muscle resulting in a characteristic EMG interference pattern. Botox is then injected. Only unilateral injections are recommended at each treatment session. The determination of which PCA muscle to treat at any injection session is determined by endoscopic review. Treatment sessions are performed only when the noninjected cord has sufficient motion to protect from stridor in the event that the injected cord would become immobile. An occasional patient with abductor spasmodic dysphonia will have increased activity of the cricothyroid muscle, which can also be evaluated by EMG, and may also benefit from supplemental injections into this muscle.
To date there has only been one report of a patient developing resistance to the injections, with the development of neutralising antibodies, probably because the doses used are very small compared to other indications.

Upper facial lines (glabellar lines, crow's feet and forehead lines).

As optimum dose levels and number of injection sites per muscle may vary among patients, individual dosing regimens should be drawn up. The recommended injection volume per injection site is 0.1 mL.

Glabellar lines.

Botox should be reconstituted with 0.9% sterile nonpreserved saline solution (100 U/2.5 mL) and injected using a sterile 30-gauge needle. A volume of 0.1 mL (4 U) is administered in each of 5 injection sites, 2 injections in each corrugator muscle and 1 injection in the procerus muscle for a total dose of 20 U.
In order to reduce the complication of ptosis, injection near the levator palpebrae superioris muscle should be avoided, particularly in patients with larger brow depressor complexes. Medial corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.
Improvement of severity of glabellar lines generally occurs within one week after treatment. The effect was demonstrated for up to 4 months.

Crow's feet.

Botox should be injected bilaterally at 3 sites in the lateral aspect of the orbicularis oculi (i.e. total of 6 injections), where most lines are seen when a smile is forced. In general, 2-6 U is recommended per injection site at a 2-3 mm depth, for a total dose of 6-18 U per side.
Injections should be at least 1 cm outside the bony orbit, not medial to the vertical line through the lateral canthus and not close to the inferior margin of the zygoma.

Forehead lines.

Botox should be injected intramuscularly at each of 4 injection sites in the frontalis muscle. In general, 2-6 U is recommended per injection site every 1-2 cm along either side of a deep forehead crease, for a total dose of 8-24 U.
Injections should be at least 2-3 cm above the eyebrow to reduce the risk of brow ptosis.

Platysma continuous bands.

Botox injection should be administered by an appropriately qualified and trained healthcare practitioner, who understands the relevant anatomy and associated neuromuscular structures and any alterations to the anatomy in a particular individual patient (e.g. due to prior surgical or aesthetic procedures).
Patients should be screened for other potential causes of amended anatomy (e.g. thyromegaly and cervical lymphadenopathy).
Use caution in patients who have had prior surgical or aesthetic treatment of the area. Changes in anatomy/landmarks or the presence of scar tissue may impact the ability to safely administer Botox injection or to obtain the desired aesthetic result.
Each treatment can require up to 36 units (up to 28 sites) (Table 6). The safe and effective use of Botox injection depends on the use of the correct number and locations for injections, proper needle placement and administration techniques.
Needle placement with respect to the mandible is very important as it reduces the potential for injury to the marginal mandibular nerve, a motor branch of the facial nerve. Injury to the nerve presents as an asymmetrical smile due to paresis of lip depressor muscles.
Using an appropriately sized sterile syringe, needle, and aseptic technique, inject 2 units/0.05 mL of reconstituted Botox into each of the 4 sites in the upper segment of platysma muscle, below the jawline on each side. In addition, inject 1 unit/0.025 mL of reconstituted Botox into each of the 5 sites along each vertical neck band, 1 to 2 continuous vertical neck bands per side. Depending on severity, the total dose may be 26 units (1 band/side), 31 units (1 band one side, 2 bands other side) or 36 units (2 bands/side) (see Table 6 and Figures 4 and 5).

Identify the treatment location.

For each side, the 4 jawline injections to the upper platysma muscle should be approximately 1.5 to 2 cm inferior and parallel to the lower mandibular border. The anterior injection site should be in line with the oral commissure, and the posterior injection site should be slightly anterior to the angle of the mandible. The remaining 2 injections should be equidistant (approximately 1 to 2 cm apart) between the anterior and posterior injection points (see Figures 4 and 5).
For each vertical neck band, 1 to 2 per side, distribute 5 injections vertically approximately 1 to 2 cm apart (see Figures 4 and 5). The most superior injection site should be approximately 1 to 2 cm inferior to the jawline injections.

Administration.

The platysma muscle is a thin muscle sheet just below the surface of the skin. Therefore, all platysma muscle injections should be administered superficially and intramuscularly with the needle perpendicular to the surface of the skin. For continuous vertical neck band injections, each band should be identified while the patient is contracting their platysma. Gently pinch the band to isolate the muscle from nearby anatomical structures during administration (see Table 6).
To reduce injection-related complications, injection should be at least 1.5 cm inferior to the lower mandibular border. Do not inject into structures deep to the platysma muscle, particularly in the anterior region of the neck.
The safety and effectiveness of dosing with Botox more frequently than every 3 months have not been evaluated.

Dilution technique.

It is good practice to perform vial reconstitution and syringe preparation over plastic lined paper towels to catch any spillage. To reconstitute vacuum dried Botox injection, use sterile normal saline without a preservative; 0.9% w/v sodium chloride injection is the recommended diluent. Draw up the proper amount of diluent (as per Table 7) in the appropriate size syringe. Since Botox is denatured by bubbling or similar violent agitation, inject the diluent into the vial gently. Discard the vial if a vacuum does not pull the diluent into the vial. Record the date and time of reconstitution on the space on the label. Botox should be administered within 24 hours after reconstitution in the vial.
During this time period, reconstituted Botox should be stored in a refrigerator (2°C to 8°C). Reconstituted Botox should be clear, colourless to slightly yellow and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, and whenever the solution and the container permit.

For reconstitution technique for intradetrusor injections for neurogenic detrusor overactivity, please see Section 4.2 Dose and Method of Administration, Neurogenic detrusor overactivity.

Lack of response.

In the absence of the desired effect after the first treatment session, i.e. no significant clinical improvement from baseline by one month after injection, the following actions should be considered:
Analysis of potential causes of lack of effect, e.g. inappropriate selection of muscles to be injected; insufficient dose; poor injection technique; muscles inaccessible to injection; underlying structural abnormalities; such as muscle contractures or bone disorders; relative weakness of antagonist muscles; change in pattern of muscle involvement; patient perception of benefit compared with initial results; inappropriate storage or reconstitution; and/or formation of toxin neutralising antibodies.
Re-evaluation of the appropriateness of treatment with botulinum toxin type A.
For the second treatment session, in the absence of any undesirable effects after the first treatment session, the physician should consider the following:
adjust the dose, taking into account the analysis of the earlier treatment failure;
use of EMG guidance as appropriate; and
maintain a three month interval between the two treatment sessions.
In the event of treatment failure or diminished effect following repeat injections, taking into account dose adjustments and targeting of injections, alternative treatment methods should be considered.
A neutralising antibody is defined as an antibody that inactivates the biological activity of the toxin. In general, the proportion of patients who lose their response to botulinum toxin therapy and have demonstrable levels of neutralising antibodies is less than 5%, though in a long-term juvenile cerebral palsy study, of 117 patients treated with Botox, antibodies were detected in 33/117 (28%) at either 27 or 39 months. Thirty one of these 33 had been responders, 19/31 (6%) continued to respond, with 7/31 (2%) becoming nonresponders and no data available for 5/31.
In the pivotal studies, none of the 615 overactive bladder (OAB) patients with analysed specimens developed the presence of neutralising antibodies to Botox. Based on the two pivotal studies and one open-label extension study, specimens analysed from patients showed that no neutralising antibodies developed in any of the 954 patients (0.0%) who had received Botox 100 U doses. Only 3 of 260 patients (1.2%) developed neutralising antibodies after subsequently receiving at least one Botox 150 U dose (the Botox dose of 150 U is not the recommended dose for the OAB indication), of which one of these three patients continued to experience clinical benefit (≥ 50% reduction from study baseline in urinary incontinence episodes).
In the pivotal studies (300 U and 200 U), none of the 475 neurogenic detrusor overactivity (NDO) patients with analysed specimens developed the presence of neutralising antibodies. In patients with analysed specimens in the drug development program (including the open-label extension study), neutralising antibodies developed in 3 of 300 patients (1.0%) after receiving only Botox 200 U doses and 5 of 258 patients (1.9%) after receiving at least one 300 U dose (the Botox dose of 300 U is not the recommended dose for the NDO indication). Four of these eight patients continued to experience clinical benefit (~ 50% or greater reduction from study baseline in urinary incontinence episodes).
The critical factors for neutralising antibody production are the frequency and dose of injection. Tolerance may be observed in some patients treated more frequently than every three months. The potential for neutralising antibody formation may be minimised by injecting with the lowest effective dose given at the longest feasible intervals between injections (injection intervals should typically be no more frequent than three months). The maximum dose should not be exceeded in any two-month period for adult spasticity patients and patients with cervical dystonia.
More than one ineffective treatment course should occur before classification of a patient as a non-responder, because there are patients who continue to respond to therapy despite the presence of neutralising antibodies.

4.3 Contraindications

Botox (botulinum toxin type A) purified neurotoxin complex is contraindicated in individuals with known hypersensitivity to any ingredient in the formulation.
Botox is contraindicated in patients with myasthenia gravis or Eaton Lambert syndrome.
Botox is contraindicated in the presence of infection at the proposed injection site(s).

Bladder dysfunction.

Intradetrusor injection of Botox is contraindicated in patients who have a urinary tract infection, and in patients with acute urinary retention who are not routinely catheterising.
Due to the risk of urinary retention, intradetrusor injection of Botox is also contraindicated in patients who are not willing and/or able to initiate catheterisation post-treatment, if required (see Clinical trials).

4.4 Special Warnings and Precautions for Use

Lack of interchangeability between botulinum toxin products.

Due to the lack of an international unit, Botox is not therapeutically equivalent to any other botulinum toxin type A preparations. The potencies of Botox and other botulinum toxin type A preparations are based on different assay methods. In view of this lack of harmonisation of unit systems for botulinum toxin type A, extreme caution is required if it should prove necessary to substitute the botulinum type A toxin of one pharmaceutical company by another. 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.

Spread of toxin effect.

Postmarketing safety data from Botox and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin, have been reported hours to weeks after injection, and may include muscular weakness, ptosis, diplopia, blurred vision, facial weakness, swallowing and speech disorders, constipation, aspiration pneumonia, difficulty breathing and respiratory depression. The risk of symptoms is probably greatest in children treated for spasticity, but these symptoms can also occur in patients who have underlying conditions and comorbidities that would predispose them to these symptoms including adults treated for spasticity and other conditions, and are treated with high doses. Swallowing and breathing difficulties can be life threatening and there have been reports of death. Advise patients or caregivers to seek immediate medical attention if any of these symptoms occur.

Pre-existing neuromuscular disorders.

Individuals with peripheral motor neuropathic diseases (e.g. amyotrophic lateral sclerosis, or motor neuropathy) should only receive Botox with extreme caution. Patients with neuromuscular junction disorders may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of Botox. Published medical literature has reported rare cases of administration of botulinum toxin to patients with known or unrecognised neuromuscular junction disorders where the patients have shown extreme sensitivity to the systemic effects of typical clinical doses. In some of these cases, dysphagia has lasted several months and required placement of a gastric feeding tube. When exposed to very high doses, patients with neurologic disorders, e.g. paediatric cerebral palsy or adult spasticity may also be at increased risk of clinically significant systemic effects.

Hypersensitivity reactions.

Serious and/or immediate hypersensitivity reactions such as anaphylaxis and serum sickness have been rarely reported, as well as other manifestations of hypersensitivity including urticaria, soft tissue oedema and dyspnoea. Some of these reactions have been reported following the use of Botox either alone or in conjunction with other products associated with similar reactions. If such a reaction occurs, further injection should be discontinued and appropriate medical therapy immediately instituted. One fatal case of anaphylaxis has been reported in which the patient died after being injected with Botox inappropriately diluted with 5 mL of 1% lidocaine. The causal role of Botox, lidocaine, or both cannot be reliably determined.
The recommended dosages and frequencies of administration for Botox should not be exceeded (see Section 4.2 Dose and Method of Administration).

Immunogenicity.

Formation of neutralising antibodies to botulinum toxin type A may reduce the effectiveness of Botox treatment by inactivating the biological activity of the toxin. The critical factors for neutralising antibody formation have not been well characterised. The potential for antibody formation may be minimised by injecting with the lowest effective dose given at the longest feasible intervals between injections.

Cardiovascular system.

There have been reports of adverse events following administration of Botox involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including pre-existing cardiovascular disease. The exact relationship of these events to Botox has not been definitely established and will continue to be monitored by Abbvie Pty Ltd.