Allergan Ltd

Section Number

Subject

Change

Throughout document

-

Removed ®

Throughout document

-

Units replaces U

2

Qualitative and Quantitative composition

Current - Botulinum toxin* type A, 100 Allergan Units/vial.

* from Clostridium botulinum

Botulinum toxin units are not interchangeable from one product to another.

For a full list of excipients, see section 6.1.

Replaces - Clostridium botulinum type A neurotoxin complex (900 kD), 100 units.

4.2

Posology and method of administration

Current - Adequate studies on geriatric dosing have not been performed. Dose selection should be the same; however, the lowest effective dose is recommended.

Replaces - There is no difference in dose between adults and the elderly.

4.3

Contraindication

Botulinum toxin type A

Replaces - Clostridium botulinum type A neurotoxin complex (900 kD)

4.4

Special warnings and precautions for use

Current - Serious and/or immediate hypersensitivity reactions have been rarely reported including anaphylaxis, serum sickness, 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 of BOTOX should be discontinued and appropriate medical therapy, such as epinephrine, immediately instituted. Please see section 4.8c) for further information.

Replaces - An anaphylactic reaction may occur very rarely after injection of botulinum toxin.  Epinephrine (adrenaline) and other anti-anaphylactic measures should therefore be available.  Please see section 4.8c) for further information

Current - Side effects related to spread of toxin distant from the site of administration have been reported (See section 4.8), sometimes resulting in death, which in some cases was associated with dysphagia, pneumonia and/or significant debility.

Patients treated with therapeutic doses may experience exaggerated muscle weakness. Patients with underlying neurological disorders including swallowing difficulties are at increased risk of these side effects. The botulinum toxin product should be used under specialist supervision in these patients and should only be used if the benefit of treatment is considered to outweigh the risk. Patients with a history of dysphagia and aspiration should be treated with extreme caution.

Replaces - There have been rare spontaneous reports of death, sometimes associated with dysphagia, pneumonia and/or other significant debility, after treatment with botulinum toxin type A. Patients with a history of dysphagia should be treated with caution.

Current - Formation of neutralizing antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX treatment by inactivating the biological activity of the toxin. Results from some studies suggest that BOTOX injections at more frequent intervals or at higher doses may lead to greater incidence of antibody formation.

Replaces - Too frequent or excessive dosing can result in antibody formation, which may lead to resistance to treatment.

Updated text indicated in bold

Current - Caution should also be exercised when BOTOX is used for treatment of patients with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis or motor neuropathy).

Replaces - Caution should also be exercised when BOTOXâ is used for treatment of patients with amyotrophic lateral sclerosis or disorders that produce peripheral neuromuscular dysfunction.

The following paragraph was added

BOTOX should only be used with extreme caution and under close supervision in patients with subclinical or clinical evidence of defective neuromuscular transmission e.g. myasthenia gravis or Eaton Lambert Syndrome; such patients may have an increased sensitivity to agents such as BOTOX, which may result in excessive muscle weakness. Patients with neuromuscular disorders may be at an increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of BOTOX.

As with any injection, procedure-related injury could occur.  An injection could result in localized infection, pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling, erythema, and/or bleeding/bruising. Needle-related pain and/or anxiety may result in vasovagal responses, e.g. syncope, hypotension, etc.  Care should be taken when injecting near vulnerable anatomic structures

CERVICAL DYSTONIA section was updated as follows (new and altered text in bold)

Current - Patients with cervical dystonia should be informed of the possibility of experiencing dysphagia which may be very mild, but could be severe.  Dysphagia may persist for two to three weeks after injection, but has been reported to last up to five months post-injection. Consequent to the dysphagia there is the potential for aspiration, dyspnoea and occasionally the need for tube feeding.  In rare cases dysphagia followed by aspiration pneumonia and death has been reported. 

Limiting the dose injected into the sternocleidomastoid muscle to less than 100 Units may decrease the occurrence of dysphagia.  Patients with smaller neck muscle mass, or patients who receive bilateral injections into the sternocleidomastoid muscle, have been reported to be at greater risk of dysphagia.  Dysphagia is attributable to the spread of the toxin to the oesophageal musculature. Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia.

Dysphagia may contribute to decreased food and water intake resulting in weight loss and dehydration. Patients with subclinical dysphagia may be at increased risk of experiencing more severe dysphagia following a BOTOX injection.

Replaces - Patients with cervical dystonia should be informed of the possibility of experiencing dysphagia which may be very mild, but could be severe.  Consequent to the dysphagia there is the potential for aspiration, dyspnoea and occasionally the need for tube feeding.  In rare cases dysphagia followed by aspiration pneumonia and death has been reported.  Dysphagia may persist for two to three weeks after injection, but has been reported to last up to five months post-injection.

Limiting the dose injected into the sternocleidomastoid muscle to less than 100 U may decrease the occurrence of dysphagia.  Patients with smaller neck muscle mass, or patients who receive bilateral injections into the sternocleidomastoid muscle, have been reported to be at greater risk of dysphagia.  Dysphagia is attributable to the spread of the toxin to the oesophageal musculature.

4.5

Interaction with other medicinal products and other forms of interaction

The following text was added

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.

Current - No interaction studies have been performed

Replaces - No specific tests have been carried out to establish the possibility of clinical interaction with other medicinal products. 

4.8

Undesirable effects

The following text was added to section a)General

In rare cases, adverse reactions may have a duration of several months or longer

Section b) Adverse reactions – frequency by indication has been updated as follows

Blepharospasm/hemifacial spasm

Current text

Nervous system disorders

Uncommon: Dizziness, facial paresis and facial palsy.

Eye Disorders

Very common: Eyelid ptosis.

Common: Punctate keratitis, lagophthalmos, dry eye, photophobia and lacrimation increase.

Uncommon: Keratitis, ectropion, diplopia, entropion, visual disturbance and vision blurred.

Rare: Eyelid oedema   

Very rare: Corneal ulceration.

Skin and subcutaneous tissue disorders

Uncommon:                Rash/dermatitis.

General disorders and administration site conditions

Common:                    Irritation and face oedema.

Uncommon:                Fatigue

Replaces

Very common: Ptosis.

Common: Superficial punctate keratitis, lagophthalmos, dry eye, irritation, photophobia, lacrimation, facial oedema.

Uncommon: Keratitis, ectropion, diplopia, dizziness, diffuse skin rash/dermatitis, entropion, facial weakness, facial droop, tiredness, visual disturbance, blurring of vision.

Rare: Eyelid swelling.

Very rare: Angle closure glaucoma, corneal ulceration.

Cervical dystonia

Current text

Infections and infestations

Common: Rhinitis and upper respiratory infection.

Nervous system disorders

Common: Dizziness, hypertonia, hypoaesthesia, somnolence and headache.

Eye Disorders:

Uncommon: Diplopia and eyelid ptosis.

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea and dysphonia.

Gastrointestinal disorders

Very common: Dysphagia (see section c. below).

Common: Dry mouth and nausea.

Musculoskeletal and connective tissue disorders

Very common: Muscular weakness.

Common: Musculoskeletal stiffness and soreness.

General disorders and administration site conditions

Very common: Pain.

Common: Asthenia, influenza like illness and malaise.

Uncommon: Pyrexia.

Replaces

Very common: Dysphagia (See Section c) below.), local weakness, pain.

Common: Dizziness, hypertonia, numbness, general weakness, drowsiness, flu syndrome, malaise, oral dryness, nausea, headache, stiffness, soreness, rhinitis, upper respiratory infection.

Uncommon: Dyspnoea, diplopia, fever, ptosis, voice alteration.

Paediatric cerebral palsy

Current text

Infections and infestations

Very common: Viral infection and ear infection.

Nervous system disorders

Common: Somnolence and paraesthesia.

Skin and subcutaneous tissue disorders

Common: Rash.

Musculoskeletal and connective tissue disorders

Common: Myalgia and muscular weakness.

Renal and urinary disorders

Common: Urinary incontinence.

General disorders and administration site conditions

Common: Gait disturbance and malaise.

Replaces

Very common: Viral infection, ear infection.

Common: Myalgia, muscle weakness, urinary incontinence, somnolence, gait abnormality, malaise, rash,

tingling.

Focal upper limb spasticity associated with stroke

Current text

Psychiatric disorders

Uncommon: Depression and insomnia.

Nervous system disorders

Common: Hypertonia

Uncommon: Hypoaesthesia, headache, paraesthesia, incoordination and amnesia.

Ear and labyrinth disorders

Uncommon: Vertigo.

Vascular disorders

Uncommon: Orthostatic hypotension.

Gastrointestinal disorders

Uncommon: Nausea and paraesthesia oral.

Skin and subcutaneous tissue disorders

Common: Ecchymosis and purpura.

Uncommon: Dermatitis, pruritus and rash.

Musculoskeletal and connective tissue disorders

Common: Pain in extremity and muscle weakness.

Uncommon: Arthralgia and bursitis.

General disorders and administration site conditions

Common: Injection site hemorrhage and injection site irritation.

Uncommon: Asthenia, pain, injection site hypersensitivity, malaise and oedema peripheral.

Some of the uncommon events may be disease related.

Replaces

Common: Ecchymosis/purpura/injection site hemorrhage, arm pain, muscle weakness, hypertonia, injection site burning.

Uncommon: Hyperesthesia, arthralgia, asthenia, pain, bursitis, dermatitis, headache, injection site hypersensitivity, malaise, nausea, paresthesia, postural hypotension, pruritus, rash, incoordination, amnesia, circumoral paresthesia, depression, insomnia, peripheral oedema, vertigo (some of the uncommon events may be disease related)

Primary hyperhidrosis of the axillae

Current text

Nervous system disorders

Common:  Headache

Vascular disorders

Common: Hot flushes.

Gastrointestinal disorders

Uncommon: Nausea

Skin and subcutaneous tissue disorders

Common: Hyperhidrosis (non-axillary sweating).

Uncommon: Pruritus.

Musculoskeletal and connective tissue disorders

Uncommon: Muscular weakness, myalgia, arthropathy and pain in extremity.

General disorders and administration site conditions

Common: Injection site reactions and pain.

Uncommon: Asthenia, injection site oedema and injection site pain

In the management of primary axillary hyperhidrosis, increase in non axillary sweating was reported in 4.5% of patients within 1 month after injection and showed no pattern with respect to anatomical sites affected. Resolution was seen in approximately 30% of the patients within four months.

Weakness of the arm has been also reported uncommonly (0.7%) and was mild, transient, did not require treatment and recovered without sequelae. This adverse event may be related to treatment, injection technique, or both. In the uncommon event of muscle weakness being reported a neurological examination may be considered. In addition, a re-evaluation of injection technique prior to subsequent injection is advisable to ensure intradermal placement of injections.

Replaces

Common: Non-axillary sweating, injection site reactions, pain, vasodilation (hot flushes).

Uncommon: Weakness of the arms, pruritus, myalgia, joint disorder, arm pain.

Section c) Additional information has been updated as follows – Updated or added text indicated in BOLD

Current text

Dysphagia ranges in severity from mild to severe, with potential for aspiration, which occasionally may require medical intervention.  See Section 4.4.

Side effects related to spread of toxin distant from the site of administration have been reported very rarely (exaggerated muscle weakness, dysphagia, aspiration/aspiration pneumonia, with fatal outcome in some cases). (See section 4.4).

The following other adverse events have been reported since the drug has been marketed: dysarthria; abdominal pain; vision blurred; pyrexia; focal facial paralysis; hypoaesthesia; malaise; myalgia; pruritus; hyperhidrosis; diarrhoea; anorexia; hypoacusis; tinnitus; radiculopathy; syncope; myasthenia gravis; erythema multiforme; dermatitis psoriasiform; vomiting and brachial plexopathy.

There have also been rare reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes.  Some of these patients had risk factors including cardiovascular disease.

Serious and/or immediate hypersensitivity reactions have been rarely reported, including anaphylaxis, serum sickness, 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 agents known to cause similar reactions.

A case of peripheral neuropathy has been reported in a large adult male after receiving four sets of BOTOX injections, totalling 1800 Units (for neck and back spasm, and severe pain) over an 11 week period.

Angle closure glaucoma has been reported very rarely following botulinum toxin treatment for blepharospasm.

New onset or recurrent seizures have been reported, typically in patients, who are predisposed to experiencing these events.  The exact relationship of these events to the botulinum toxin injection has not been established. The reports in children were reports predominantly from cerebral palsy patients treated for spasticity.

Needle-related pain and/or anxiety may result in vasovagal responses, e.g. syncope, hypotension, etc..

Replaces

Dysphagia ranges in severity from mild to severe, with potential for aspiration, which occasionally may require medical intervention.  See Section 4.4, Special warnings and precautions for use.

There have been rare spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility, after treatment with botulinum toxin type A.

The following have been reported rarely since the medicinal product has been marketed; skin rash (including erythema multiforme, urticaria and psoriaform eruption), pruritus, and allergic reaction.

There have also been rare reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes.  Some of these patients had risk factors including cardiovascular disease.

Rare reports of anaphylactic reactions associated with BOTOX^® use in conjunction with other agents known to cause similar reactions have been received.

A case of peripheral neuropathy has been reported in a large adult male after receiving four sets of BOTOX^® injections, totalling 1800 U (for neck and back spasm, and severe pain) over an 11 week period.

Angle closure glaucoma has been reported very rarely following botulinum toxin treatment for blepharospasm.

A female patient developed brachial plexopathy two days after injection of 120 units of BOTOX^® for the treatment of cervical dystonia, with recovery after five months.

In the management of primary axillary hyperhidrosis, increase in non-axillary sweating was reported in 4.5% of patients within 1 month after injection and showed no pattern with respect to anatomical sites affected.  Resolution was seen in approximately 30% of the patients within four months.  Weakness of the arm has been also reported uncommonly (0.7%) and was mild, transient, did not require treatment and recovered without sequelae.  This adverse event may be related to treatment, injection technique, or both.  In the uncommon event of muscle weakness being reported a neurological examination may be considered.  In addition, a re-evaluation of injection technique prior to subsequent injection is advisable to ensure intradermal placement of injections.

There have been rare reports of seizures or convulsions, mostly in patients, who are predisposed to experiencing these events.  The exact relationship of these events to the botulinum toxin injection has not been established.

Needle-related pain and/or anxiety may result in vasovagal responses, e.g. syncope, hypotension, etc.

4.9

Overdose

Updated or added text indicated in BOLD

Current text

No cases of systemic toxicity resulting from accidental injection of BOTOX have been observed. No cases of ingestion of BOTOX have been reported.  Signs of overdose are not apparent immediately post-injection.  Should accidental injection or ingestion occur, the patient should be medically supervised for several days for signs and symptoms of systemic weakness or muscle paralysis.

Patients presenting with the symptoms of botulinum toxin type A poisoning (generalised weakness, ptosis, diplopia, swallowing and speech disorders, or paresis of the respiratory muscles) should be considered for admission to hospital.

With increasing dosage, generalised and profound muscular paralysis occurs.  When the musculature of the oropharynx and oesophagus are affected, aspiration may occur which may lead to development of aspiration pneumonia.  If the respiratory muscles become paralysed, intubation and assisted respiration will be required until recovery takes place.

Replaces - There have not been any reported instances of systemic toxicity resulting from accidental injection of BOTOX^®.  Ingestion of BOTOX^® is unknown.  Signs of overdose are not apparent immediately post-injection.  Should accidental injection or ingestion occur, the patient should be medically supervised for several days for signs and symptoms of systemic weakness or muscle paralysis.

Patients presenting with the symptoms of botulinum toxin type A poisoning (generalised weakness, ptosis, diplopia, swallowing and speech disorders, or paresis of the respiratory muscles) should be considered for admission to hospital.

With increasing dosage, generalised and profound muscular paralysis occurs.  When the musculature of the oropharynx and oesophagus are affected, aspiration pneumonia may ensue.  If the respiratory muscles become paralysed, intubation and assisted respiration will be required until recovery takes place.

6.2

Incompatibilities

Current text - In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.

Replaces - None known, other than described in 4.5 above.

6.3

Shelf life

Current text

3 years.

After reconstitution, stability has been demonstrated for 24 hours at 2°C – 8°C.

Replaces - Unopened vial - 36 months.

After reconstitution, immediate use of the solution is recommended; however stability has been demonstrated for 24 hours at 2 to 8°C.

6.4

Special precautions for storage

Current text

Store in a refrigerator (2°C-8°C), or store in a freezer (at or below -5°C).

For storage conditions of the reconstituted medicinal product see section 6.3.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C (see also section 6.6).

Replaces - Unopened vials should be stored either at 2°C-8°C (in a refrigerator), or in a freezer at or below -5°C.  After reconstitution BOTOX® may be stored in a refrigerator (2-8°C) for up to 24 hours prior to use.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C (see also section 6.6).

6.5

Nature and content of container

Current text

Clear glass vial, with rubber stopper and tamper-proof aluminium seal, containing white powder for solution for injection.

Pack size:

·         Carton comprising one 100 Allergan Unit vial and package leaflet.

·         Packs containing two, three or six cartons.

Not all pack sizes may be marketed.

Replaces - Clear glass vial, with rubber stopper and tamper-proof aluminium seal, containing white powder for solution for injection.

6.6

Special precautions for disposal and other handling

The following text has been added

Any unused product or waste material should be disposed of in accordance with local requirements.

Administrative Data

Administrative Data (heading only)  - deleted

8

Marketing Authorization Numbers

Current text

MARKETING AUTHORISATION NUMBER(S)

PL 00426/0074

Replaces

MARKETING AUTHORISATION NUMBER

PL 0426/0074

10

Date of revision of the text

Current text

DATE OF REVISION OF THE TEXT

7th June 2007

Replaces

DATE OF (PARTIAL) REVISION OF TEXT

20 April 2006

Section Number

Subject

Change

6.3

Shelf life

Following statement added:

After reconstitution, immediate use of the solution is recommended; however stability has been demonstrated for 24hours at 2-8ºC

6.4

Special precautions for storage

Recommended storage after reconstitution changed from 4 to 24 hours in a refrigerator at 2-8ºC.

Following statement added:

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C (see also section 6.6)

6.6

Instructions for use and handling

Storage of Botox^® at 2-8ºC after reconstitution has been changed from 4 to 24 hours prior to use.

Following statement added:

Each vial is for single use only