1. Name Of The Medicinal Product
BOTOX
100 Allergan units
Powder for solution for injection
2. Qualitative And Quantitative Composition
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.
3. Pharmaceutical Form
Powder for solution for injection.
4. Clinical Particulars
4.1 Therapeutic Indications
BOTOX is indicated for:
• the symptomatic relief of blepharospasm, hemifacial spasm and idiopathic cervical dystonia (spasmodic torticollis)
• the management of severe hyperhidrosis of the axillae, which does not respond to topical treatment with antiperspirants or antihidrotics
• the 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)
BOTOX is also indicated for focal spasticity, including the treatment of:
• dynamic equinus foot deformity due to spasticity in ambulant paediatric cerebral palsy patients, two years of age or older
and
• wrist and hand disability due to upper limb spasticity associated with stroke in adults.
BOTOX is also indicated for the temporary improvement in the appearance of moderate to severe vertical lines between the eyebrows seen at frown (glabellar lines), in adults <65 years old, when the severity of these lines has an important psychological impact for the patient.
4.2 Posology And Method Of Administration
Botulinum toxin units are not interchangeable from one product to another. Doses recommended in Allergan units are different from other botulinum toxin preparations.
This product is for single use only and any unused solution should be discarded. The most appropriate vial size should be selected for the indication.
The following information is important:
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 50 Allergan Units, BOTOX 100 Allergan Units and BOTOX 200 Allergan Units. Each syringe should be labelled accordingly.
BOTOX must only be reconstituted with sterile sodium chloride 9 mg/ml (0.9%) solution for injection. The appropriate amount of diluent (see dilution table below) should be drawn up into a syringe.
Dilution table for BOTOX 50, 100 and 200 Allergan Units vial size:
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BOTOX should only be given by physicians with appropriate qualifications, and expertise in the treatment and the use of the required equipment.
For instructions on use, handling and disposal of vials please refer to section 6.6.
Elderly population
Adequate studies on geriatric dosing have not been performed. The lowest effective dose with the longest clinically indicated interval between injections is recommended. Elderly patients with significant medical history and concomitant medications should be treated with caution.
There is limited phase 3 clinical data with BOTOX for glabellar lines in patients older than 65 years (see section 5.1). Until more studies have been performed in this age group, BOTOX is not recommended in patients older than 65 years.
Paediatric population
The safety and effectiveness of BOTOX in the treatment of blepharospasm, hemifacial spasm, idiopathic cervical dystonia and primary hyperhidrosis of the axillae in children (under 12 years) have not been demonstrated.
The safety and efficacy of BOTOX in adolescents aged 12 to 17 years for the treatment of severe axillary hyperhidrosis have not been established. Currently available data are described in section 4.8 and 5.1 but no recommendation on a posology can be made (see sections 4.8 and 5.1).
The safety and effectiveness of BOTOX in the treatment of glabellar lines and in the prophylaxis of chronic migraine headaches have not been demonstrated in individuals under 18 years of age. The use of BOTOX is not recommended in patients less than 18 years for these indications.
Posology
Generally valid optimum dose levels and number of injection sites per muscle have not been established for all indications. In these cases, individual treatment regimens should therefore be drawn up by the physician. Optimum dose levels should be determined by titration but the recommended maximum dose should not be exceeded.
Blepharospasm
Reconstituted BOTOX is injected using a sterile, 27-30 gauge/0.40-0.30 mm needle. Electromyographic guidance is not necessary. The initial recommended dose is 1.25-2.5 Units (0.05-0.1 ml volume at each site) injected into the medial and lateral orbicularis oculi of the upper lid and the lateral orbicularis oculi of the lower lid. Additional sites in the brow area, the lateral orbicularis and in the upper facial area may also be injected if spasms here interfere with vision. Avoiding injection near 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. The following diagrams indicate the possible injection sites:
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 indefinitely. At repeat treatment sessions, the dose may be increased up to two-fold 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 little benefit obtainable from injecting more than 5 Units per site. The initial dose should not exceed 25 Units per eye. Normally no additional benefit is conferred by treating more frequently than every three months. It is rare for the effect to be permanent.
In the management of blepharospasm total dosing should not exceed 100 Units every 12 weeks.
Hemifacial spasm
Patients with hemifacial spasm or VIIth nerve disorders should be treated as for unilateral blepharospasm, with other affected facial muscles being injected as needed. Electromyographic control may be necessary to identify affected small circumoral muscles.
Cervical dystonia
Several dosing regimens have been used in clinical trials for treatment of cervical dystonia with BOTOX. Dosing must be tailored to the individual patient based on the patient's head and neck position, location of pain, muscle hypertrophy, patient's body weight, and patient response.
In initial controlled clinical trials to establish safety and efficacy for cervical dystonia, doses of reconstituted BOTOX ranged from 140 to 280 Units. In more recent studies, the doses have ranged from 95 to 360 Units (with an approximate mean of 240 Units). As with any drug treatment, initial dosing in a naïve patient should begin at the lowest effective dose. No more than 50 Units should be given at any one injection site. No more than 100 Units should be given to the sternomastoid. To minimise the incidence of dysphagia, the sternomastoid should not be injected bilaterally. No more than 200 Units total should be injected for the first course of therapy, with adjustments made in subsequent courses dependent on the initial response. A total dose of 300 Units at any one sitting should not be exceeded.
The following doses are recommended:
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The treatment of cervical dystonia typically may include injection of BOTOX into the sternocleidomastoid, levator scapulae, scalene, splenius capitis, semispinalis, longissimus and/or the trapezius muscle(s). This list is not exhaustive as any of the muscles responsible for controlling head position may be involved and therefore require treatment. The muscle mass and the degree of hypertrophy are factors to be taken into consideration when selecting the appropriate dose. Muscle activation patterns can change spontaneously in cervical dystonia without a change in the clinical presentation of dystonia.
A 25, 27 or 30 gauge/0.50-0.30 mm needle may be used for superficial muscles, and a 22 gauge needle may be used for deeper musculature. In case of any difficulty in isolating the individual muscles, injections should be made under electromyographic assistance.
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.
Clinical improvement generally occurs within the first two weeks after injection. The maximum clinical benefit generally occurs approximately six weeks post-injection. Treatment intervals of less than 10 weeks are not recommended. The duration of beneficial effect reported in clinical trials showed substantial variation (from 2 to 33 weeks) with a typical duration of approximately 12 weeks.
Primary hyperhidrosis of the axillae
The recommended injection volume for intradermal injection in axillary hyperhidrosis is 0.1-0.2 ml. Reconstituted BOTOX (100 Units/4 mL) is injected using a 30 gauge needle. 50 Units of BOTOX is injected intradermally to each axilla, evenly distributed in multiple sites approximately 1-2 cm apart. The hyperhidrotic area to be injected may be defined by using standard staining techniques, e.g. Minor´s iodine-starch test. Doses other than 50 Units per axilla have not been studied and therefore cannot be recommended.
Clinical improvement generally occurs within the first week after injection. Repeat injection of BOTOX can be administered when the clinical effect of a previous injection diminishes and the treating physician deems it necessary. Treatment response has been reported to persist for 4-7 months. Injections should not be repeated more frequently than every 16 weeks (see section 5.1).
Paediatric cerebral palsy
Reconstituted BOTOX is injected using a sterile 23-26 gauge/0.60-0.45 mm needle. It is administered as a divided dose through single injections into the medial and lateral heads of the affected gastrocnemius muscle. In hemiplegia, the initial recommended total dose is 4 Units/kg body weight in the affected limb. In diplegia, the initial recommended total dose is 6 Units/kg body weight divided between the affected limbs. The total dose should not exceed 200 Units.
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 not more frequently than every three months. It may be possible to adapt the dosage regimen to obtain an interval of at least six months between treatment sessions.
Focal upper limb spasticity associated with stroke
Reconstituted BOTOX is injected using a sterile 25, 27 or 30 gauge needle for superficial muscles, and a longer needle for deeper musculature. Localisation of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful. Multiple injection sites may allow BOTOX to have more uniform contact with the innervation areas of the muscle and are especially useful in larger muscles.
The exact dosage and number of injection sites may be tailored to the individual based on the size, number and location of muscles involved, the severity of spasticity, the presence of local muscle weakness, and the patient response to previous treatment.
In the controlled clinical trials the following doses were administered:
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In controlled and open non-controlled clinical trials doses between 200 and 240 Units divided among selected muscles have been used at a given treatment session.
In controlled clinical trials patients were followed for 12 weeks after single treatment. Improvement in muscle tone occurred within two weeks with the peak effect generally seen within four to six weeks. In an open, non-controlled continuation study, most of the patients were re-injected after an interval of 12 to 16 weeks, when the effect on muscle tone had diminished. These patients received up to four injections with a maximal cumulative dose of 960 Units over 54 weeks. If it is deemed appropriate by the treating physician, repeat doses may be administered, when the effect of a previous injection has diminished. Re-injections should not occur before 12 weeks. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of BOTOX and muscles to be injected. The lowest effective dose should be used.
Chronic Migraine
The recommended reconstituted BOTOX 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 to 31 and up to 39 sites. Injections should be divided across 7 specific head/neck muscle areas as specified in the diagrams below. 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 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 the table below.
The following diagrams indicate the injection sites:
BOTOX Dosing By Muscle:
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a1 IM injection site = 0.1 mL = 5 U BOTOX
b Dose distributed bilaterally
The recommended re-treatment schedule is every 12 weeks.
Glabellar lines
Reconstituted BOTOX (50 U/1.25 mL) is injected using a sterile 30 gauge needle. A volume of 0.1 mL (4 U) is administered in each of the 5 injection sites: 2 injections in each corrugator muscle and 1 injection in the procerus muscle for a total dose of 20 U.
Before injection, the thumb or index finger are to be placed firmly below the orbital rim in order to prevent extravasation below the orbital rim. The needle should be oriented superiorly and medially during the injection. In order to reduce the risk of ptosis, injections near the levator palpebrae superioris muscle must be avoided, particularly in patients with larger brow-depressor complexes (depressor supercilii). Injections in the corrugator muscle must be done in the central part of that muscle, at least 1 cm above the arch of the eyebrows.
Care should be taken to ensure that BOTOX is not injected into a blood vessel when it is injected in the glabellar lines.
Improvement of severity of glabellar lines generally occurs within one week after treatment. The effect was demonstrated for up to 4 months after injection.
Treatment intervals should not be more frequent than every three months. In the event of treatment failure or diminished effect following repeat injections, alternative treatment methods should be employed.
In case of insufficient dose and in the absence of any undesirable effects secondary to the first treatment session, adjusting the total dose up to 40 or 50 units should be considered in a second treatment session, taking into account the analysis of the previous treatment failure (see information in All indications).
All indications
In case of treatment failure after the first treatment session, i.e. absence, at one month after injection, of significant clinical improvement from baseline, the following actions should be taken:
- Clinical verification, which may include electromyographic examination in a specialist setting, of the action of the toxin on the injected muscle(s);
- Analysis of the causes of failure, e.g. bad selection of muscles to be injected, insufficient dose, poor injection technique, appearance of fixed contracture, antagonist muscles too weak, formation of toxin-neutralising antibodies;
- Re-evaluation of the appropriateness of treatment with botulinum toxin type A;
- In the absence of any undesirable effects secondary to the first treatment session, instigate a second treatment session as following: i) adjust the dose, taking into account the analysis of the earlier treatment failure; ii) use EMG; and iii) maintain a three-month interval between the two treatment sessions.
In the event of treatment failure or diminished effect following repeat injections alternative treatment methods should be employed.
4.3 Contraindications
BOTOX is contraindicated:
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4.4 Special Warnings And Precautions For Use
The relevant anatomy, and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering BOTOX and injection into vulnerable anatomic structures must be avoided. The recommended dosages and frequencies of administration of BOTOX should not be exceeded.
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. One case of anaphylaxis has been reported in which the patient died after being injected with BOTOX inappropriately diluted with 5 ml of 1% lidocaine. Please see “Additional information” in section 4.8 for further information.
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.
Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.
Dysphagia has also been reported following injection to sites other than the cervical musculature (see section 4.4 'Cervical Dystonia').
Clinical fluctuations during the repeated use of BOTOX (as with all botulinum toxins) may be a result of different vial reconstitution procedures, injection intervals, muscles injected and slightly differing potency values given by the biological test method used.
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. When appropriate, the potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest clinically indicated intervals between injections.
As with any treatment with the potential to allow previously-sedentary patients to resume activities, the sedentary patient should be cautioned to resume activity gradually.
Caution should be used when BOTOX is used in the presence of inflammation at the proposed injection site(s) or when excessive weakness or atrophy is present in the target muscle. 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).
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 Lambert-Eaton 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.
Blepharospasm
Reduced blinking following botulinum toxin injection into the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. Careful testing of corneal sensation in eyes previously operated upon, avoidance of injection into the lower lid area to avoid ectropion, and vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means.
Ecchymosis occurs easily in the soft eyelid tissues. This can be minimised by applying gentle pressure at the injection site immediately after injection.
Because of the anticholinergic activity of botulinum toxin, caution should be exercised when treating patients at risk for angle closure glaucoma, including patients with anatomically narrow angles.
Cervical dystonia
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.
Primary hyperhidrosis of the axillae
Medical history and physical examination, along with specific additional investigations as required, should be performed to exclude potential causes of secondary hyperhidrosis (e.g. hyperthyroidism, phaeochromocytoma). This will avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of underlying disease.
Focal spasticity associated with paediatric cerebral palsy and spasticity of the hand and wrist in adult post-stroke patients
BOTOX is a treatment of focal spasticity that has only been studied in association with usual standard of care regimens, and is not intended as a replacement for these treatment modalities. BOTOX is not likely to be effective in improving range of motion at a joint affected by a fixed contracture.
Post-marketing reports of possible distant spread of toxin have been very rarely reported in paediatric patients with co-morbidities, predominantly with cerebral palsy. In general the dose used in these cases was in excess of that recommended (see section 4.2).
There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin. Caution should be exercised when treating paediatric patients who have significant neurologic debility, dysphagia, or have a recent history of aspiration pneumonia or lung disease.
Chronic migraine
No efficacy has been shown for BOTOX in the prophylaxis of headaches in patients with episodic migraine (headaches on < 15 days per month).
Glabellar lines
It is mandatory that BOTOX is used for one single patient treatment only during a single session. The excess of unused product must be disposed of as detailed in section 6.6. Particular precautions should be taken for product preparation and administration as well as for the inactivation and disposal of the remaining unused solution (see section 6.6).
The use of BOTOX is not recommended in individuals under 18 years and in patients older than 65 years.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Theoretically, the effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or spectinomycin, or other medicinal products that interfere with neuromuscular transmission (e.g. neuromuscular blocking agents, both depolarising (succinylcholine) and non-depolarising (tubocurarine-derivatives), lincosamides, polymyxins, quinidine, magnesium sulphate, and anticholinesterases).
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.
No interaction studies have been performed. No interactions of clinical significance have been reported.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data from the use of botulinum toxin type A in pregnant women. Studies in animals have shown reproductive toxicity (see Section 5.3). The potential risk for humans is unknown. BOTOX should not be used during pregnancy unless clearly necessary.
Lactation
There is no information on whether BOTOX is excreted in human milk. The use of BOTOX during breastfeeding cannot be recommended.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. However, BOTOX may cause asthenia, muscle weakness, somnolence, dizziness and visual disturbance, which could affect driving and the operation of machinery.
4.8 Undesirable Effects
a) General
Based on controlled clinical trial data patients would be expected to experience an adverse reaction after treatment with BOTOX at the rates of 35% for blepharospasm, 28% for cervical dystonia, 17% for paediatric cerebral palsy and 11% for primary hyperhidrosis of the axillae. Sixteen percent of participants in clinical trials treated with BOTOX for focal spasticity of the upper limb associated with stroke and 23% with glabellar lines experienced an adverse reaction. In clinical trials for chronic migraine, the incidence was 26% with the first treatment and declined to 11% with a second treatment.
In general, adverse reactions occur within the first few days following injection and, while generally transient, may have a duration of several months or, in rare cases, longer.
Local muscle weakness represents the expected pharmacological action of botulinum toxin in muscle tissue.
As is expected for any injection procedure, localised pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling/oedema, erythema, localised infection, bleeding and/or bruising have been associated with the injection. Needle-related pain and/or anxiety have resulted in vasovagal responses, including transient symptomatic hypotension and syncope. Fever and flu syndrome have also been reported after injections of botulinum toxin.
b) Adverse reactions - frequency by indication
For each indication the frequency of adverse reactions arising from clinical experience is given. The frequency is defined as follows:
Very Common (
Blepharospasm/hemifacial spasm
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