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Botulinum Toxins


Toxinas botulfnicas.

ATC M03AX01.

ATC Vet — QM03AX01.

Description. Botulinum toxins A and B are neurotoxins produced by Clostridium botulinum. They are proteins comprising a heavy chain thought to be responsible for binding to the target cells and translocation of the toxin across the cell membrane, linked by a disulfide bond to a light chain responsible for the toxic activity.

Botulinum A Toxin

Botuliinitoksiini tyyppi A; Botulinum A Toksini; Toxin typ A mot botulism; Toxina botulfnica A; Toxine botulinique type A; Toxinum botulinicum typum A.

Pharmacopoeias. Europe includes the injection.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Botulinum Toxin Type A for Injection; Toxinum Botulinicum Typum A ad Iniectabile). A dried preparation containing purified botulinum neurotoxin type A, which may be present in the form of a complex with haemagglutinins and non-toxic proteins, prepared from a suitable strain of Clostridium botulinum type A.

Botulinum B Toxin

Botulinum B Toksini; Toxina botulfnica B.

Units

The dose of preparations containing botulinum toxins A or B is expressed in terms of units, but the available preparations are used at different doses for the same indications, and the units of one preparation cannot be considered to apply to another.

Adverse Effects

Injections of botulinum toxins have been associated with a transient burning sensation, bruising at the injection site, and local weakness. Adverse reactions related to the spread of botulinum toxins distant to the site of injection have been reported and sometimes this was associated with significant debility or a fatal outcome in very rare cases. Exaggerated muscle weakness may occur with therapeutic doses. Deep or misplaced injections may paralyse nearby muscle groups and excessive doses may paralyse distant muscles. Overdosage can produce a widespread paralysis. There have been occasional reports of hyper sensitivity reactions such as skin rashes and flulike symptoms. There have also been rare reports of cardiovascular adverse effects, including arrhythmia and myocardial infarction, and of seizures or convulsions, particularly in predisposed patients.

• The most common adverse effects after injection into muscles around the eye, such as in the management of blepharospasm, hemifacial spasm, or strabismus, are ptosis, lachrymation, photophobia, ocular irritation, and facial swelling. Some patients may be unable to close the eyelid completely. Other adverse effects that have been reported include ectropion and entropion, and diplopia. Patients experience a reduction in blinking and this can lead to dry eye, keratitis, and corneal damage. Angle-closure glaucoma has been reported. Vertical deviation has also occurred in patients treated for horizontal strabismus. Needle penetrations of the eye during treatment of strabismus have resulted in vitreous and ret-robulbar haemorrhages.

Dysphagia is the most common adverse effect after injection into neck muscles in the treatment of spasmodic torticollis and there may be pooling of saliva with risk of aspiration in severely affected patients (important, see also Precautions, below). Dry mouth, paralysis of the vocal cords, and weakness of the neck muscles may also occur. Generalised weakness, malaise, nausea, and visual disturbances have occasionally been reported. Other effects which have occurred rarely include drowsiness, numbness, stiffness, ptosis, and headache. Respiratory difficulties, associated with the use of large doses, have occurred on rare occasions.

• Adverse effects most frequently associated with injection into the lower limbs in the treatment of cerebral palsy include falling, leg pain, and local and general weakness; lethargy and leg cramps have also been reported.

• Common adverse effects after injection into the upper limb in the treatment of spasticity associated with stroke are arm pain, dysphagia, muscle weakness, and hypertonia. A perceived increase in non-axillary sweating, within one month of the injection, has been reported after treatment for hyperhidrosis of the axillae; rarely, mild transient weakness of the arms has also occurred.

• Headache is the most frequent adverse effect after injection into the muscles around the forehead in the treatment of glabellar (frown) lines. Other adverse effects frequently reported include ptosis, facial pain, muscle weakness, and nausea.

Incidence of adverse effects. It has been suggested that the difference between botulinum A toxin preparations may not be confined to just anumerical dosage adjustment. Reviews of the literature have suggested that there may also be a difference in the incidence of adverse effects. The reported frequency of dysphagia for Dysport (28% and 44%) in patients with spasmodic torticollis was greater than that for Botox (9.5 to 17%). This variation might relate to differences in bioactivity not recognised by the mouse lethality bioassay which is used to determine the potency of preparations.

Angiosarcoma. It has been suggested that botulinum A toxin injection might have acted as a triggering factor for angiosarcoma in a 66-year-old patient being treated for blepharospasm.

Antibody formation. Neutralising antibodies that reduce or abolish the beneficial effects of treatment have been found after prolonged treatment with botulinum A toxin.A review in 1994 considered that there was growing concern over the development of antibodies after repeated injections, as many of the conditions for which botulinum toxin is indicated require indefinite treatment. Antibody formation was reported to be more common with high doses (as in spasmodic torticollis) than after low doses (as for blepharospasm). The occurrence of antibodies appeared to correlate with the dose per injection, the quantity of botulinum protein given per injection, the number of injections given, and the frequency of injections.

Antibodies have also developed after the use of botulinum B toxin. However, botulinum toxin B is antigenically distinct from botulinum A toxin, and may be of value in patients who develop resistance to treatment associated with antibody formation to type A toxin. Botulinum F toxin is also antigenically distinct and is being studied in a similar way.

Biliary colic. A 43-year-old woman with no history of gallbladder disease had single episodes of biliary colic after each of 3 sessions of treatment with botulinum A toxin for blepharospasm. Botulinum A toxin might have exerted a systemic effect to block acetylcholine release leading to gallbladder hypomotility with delayed emptying and stasis.

Dysphagia. By November 1993, the UK CSM had received 4 reports of severe dysphagia with choking in patients given injections of botulinum A toxin into the neck muscles as a treatment for torticollis. The dysphagia developed 5 to 7 days after the injection and in one patient it was persisting 6 weeks after the injection. The dysphagia led to aspiration of the stomach contents into the lungs and one patient with a history of poor lung function died from bronchopneumonia. Dysphagia is also reported to be a common adverse effect in patients with spasmodic torticollis being treated with Botulinum B toxin. See also Incidence of Adverse Effects, above for further reference to dysphagia as an adverse effect.

Effects on the eyes. Acute angle-closure glaucoma has been reported in an 83-year-old woman after a series of injections of botulinum A toxin for the treatment of blepharospasm. Permanent extra-ocular muscle damage after botulinum A toxin injection into the left inferior rectus muscle has been reported in a 70-year-old man.

Treatment of Adverse Effects

The use of artificial tears may relieve keratitis and dry eye. In the event of overdosage general supportive care is required. The patient should be monitored for several days for signs of paralysis and artificial respiration may be necessary. Since the effects of botulinum toxins are irreversible once bound to nerve terminals, it is doubtful that specific botulinum antitoxin will be of value unless given very rapidly after overdosage.

Precautions

Botulinum toxin is contra-indicated in generalised disorders of muscle activity such as myasthenia gravis. As with other biological products, the potential for botulinum toxin to cause anaphylaxis should be considered. Botulinum toxins should be given with extreme caution to patients with neurological disorders or a history of dysphagia or aspiration. Patients or their carers should be advised to seek immediate medical attention if problems with swallowing or speech, or respiratory disorders develop.

Botulinum toxins should only be used by appropriately qualified and trained specialists. Injections must be made with great care, especially those into the neck, to avoid unintended paralysis; the relevant anatomy, and any alterations due to previous surgery, must be understood before injection. Botulinum toxins should not be given if there is any infection at the proposed injection site.

The effects of botulinum toxins in pregnancy are unknown; fetal malformations and abortion have been reported in rabbits, and licensed product information recommends that botulinum toxins should not be given to pregnant women. Breast feeding is also considered a contra-indication: it is not clear whether the toxin is distributed into breast milk.

When injected into the muscles around the eyes, as for the treatment of blepharospasm, hemifacial spasm, or strabismus, reduced blinking can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with seventh cranial nerve disorders. Corneal sensation should be carefully tested in previously treated eyes, injection into the lower eyelid area avoided, and any resulting epithelial defect vigorously treated.

Handling. Residual botulinum A toxin or spillages should be inactivated by autoclaving or use of a dilute hypochlorite solution (0.5%). Botulinum B toxin may be decontaminated in a similar manner; a strong caustic solution may also be used.

Interactions

The effect of botulinum toxins may theoretically be potentiated by aminoglycosides or spectinomycin. Interactions may also occur with other drugs that have neuromuscular blocking activity, including lincosamides, polymyxins, tetracyclines, and muscle relaxants.

Uses and Administration

Botulinum toxins cause neuromuscular blockade by inhibiting the calcium-ion mediated release of acetylcholine at the motor nerve terminals, resulting in a diminished endplate potential and subsequent flaccid paralysis of the affected muscles. The paralysis persists until new nerve terminals form, usually within 2 to 4 months.

Botulinum A toxin is given as a complex usually with haemagglutinin by local injection in the treatment of hemifacial spasm, blepharospasm, spasmodic torticollis, lower limb spasticity in children with cerebral palsy, and upper limb spasticity associated with stroke in adults. Botulinum A toxin is also used for the management of strabismus and hyperhidrosis, and has also been approved for the treatment of glabellar (frown) lines in adults up to 65 years of age. It is being investigated for use in the management of several other disorders. Botulinum B toxin is also used in the management of spasmodic torticollis and, being antigenically distinct, it has the potential for use in patients who develop resistance to treatment due to the development of antibodies to type A toxin.

Doses of botulinum toxins A and B are expressed in terms of units, which have not been standardised between preparations (see under Units, above). Doses are therefore specific to each individual preparation; details are given below.

Botulinum F toxin is under investigation for the treatment of similar neuromuscular disorders.

Achalasia. The treatment of choice for achalasia (see Oesophageal Motility Disorders) is mechanical dilatation of the lower oesophageal sphincter, or if necessary surgery, but more recently injection of botulinum A toxin has been found to be effective. However, one year after treatment only 7 of 22 (32%) patients who received botulinum A toxin were in symptomatic remission compared with 14 of 20 (70%) patients treated with mechanical dilatation. It was recommended that its use would be better reserved for patients thought to be at risk from mechanical dilatation or surgery. Another study showed that intrasphincteric injection of botulinum toxin A was safe and effective for the treatment of achalasia in the short and medium term, although only a weak correlation with dose emerged.

Anal fissure. Anal fissure is a superficial tear in the mucosa of the distal anal canal characterised by pain on defaecation, rectal bleeding, and spasm of the anal sphincter. Healing, which is usually uneventful, may be helped by conservative management with bran and bulk laxatives and topical local anaesthetics for pain relief. Surgical treatment has been used for patients who develop a chronic condition but has been associated with high rates of long-term incontinence and recurrence. Although systematic reviews considered that surgery was more effective than alternative medical therapies, a number of these have been investigated. As hypertonicity of the internal anal sphincter may be involved in the pathophysiology of chronic anal fissure, local injections of botulinum A toxin have been used to produce paresis of this sphincter. The duration of the effect appears to be long enough to allow complete healing of the fissure in most patients although some may relapse; a long-term, follow-up trial involving 57 completely healed patients, noted a high recurrence rate (41.5%) once the effects of botulinum toxin disappeared. Temporary incontinence had been the only adverse effect reported during treatment.

Topical application of nitrates can relax the anal sphincter; numerous studies have reported benefit from topical application of glyceryl trinitrate, although a high rate of spontaneous resolution with placebo has cast doubt over the degree of advantage in some studies. Follow-up of patients treated with glyceryl trinitrate indicated that after 24 to 38 months most had not experienced further problems or had had occasional recurrences which in the majority of cases had responded to further topical treatment. Isosorbide dinitrate ointment has also been tried, and may be of benefit with botulinum A toxin. Topical calcium antagonists also seem to be effective. Both diltiazem and nifedipine seem to be of benefit and there is evidence that they may be a better choice than topical glyceryl trinitrate. Nifedipine has been combined with botulinum toxin; it has also been given orally.

Anismus. Anismus is a condition in which inappropriate contraction of the anal sphincters occurs when bowel evacuation is attempted; it seems to be a form of dystonia. Treatment with botulinum A toxin was investigated in 7 patients with intractable constipation due mainly to anismus. The toxin was injected bilaterally into the puborectalis muscle using an electromyographically guided needle; patients were allowed to continue with their laxatives throughout the study if required. Symptoms improved in all but one of the patients, although two patients could not be regarded as treatment successes because they developed faecal incontinence; four patients had an excellent clinical outcome. However, another study involving 24 patients found the clinical effectiveness of botulinum A toxin to be limited, and further studies are needed to determine its role in the treatment of anismus.

Blepharospasm. Blepharospasm is a focal dystonia characterised by repeated involuntary blinking caused by spasms of the orbicularis oculi muscle of the eye, and can result in functional blindness. Blepharospasm is often associated with other dysto-nias of the head and neck, such as Meige syndrome, in which patients also suffer from involuntary contractures of the muscles around the mouth. Oral drug treatment as used for dystonias in general is usually ineffective, and surgery (facial nerve avulsion) is often followed by recurrent spasm. Tocal injections of botulinum A toxin into the orbicularis oculi muscle mimic the effect of surgical denervation of the muscle and are reported to have been effective in over 70% of patients. Symptomatic improvement has been reported to last from about 9 to 15 weeks; no increase in duration of effect is apparent following multiple injections. In one retrospective study in patients with blepharospasm and Meige syndrome, treatment with botulinum A toxin was still effective in most patients 11 years after the start of therapy.

For blepharospasm botulinum A toxin is injected into the orbicularis oculi of the upper and lower lids; injection into additional sites in the brow area and upper facial area may be indicated if the spasms interfere with vision. Doses of botulinum A toxin are expressed in terms of units, which have not been standardised between preparations. Doses are therefore specific to each individual preparation:

The preparation Botox (Allergan, UK) is injected intramuscularly in an initial dose of 1.25 to 2.5 units at each site to a total of up to 25 units per eye. An effect is usually obtained within 3 days and reaches a peak after 1 to 2 weeks; each treatment lasts for about 3 months. If the response lasts less than 2 months the dose may be increased up to 5 units at each site but the total dose given in a 12-week period should not exceed 100 units. Giving more often than every 3 months confers no additional benefit. Botox (Allergan) is also available in the USA and given in similar doses, although higher cumulative doses of up to 200 units are allowed in a 30-day period

• The preparation Xeomin (Merz, UK) is injected intramuscularly in an initial dose of 1.25 to 2.5 units at each site to a total of up to 25 units per eye. An effect is usually obtained within 4 days; each treatment lasts for about 3 to 4 months. If the response lasts less than 2 months the dose may be increased up to 5 units at each site but the total dose given in a 12-week period should not exceed 100 units. Giving more often than every 3 months confers no additional benefit.

• For the preparation Dysport (Ipsen, UK) the initial dose is a total of 120 units per eye given as subcutaneous injections of 20 and 40 units per site. Subsequently the total dose may need to be reduced to 60 to 80 units per eye. With this preparation the relief of symptoms may begin within 2 to 4 days with a maximum effect being obtained within 2 weeks. Injections of Dysport should be repeated every 12 weeks or as required.

Cosmetic use. Botulinum A toxin has been used for the cosmetic treatment of facial lines and wrinkles and age-related neck degeneration.

For the temporary improvement in appearance of moderate to severe glabellar (frown) lines two doses of botulinum A toxin are injected into each of the corrugator muscles and one dose into the procerus muscle. Doses of botulinum A toxin are expressed in terms of units, which have not been standardised between preparations. Doses are therefore specific to each individual preparation: the preparation Botox Cosmetic (Allergan, USA) is injected intramuscularly, not closer than 1 cm above the central eyebrow. A dose of 4 units is given into each of 5 sites to a total dose of 20 units. An effect is obtained in 1 to 2 days which increases in intensity in the first week; each treatment lasts for about 3 to 4 months. More frequent dosing is not recommended as safety and effectiveness have not been evaluated.

A preparation with a similar dosage regimen (Vistabel; Allergan, UK) is available in the UK.

Gastric motility disorders. Some benefit has been reported from the use of botulinum A toxin injection in gastric motility disorders. In an open-label study 6 diabetic patients with gastroparesis experienced an improvement in gastric emptying after treatment with botulinum A toxin.

Hand dystonia. Hand dystonia, or hand cramp, is a type of focal dystonia. It is more commonly reported in people who perform repetitive movements with their hands, such as writers, keyboard operators, and musicians. Treatment was traditionally with antimuscarinics, although with limited success, but botulinum toxin has increasingly become the first-line option. A double-blind study reported that 8 out of 10 patients had greater subjective improvement in focal hand dystonia, compared with placebo, after treatment with botulinum A toxin given by the intramuscular route; objective improvement in muscle strength was seen in 6 patients. However, pain and severe weakness in the shoulder region resembling neuralgic amyotrophy has been reported in 2 patients injected with botulinum A toxin for writer’s cramp. It was considered that if unexplained pain occurred in the shoulder or upper arm after a first injection of botulinum A toxin further injections were contra-indicated.

Headache. The therapeutic effect of botulinum A toxin in headache was first seen as a coincidental adverse effect in patients receiving the drug for hyperfunctional facial lines. A review of subsequent studies concluded that efficacy could be demonstrated for the prophylaxis of migraine; a small number of patients who received treatment during the acute phase of a migraine attack also experienced pain relief. Contradictory results had been reported in the studies evaluating tension-type headache and continue to be reported. However, in the original review it was emphasised that an important finding had been the need to inject botulinum A toxin at the site of the pain or trigger points and not on a standardised basis, and that this should be considered in future studies. Improvement had been noted in individual cases of cluster headache and in some patients with headache attributed to disorders of the neck.

Some benefit has also been seen with botulinum B toxin in the treatment of migraine and tension-type headaches.

Hemifacial spasm. Hemifacial spasm is characterised by involuntary unilateral synchronous contractions of muscles innervated by the facial nerve. The spasms usually begin with twitching of muscles around the eye or mouth but as the disease progresses their frequency increases and they spread to involve the rest of the facial muscles. Hemifacial spasm may be improved by surgery but there is a risk of irreversible paralysis. Few drugs are effective for hemifacial spasm but carbamazepine has been reported to have been of help on occasions. Reports suggest that injections of botulinum A toxin may be effective in relieving symptoms in at least 75% of patients but there do not appear to be any studies comparing it against other treatments. Repeat injections are required by most patients every 3 to 4 months but long-term efficacy appears to be maintained. Dosage regimens of botulinum A toxin used in hemifacial spasm are similar to those used for blepharospasm (see above) although an electro-myographically guided needle may be required to identify small muscles around the mouth. References.

Hyperhidrosis. A number of drugs and surgical techniques have been used in the treatment of hyperhidrosis. Botulinum A toxin is used in the management of focal hyperhidrosis because of its ability to block cholinergic transmission at nerve terminals innervating the sweatglands. Encouraging results have been obtained in patients with severe resistant focal hyperhidrosis using intradermal or subcutaneous injections and results from two larger multicentre studies confirm that intradermal injection of botulinum A is effective and well-tolerated for the treatment of axillary hyperhidrosis. In the UK, it is given for this purpose as the preparation Botox (Allergan, UK), by intradermal injection in doses of 50 units to each axilla, evenly distributed in multiple sites approximately 1 to 2 cm apart. Clinical improvement generally occurs within a week of injection, and may last for 4 to 7 months; repeat injections may be given once the effects of the previous injection have subsided. Botox (Allergan) is also available in the United States of America for the treatment of axillary hyperhidrosis; it is given in similar doses.

Some workers prefer to use intradermal injections for palmar hyperhidrosis in order to minimise the risk of reversible weakness of the small muscles of the hand reported with subcutaneous injection.

Hyperlachrymation. Botulinum A toxin may be of benefit in the management of hyperlachrymation (‘crocodile tears’).

Laryngeal dystonias. Botulinum A toxin has been tried in the treatment of spasmodic dysphonia, focal laryngeal dystonia, and dysfunctional spasm after total laryngectomy. Botulinum B toxin has also been used.

Micturition disorders. Preliminary results suggest that injection of botulinum A toxin into the detrusor muscle can increase functional bladder capacity and restore continence in patients with urinary incontinence after spinal cord injury who are resistant to antimuscarinics. Similar results have been found in children with detrusor hyperreflexia caused by myelomeningocele.

Botulinum A toxin has also been tried in other bladder dysfunctions. Reviews have concluded that although there is some evidence that injection of botulinum toxins into the detrusor wall can improve symptoms of overactive bladder syndrome, further studies are warranted.

In a few small studies the injection of botulinum A toxin into the prostate gland has been reported to relieve the symptoms of urinary retention associated with benign prostatic hyperplasia.

Nystagmus. Surgery, corrective spectacles, and drug therapy have all been tried for the treatment of nystagmus (rapid involuntary movement of the eyeball). Retrobulbar injection of botulinum A toxin has produced improvement in patients with acquired or congenital nystagmus. In 6 patients with acquired nystagmus visual acuity was improved, and the amplitude of the nystagmus was reduced, but the frequency was generally unchanged and the need for repeated injections and adverse effects such as diplopia limited patient acceptability.

Ocular surgery. Ptosis is a common adverse effect of botulinum A toxin but therapeutic ptosis induced with botulinum toxin has been described as a useful adjunct in the management of patients undergoing epikeratoplasty since it promoted stabilisation of the epithelium on the graft.

Pain. There have been anecdotal reports of the use of botulinum A toxin in the treatment of painful disorders such as postcholecystectomy pain associated with sphincter of Oddi dysfunction, and relief of orofacial pain associated with temporomandibular joint dysfunction and facial arthromyalgia. Promising results have been obtained from an open study investigating botulinum toxin as a treatment for chronic refractory tennis elbow in 14 patients. Its efficacy in relieving pain in other chronic conditions such as low back pain, and myofascial pain, in addition to improving function, has also been shown in individual studies. The general management of pain is discussed on p.2 with separate sections on biliary and renal colic, low back pain, orofacial pain, and soft-tissue rheumatism.

Sialorrhoea. Botulinum toxins may be effective in the treatment of sialorrhoea and drooling associated with conditions such as cerebral palsy and Parkinson’s disease. A review found botulinum toxin A to be safe and effective in the treatment of sialorrhoea; however, further studies are warranted.

Spasmodic torticollis. Spasmodic torticollis (cervical dystonia) is a focal dystonia (p. 809) characterised by spasmodic rotation of the head as a result of dystonic spasm of the neck muscles. The head may turn to one side (torticollis), extend (retrocollis), or flex (antecollis). Spasms may be repetitive or sustained. Response of spasmodic torticollis to drug therapy is usually poor and surgery has been associated with potentially serious complications. Intramuscular injections of botulinum toxins can be effective but dysphagia, which can have severe consequences (see under Adverse Effects, above) occurs in a significant number of patients. Other adverse effects have included lethargy, local weakness, vertigo, and dysphonia.

When injecting botulinum toxins localisation of the involved muscles with electromyographic guidance may be useful. Multiple injection sites allow more uniform contact with the innerva-tion areas of the dystonic muscle and are especially useful in larger muscles. Bilateral injection of the sternocleidomastoid muscle is not recommended as there is an increased risk of adverse effects, especially dysphagia. Reduced doses may be required for patients with reduced muscle mass. Doses of botulinum toxins, which are expressed in terms of units, have not been standardised between preparations. Doses are therefore specific to each individual preparation. In the UK the usual initial dose of botulinum A toxin as the preparation Dysport (Ipsen, UK) is 500 units injected in divided doses into the two or three most active neck muscles:

for rotational torticollis, 350 units is given initially into the splenius capitis muscle (ipsilateral to the direction of the chin/head rotation) and 150 units into the sternocleidomastoid muscle (contralateral to rotation)

• for laterocollis, 350 units is given initially into the ipsilateral splenius capitis muscle and 150 units into the ipsilateral sternocleidomastoid muscle; if associated with shoulder elevation, ipsilateral trapezoid or levator scapulae muscles may also require treatment; if 3 muscles need treatment, 300 units are injected into the splenius capitis muscle, 100 units into the sternocleidomastoid muscle, and 100 units into the third muscle

• for retrocollis, 250 units is given into each of the splenius capitis muscles which may be followed after 6 weeks by bilateral trapezius injections in a dose of up to 250 units per muscle; bilateral splenii injections may increase the risk of neck muscle weakness

Subsequent doses may range from 250 to 1000 units, although the higher doses may be accompanied by an increase in adverse effects such as dysphagia; doses above 1000 units are not recommended. An initial effect is usually observed within 1 week; injections usually need to be repeated every 12 weeks or as required.

In the UK, botulinum A toxin as the preparation Xeomin (Merz, UK) is indicated for spasmodic torticollis. Licensed product information recommends that doses should be tailored to meet individual patient requirements. In practice, the maximum total dose is usually not more than 200 units but up to 300 units may be given. No more than 50 units should be given at any one injection site; limiting the dose injected into the sternocleidomastoid muscle to less than 100 units may reduce the risk of dysphagia. An initial effect is usually observed within 1 week; each treatment lasts for about 3 to 4 months and injections may be repeated if necessary after at least 10 weeks. Recommended doses in the UK for botulinum A toxin as the preparation Botox (Allergan, UK) are listed below but licensed product information states that in practice the maximum total dose is not usually more than 200 units. No more than 50 units should be given at any one injection site; limiting the dose injected into the sternocleidomastoid muscle to less than 100 units may reduce the risk of dysphagia.

Type I (head rotated toward side of shoulder elevation) — sternocleidomastoid muscle: total dosage of 50 to 100 units divided amongst at least 2 sites; levator scapulae: total of 50 units amongst 1 or 2 sites; scalene: total of 25 to 50 units amongst 1 or 2 sites; splenius capitis: total of 25 to 75 units amongst 1 to 3 sites; trapezius: total of 25 to 100 units amongst 1 to 8 sites

Type II (head rotation only) — sternocleidomastoid muscle: total dosage of 25 to 100 units divided amongst at least 2 sites if more than 25 units is given

Type III (head tilted toward side of shoulder elevation) — sternocleidomastoid muscle: total dosage of 25 to 100 units at posterior border divided amongst at least 2 sites if more than 25 units is given; levator scapulae: total of 25 to 100 units amongst at least 2 sites; scalene: total of 25 to 75 units amongst at least 2 sites; trapezius: total of 25 to 100 units amongst 1 to 8 sites

Type iF (bilateral posterior cervical muscle spasm with elevation of the face) — splenius capitis and splenius cervicis: a total dosage of 50 to 200 units divided amongst 2 to 8 sites and which include both sides of the neck

Botulinum A toxin as the preparation Botox (Allergan, USA) is also available in the USA for the treatment of spasmodic torticollis. Licensed product information recommends that doses should be tailored to meet individual patient requirements. In the UK the usual initial dose of botulinum B toxin as the preparation NeuroBloc (Zeneus Pharma, UK) is 5000 to 10 000 units given by intramuscular injection in divided doses into the two to four most affected muscles.

Botulinum B toxin as the preparationMyoWoc (Solstice, USA) is also available in the United States of America. The initial dose is 2500 to 5000 units given by intramuscular injection divided between the affected muscles. Licensed product information recommends that patients with no history of tolerating botulinum injections should be started on a lower initial dose. References.

Spasticity. The mainstay of management of spasticity, as discussed on site, is physiotherapy together with antispastic drugs. Chemical neurolysis should only be considered when there is intractable continuous pain. Local injections of botulinum A toxin, as an alternative to chemical neurolysis, have been used in the management of limb spasticity in multiple sclerosis, and in post-stroke patients, and children with cerebral palsy. However, systematic reviews have found insufficient evidence to support or refute such use in children with cerebral palsy. Botulinum B toxin has also been tried. Doses of botulinum A toxin, which are expressed in terms of units, have not been standardised between preparations. Doses are therefore specific to each individual preparation: Botulinum A toxin is used in the management of dynamic equinus foot deformity associated with spasticity in children with cerebral palsy.

• For children over 2 years of age the recommended total dose of botulinum A toxin as the preparation Botox (Allergan, UK) is 4 units/kg inj ected into each of 2 sites in the medial and lateral heads of the gastrocnemius muscle. When both lower limbs are to be injected on the same occasion this total dose should be divided between the 2 limbs. Clinical improvement generally occurs within the first 2 weeks. Repeat doses should not be given more frequently than every 2 months.

• For children over 2 years of age the recommended total dose of botulinum A toxin as the preparation Dysport (Ipsen, UK) is 10 to 30 units/kg divided between both calf muscles, primarily targeted to the gastrocnemius muscle. The maximum dose administered should not exceed 1000 units per patient. Clinical improvement generally occurs within the first 2 weeks. Repeat doses should not be given more frequently than every 12 weeks.

Botulinum A toxin is also used in the treatment of upper limb spasticity in adults.

• In the treatment of upper limb spasticity associated with stroke, the exact dosage and number of injection sites of botulinum A toxin as the preparation Botox (Allergan, UK) should be tailored to the individual based on the muscles involved, the severity of the spasticity, and the presence of local weakness. The manufacturer recommends a total dose of 50 units into the flexor digitorum profundus, the flexor digito-rum sublimis, the flexor carpi radialis, or the flexor carpi ul-naris, and a total dose of 20 units into the adductor pollicis or flexor pollicis longus. In clinical studies, cumulative doses did not exceed 360 units at any treatment session.

• In the treatment of focal spasticity of the arm, the recommended total dose of botulinum A toxin as the preparation Dysport (Ipsen, UK) is 1000 units divided into: a dose of 150 units into the flexor digitorum profundus, the flexor carpi ulnaris, and the flexor carpi radialis; 150 to 250 units into the flexor digitorum superficialis; and 300 to 400 units into the biceps brachii. All muscles should be injected at one site except the biceps brachii which should be injected at 2 sites. Lower doses are recommended in patients whose target muscles are small, where the biceps brachii is not to be injected, or in patients receiving multi-level injections. Clinical improvement generally occurs within the first 2 weeks.

Stiff-man syndrome. A patient with stiff-man syndrome (see Muscle Spasm) had marked improvement of ambulation and cessation of pain after injection of botulinum A toxin into affected paraspinal muscles. In another case report, improvement in rigidity and muscle spasm was reported in 2 patients after botulinum treatment; muscle spasms reduced within 3 days of treatment. It was also found that there was an increase in the duration of effect of botulinum A toxin after each subsequent injection and only a gradual return of painful spasm.

Strabismus. Botulinum A toxin has been used to weaken over-active extra-ocular muscles as an alternative or adjunct to surgery in the correction of strabismus. Not all patients respond to botulinum A toxin and many patients who do respond require more than one injection to maintain improvement. Botulinum A toxin does not appear to offer a better degree of correction than traditional surgery, and it has been suggested that it should be reserved for use in patients unresponsive to, or unsuitable for, surgery. In the United States of America botulinum A toxin as the preparation Botox (Allergan, USA) is indicated for the treatment of strabismus in patients 12 years of age or older. Depending on the direction and degree of deviation to be corrected the recommended initial dose of Botox to be injected into any one extra-ocular muscle ranges from 1.25 to 5 units. Paralysis is usually seen within the first 2 days and increases in intensity during the first week. The paralysis lasts for 2 to 6 weeks and gradually resolves over a further 2 to 6 weeks. It is recommended that patients are re-examined 7 to 14 days after injection to assess the effect of the dose given. If treatment is required for residual or recurrent strabismus, patients are either given treatment at the previous dosage if response was judged to have been adequate or up to twice the previous dose if paralysis had been incomplete; no more than 25 units should be injected into any one muscle. Repeat injections should not be given until the effects of the previous dose have dissipated. Injections should be diluted with unpreserved 0.9% sodium chloride solution so that the volume given per muscle is between 0.05 mL and 0.15 mL. Injections should also be made using an electromy-ographically guided needle to aid location of the target muscle. References.

Stuttering. Botulinum toxin may be of benefit in the treatment of stuttering.

Tourette’s syndrome. Improvement in tics was noted in patients with Tourette’s syndrome (see Tics) treated with botulinum A toxin.

Tremor. Local injection of botulinum A toxin has been tried in patients with essential tremor that fails to respond to conventional treatment. Botulinum A toxin injection has also been successfully used to treat essential palatal tremor and associated symptoms such as uncomfortable ear clicking.

Vaginismus. Report of one patient who had relief of vaginismus (painful involuntary spasm of the vaginal or perianal muscles severe enough to prevent intercourse) for more than 24 months after injection of botulinum toxin into the vaginal wall muscles.

Preparations

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2: Botulinum Toxin Type A for Injection.

Proprietary Preparations

Argentina: Botox; Dysport;

Australia: Botox; Dysport;

Austria; Botox; Dysport; NeuroBloc;

Belgium: Botox; Dysport;

Brazil: Botox; Dysport; Prosigne;

Canada: Botox;

Chile: Dyslor;

Czech Republic: Botox; Dysport; NeuroBloc; Vistabel;

Denmark: Botox; Dysport; Vistabel;

Finland: Botox; Dysport; Vistabel;

France: Botox; Dysport; NeuroBloc; Vistabel;

Germany; Botox; Dysport; NeuroBloc ; Xeomin;

Greece: Botox; Dysport; Vistabel;

Hong Kong; Botox; BTXA; Dysport;

Hungary: Botox; Dysport; Vistabel;

Indonesia: Lanzox;

Ireland: Botox; Dysport; NeuroBloc;

Israel: Botox; Dysport;

Italy: Botox; Dysport; NeuroBloc; Botox;

Malaysia: Botox; Dysport;

Mexico: Botox;

The Netherlands: Botox; Dysport; NeuroBloc;

Norway: Botox; Dysport; Vistabel;

New Zealand: Botox; Dysport;

Philippines: Botox; Dysport;

Poland: Botox; Dysport;

Portugal: Botox; Dysport; NeuroBloc; Vistabel; Xeomin;

Russia: Botox; Dysport;

South Africa; Botox;

Singapore: Botox; Dysport;

Spain: Botox; Dysport; NeuroBloc; Vistabel;

Sweden: Botox; Dysport; Vistabel;

Switzerland: Botox; Dysport; Vistabel;

Thailand: Botox; Dysport;

Turkey: Botox; Dysport;

United Kingdom (UK): Botox; Dysport; NeuroBloc; Vistabel; Xeomin;

United States of America (US and USA): Botox; Nyobloc;

Venezuela: Botox; Dysport.

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