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Glossary
| BANM | British Approved Name (Modified) |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
Risperidone 3mg Film-coated Tablets
Each tablet contains 3 mg of the active substance risperidone.
Excipient: 183.75mg lactose monohydrate per tablet.
For a full list of excipients, see section 6.1
Film coated Tablet
White, 11 x 6.5 mm oval biconvex, scored, coated tablet, marking "T3".
The tablet can be divided into equal halves.
Risperidone tablets are indicated for the treatment of acute and chronic schizophrenic psychoses, and other psychotic conditions, in which positive symptoms (such as hallucinations, delusions, thought disturbances, hostility, suspiciousness), and/or negative symptoms (such as blunted affect, emotional and social withdrawal, poverty of speech) are prominent. Risperidone tablets also alleviate affective symptoms (such as depression, guilt feelings, anxiety) associated with schizophrenia.
Risperidone tablets are also effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.
Risperidone tablets are indicated for the treatment of mania in bipolar disorder. These episodes are characterized by symptoms such as elevated, expansive or irritable mood, inflated self-esteem, decreased need for sleep, pressured speech, racing thoughts, distractibility, or poor judgment, including disruptive or aggressive behaviours.
Risperidone tablets are not licensed for the treatment of behavioural symptoms of dementia (see section 4.4).
4.2. a Schizophrenia:
Switching from other antipsychotics: where medically appropriate, gradual discontinuation of the previous treatment while Risperidone therapy is initiated is recommended. Where medically appropriate when switching patients from depot antipsychotics, consider initiating Risperidone therapy in place of the next scheduled injection. The need for continuing existing antiparkinson medication should be re-evaluated periodically.
Adults
Risperidone tablets may be given once or twice daily. All patients, whether acute or chronic, should start with 2 mg/day Risperidone tablets. The dosage may be increased to 4 mg/day on the second day. Some patients, such as first episode patients, may benefit from a slower rate of titration. From then on the dosage can be maintained unchanged, or further individualised, if needed. Most patients will benefit from daily doses between 4 and 6 mg/day although in some, an optimal response may be obtained at lower doses.
Doses above 10 mg/day generally have not been shown to provide additional efficacy to lower doses and may increase the risk of extrapyramidal symptoms. Doses above 10 mg/day should only be used in individual patients if the benefit is considered to outweigh the risk. Doses above 16 mg/day have not been extensively evaluated for safety and therefore should not be used.
Elderly
A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.
Children
Use of Risperidone tablets for schizophrenia in children aged less than 15 years has not been formally evaluated.
Renal and liver disease
A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.
Risperidone tablets should be used with caution in this group of patients until further experience is gained.
4.2. b Bipolar Mania:
Adults
Risperidone should be administered on a once daily schedule, starting with 2 mg. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments of 1 mg per day. A dosing range between 1 and 6 mg per day is recommended.
As with all symptomatic treatments, the continued use of Risperidone tablets must be evaluated and justified on an ongoing basis.
Elderly
A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.
Renal and liver disease
A starting dose of 0.5 mg bd is recommended. This dosage can be individually adjusted with 0.5 mg bd increments to 1 to 2 mg bd.
Risperidone tablets should be used with caution in this group of patients until further experience is gained.
Combined use with mood stabilisers
There is limited information on the combined use of Risperidone tablets with carbamazepine in bipolar mania. Carbamazepine has been shown to induce the metabolism of risperidone producing lower plasma levels of the antipsychotic fraction of Risperidone tablets (see Section 4.5). It is therefore not recommended to co-administer Risperidone tablets with carbamazepine in bipolar mania patients until further experience is gained. The combined use with lithium or valproate does not require any adjustment of the dose of Risperidone tablets.
Method of administration
Oral use.
Risperidone tablets are contraindicated in patients with a known hypersensitivity to risperidone or any other ingredients in the product.
Elderly patients with dementia
Elderly patients with dementia treated with atypical antipsychotic drugs had an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including risperidone. In placebo-controlled trials with risperidone in this population, the incidence of mortality was 4.0% for risperidone–treated patients compared to 3.1% for placebo-treated patients. The mean age (range) of patients who died was 86 years (67-100).
In these trials treatment with furosemide plus risperidone was associated with a higher incidence of mortality compared to treatment with risperidone or furosemide alone, however, the mechanism for an interaction is unclear. Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.
No consistent pattern for cause of death observed. Nevertheless caution should be exercised and the risks and benefits of the combination of risperidone and furosemide or co-medication with other potent diuretics considered prior to the decision to use. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.
Cerebrovascular Adverse Events (CAE)
Risperidone tablets are not recommended for the treatment of behavioural symptoms of dementia because of an increased risk of cerebrovascular adverse events (including cerebrovascular accidents and transient ischaemic attacks). Treatment of acute psychoses in patients with a history of dementia should be limited to short term only and should be under specialist advice.
Data from randomised clinical trials conducted in elderly >65 years) patients with dementia indicate that there is an approximately 3-fold increased risk of cerebrovascular adverse events (including cerebrovascular accidents and transient ischaemic attacks) with risperidone, compared with placebo. Cerebrovascular adverse events occurred in 3.3% (33/989) of patients treated with risperidone and 1.2% (8/693) of patients treated with placebo. The Odds Ratio (95% exact confidence interval) was 2.96 (1.33, 7.45).
Physicians should consider carefully the risk of cerebrovascular adverse events with Risperidone tablets (given the observations in elderly patients with dementia detailed above) before treating any patient with a previous history of CVA/TIA. Consideration should also be given to other risk factors for cerebrovascular disease including hypertension, diabetes, current smoking, atrial fibrillation, etc.
Alpha-blocking activity
Due to the alpha-blocking activity of Risperidone tablets, orthostatic hypotension can occur, especially during the initial dose-titration period. A dose reduction should be considered if hypotension occurs.
Risperidone tablets should be used with caution in patients with known cardiovascular disease including those associated with prolongation of the QT interval and the dose should be gradually titrated. In clinical trials, Risperidone was not associated with an increase in QTc intervals. As with other antipsychotics, caution is advised when prescribing with medications known to prolong the QT interval.
If further sedation is required, an additional drug (such as a benzodiazepine) should be administered rather than increasing the dose of Risperidone tablets.
Tardive Dyskinesia/Extrapyramidal Symptoms (TD/EPS)
Drugs with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia, characterised by rhythmical involuntary movements, predominantly of the tongue and/or face. It has been reported that the occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotic drugs should be considered.
Neuroleptic Malignant Syndrome (NMS)
Neuroleptic malignant syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated CPK levels, has been reported to occur with neuroleptics. In this event all antipsychotic drugs including risperidone should be discontinued.
It is recommended to halve both the starting dose and the subsequent dose increments in geriatric patients and in patients with renal or liver insufficiency.
Caution should also be exercised when prescribing Risperidone tablets to patients with Parkinson's disease since, theoretically, it may cause a deterioration of the disease.
Hyperglycaemia
Hyperglycaemia or exacerbation of pre-existing diabetes has been reported in very rare cases during treatment with Risperdal. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus (see also section 4.8 Undesirable effects).
Venous thromboembolism (VTE)
Cases of venous thrombolembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with risperidone and preventative measures undertaken.
Other
Classical neuroleptics are known to lower the seizure threshold. Caution is recommended when treating patients with epilepsy.
As with other antipsychotics, patients should be advised of the potential for weight gain.
Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable.
Possible interactions of Risperidone tablets with other drugs have not been systematically evaluated. Given the primary CNS effects of risperidone, it should be used with caution in combination with other centrally acting drugs including alcohol.
Risperidone tablets may antagonise the effect of levodopa and other dopamine-agonists.
Carbamazepine has been shown to decrease the plasma levels of the antipsychotic fraction of Risperidone tablets. A similar effect might be anticipated with other drugs which stimulate metabolising enzymes in the liver. On initiation of carbamazepine or other hepatic enzyme-inducing drugs, the dosage of Risperidone tablets should be re-evaluated and increased if necessary. Conversely, on discontinuation of such drugs, the dosage of Risperidone tablets should be re-evaluated and decreased if necessary.
Phenothiazines, tricyclic antidepressants and some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction. Fluoxetine and paroxetine, CYP2D6 inhibitors, may increase the plasma concentration of risperidone but less so of the active antipsychotic fraction. When concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of Risperidone. Based on in vitro studies, the same interaction may occur with haloperidol. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction. Cimetidine and ranitidine increase the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction. Erythromycin, a CYP 3A4 inhibitor, does not change the pharmacokinetics of risperidone and the active antipsychotic fraction. The cholinesterase inhibitor galantamine does not show a clinically relevant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction. A study of donepezil in non-elderly healthy volunteers also showed no clinically relevant effect on the pharmacokinetics of risperidone and the antipsychotic fraction.
When Risperidone tablets are taken together with other highly protein-bound drugs, there is no clinically relevant displacement of either drug from the plasma proteins.
See section 4.4 (Special warnings and special precautions for use) regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.
Risperidone does not show a clinically relevant effect on the pharmacokinetics of valproate or topiramate. The potential for reduced toleration of the combination treatment should be taken into consideration when co-administering risperidone and topiramate.
In patients on long-term lithium and older/typical neuroleptic therapy, no significant change occurred in the pharmacokinetics of lithium after substitution of the concomitant neuroleptic with risperidone.
Food does not affect the absorption of risperidone.
Pregnancy
Although, in experimental animals, risperidone did not show direct reproductive toxicity, some indirect, prolactin- and CNS-mediated effects were observed, typically delayed oestrus and changes in mating and nursing behaviour in rats. No teratogenic effect of risperidone was noted in any study. The safety of Risperidone tablets for use during human pregnancy has not been established. Reversible extrapyramidal symptoms in the neonate were observed following postmarketing use of risperidone during the last trimester of pregnancy. Therefore, Risperidone should only be used during pregnancy if the benefits outweigh the risks.
Lactation
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in the milk. It has been demonstrated that risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving Risperidone should not breast feed.
Risperidone may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.
Risperidone tablets are generally well tolerated and in many instances it has been difficult to differentiate adverse events from symptoms of the underlying disease. Adverse events observed in association with the use of Risperidone tablets include:
Common: insomnia, agitation, anxiety, headache.
Less common: somnolence, fatigue, dizziness, impaired concentration, constipation, dyspepsia, nausea/vomiting, abdominal pain, blurred vision, priapism, erectile dysfunction, ejaculatory dysfunction, orgasmic dysfunction, urinary incontinence, rhinitis, rash and other allergic reactions.
Cerebrovascular accidents have been observed during treatment with risperidone. (see Section 4.4 Special warnings and precautions for use).
Hyperglycaemia and exacerbation of pre-existing diabetes have been reported in very rare cases during risperidone treatment.
The incidence and severity of extrapyramidal symptoms are significantly less than with haloperidol. However, in some cases the following extrapyramidal symptoms may occur: tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia. If acute in nature, these symptoms are usually mild and are reversible upon dose reduction and/or administration of antiparkinson medication, if necessary. In clinical trials in patients with acute mania risperidone treatment resulted in an incidence of EPS>10%. This is lower than the incidence observed in patients treated with classical neuroleptics.
Occasionally, orthostatic dizziness, hypotension including orthostatic, tachycardia including reflex tachycardia and hypertension have been observed following administration of Risperidone tablets.
Risperidone tablets can induce a dose-dependent increase in plasma prolactin concentration. Possible associated manifestations are: galactorrhoea, gynaecomastia, disturbances of the menstrual cycle and amenorrhoea.
Weight gain, oedema and increased hepatic enzyme levels have been observed during treatment with Risperidone tablets.
A decrease in neutrophil and/or thrombocyte count has been reported.
As with classical neuroleptics, rare cases of the following have been reported in schizophrenic patients: water intoxication with hyponatraemia, either due to polydipsia or to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH); tardive dyskinesia, body temperature dysregulation and seizures.
Benign pituitary adenomas have been reported very rarely in risperidone users during postmarketing surveillance. No causal association has been established.
Very rare cases of angioedema have been reported in postmarketing experience.
Sedation has been reported more frequently in children and adolescents than in adults. In general, sedation is mild and transient.
Withdrawal reactions have been reported in association with antipsychotic drugs (see section 4.4 Special warnings and special precautions for use).
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs-Frequency unknown.
In general, reported signs and symptoms have been those resulting from an exaggeration of the drug's known pharmacological effects. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. In overdose, rare cases of QT-prolongation have been reported. In case of acute overdosage, the possibility of multiple drug involvement should be considered.
Establish and maintain a clear airway, and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
There is no specific antidote to Risperidone tablets. Therefore appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.
Pharmacotherapeutic group: Other antipsychotics
ATC code: N05AX
Risperidone is a novel antipsychotic belonging to a new class of antipsychotic agents, the benzisoxazole-derivatives.
Risperidone is a selective monoaminergic antagonist with a high affinity for both serotonergic 5-HT2 and dopaminergic D2 receptors. Risperidone binds also to alpha1-adrenergic receptors and, with lower affinity, to H1-histaminergic and alpha2-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, that is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy than classical neuroleptics. Balanced central serotonin and dopamine antagonism may reduce the tendency to cause extrapyramidal side effects, and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.
Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absorption of risperidone is not affected by food.
The most important route of metabolism of risperidone is hydroxylation by cytochrome CYP 2D6 to 9-hydroxy-risperidone which has a similar pharmacological activity to risperidone. This hydroxylation is subject to debrisoquine-type genetic polymorphism but this does not affect the active antipsychotic fraction since this consists of risperidone and its active metabolite 9-hydroxyrisperidone. After oral administration, the elimination half-life of the active antipsychotic fraction is 24 hours.
A single-dose study showed higher active plasma concentrations and a slower elimination of risperidone in the elderly and in patients with renal insufficiency. Risperidone plasma concentrations were normal in patients with liver insufficiency.
Topiramate modestly reduces the bioavailability of risperidone, but not that of the active antipsychotic fraction. Therefore, this interaction is unlikely to be of clinical significance. The bioavailability of topiramate is slightly decreased when administered in combination with risperidone. This interaction is not likely to be clinically significant.
There are no preclinical data of relevance to the prescriber other than those already provided in other sections of the SPC.
Lactose anhydrous
Cellulose, microcrystalline
Starch pregelatinised
Magnesium stearate
Hypromellose 6
Macrogol 6000
Titanium dioxide (E171)
No incompatibilities known.
2 years (bottle) or 3 years (blister)
This medicinal product does not require any special storage conditions
Blister pack: PVC-PVDC / Al foil. Pack sizes 14, 20, 28, 30, 42, 56 or 60 film coated tablets
HDPE Container with LDPE Cap. Pack sizes 20, 40, 60 or 100 film coated tablets
Not all pack sizes may be marketed
No special requirements.
Actavis Group PTC ehf
Reykjavíkurvegi 76-78
220 Hafnarfjordur
Iceland.
PL 30306/0093
01/04/2008
17th February 2010
(IF APPLICABLE)
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Lactosi may be available in the countries listed below.
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In the US, Ancobon (flucytosine systemic) is a member of the drug class miscellaneous antifungals and is used to treat Candida Infections - Systemic, Candida Urinary Tract Infection, Cryptococcal Meningitis - Immunocompetent Host, Cryptococcal Meningitis - Immunosuppressed Host, Cryptococcosis and Fungal Endocarditis.
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| DCF | Dénomination Commune Française |
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| DCF | Dénomination Commune Française |
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Rec.INN
0088852-12-4
C22-H36-O5
380
Vasodilator
Prostaglandin analogue
(E)-7-[(1R,2R,3R)-3-hydroxy-2-[(E)-(3S,5S)-3-hydroxy-5-methyl-1-nonenyl]-5-oxocyclopentyl]-2-heptenoic acid
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| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
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Xeomin 100 LD50 units powder for solution for injection
1 vial contains 100 LD50 units* of Clostridium Botulinum neurotoxin type A (150 kD), free of complexing proteins.
* One unit corresponds to the median lethal dose (LD50) when the reconstituted product is injected intraperitoneally into mice under defined conditions.
Due to differences in the LD50 assay, these units are specific to Xeomin and are not interchangeable with other Botulinum toxin preparations.
Excipient(s):
For a full list of excipients, see section 6.1.
Powder for solution for injection
White powder
Xeomin is indicated for the symptomatic treatment of blepharospasm, cervical dystonia of a predominantly rotational form (spasmodic torticollis) and of post-stroke spasticity of the upper limb presenting with flexed wrist and clenched fist in adults.
Unit doses recommended for Xeomin are not interchangeable with those for other preparations of Botulinum toxin.
Xeomin may only be used by physicians with suitable qualifications and proven experience in the application of Botulinum toxin and in the use of the necessary equipment, e.g. electromyography (EMG).
Reconstituted Xeomin is intended for intramuscular injection.
The optimum dosage and number of injection sites in the treated muscle should be determined by the physician individually for each patient. A titration of the dose should be performed.
For instructions on reconstitution / dilution of the vials, see section 6.6. After reconstitution, Xeomin should be used for only one injection session and for only one patient.
A decrease or increase in the Xeomin dose is possible by administering a smaller or larger injection volume. The smaller the injection volume the less pressure sensation and the less spread of Botulinum neurotoxin type A in the injected muscle occurs. This is of benefit in reducing effects on nearby muscles when small muscle groups are being injected.
Blepharospasm
After reconstitution, the Xeomin solution is injected using a suitable sterile needle (e.g. 27-30 gauge / 0.30-0.40 mm). Electromyographic guidance is not necessary. An injection volume of approximately 0.05 to 0.1 ml is recommended.
Xeomin is 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.
The initial recommended dose is 1.25 to 2.5 U (0.05-0.1 ml volume) per injection site. The initial dose should not exceed 25 U per eye. In the management of blepharospasm, total dosing should not exceed 100 U every 12 weeks.
Injections near the levator palpebrae superioris should be avoided to reduce the occurrence of ptosis. Diplopia may develop as a result of Botulinum neurotoxin type A diffusion into the inferior oblique. Avoiding medial injections into the lower lid may reduce this adverse reaction.
The median time to first onset of effect is observed within four days after injection. The effect of each treatment generally lasts approximately 3-4 months, however, it may last significantly longer or shorter. The treatment can be repeated if required.
At repeat treatment sessions, the dose may be increased up to two-fold if the response to the initial treatment is considered insufficient – usually defined as an effect that does not last longer than two months. However, there appears to be no additional benefit obtainable from injecting more than 5.0 U per site. Normally, no additional benefit is conferred by treating more frequently than every three months.
Spasmodic torticollis
In the management of spasmodic torticollis, Xeomin dosing must be tailored to the individual patient, based on the patient's head and neck position, location of possible pain, muscle hypertrophy, patient's body weight, and response to the injection. A suitable sterile needle (e.g. 25-30 gauge / 0.30-0.50 mm) is used for injections into superficial muscles, and an e.g. 22 gauge / 0.70 mm needle may be used for injections into deeper musculature. An injection volume of approximately 0.1 to 0.5 ml per injection site is recommended.
In the management of spasmodic torticollis, Xeomin is usually injected into the sternocleidomastoid, levator scapulae, scalenus, splenius capitis, 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. If difficulties arise isolating single muscles, injections should be performed using electromyographic guidance. The muscle mass and the degree of hypertrophy or atrophy are factors to be taken into consideration when selecting the appropriate dose.
Normally, in practice, the total dose administered does not exceed 200 U. Doses of up to 300 U may be given. No more than 50 U should be given at any one injection site.
Multiple injection sites permit Xeomin more uniform coverage of the innervated areas of the dystonic muscle and are especially useful in larger muscles. The optimum number of injection sites is dependent upon the size of the muscle to be chemically denervated.
The sternocleidomastoid should not be injected bilaterally as there is an increased risk of adverse reactions (in particular dysphagia) when bilateral injections or doses in excess of 100 U are administered into this muscle.
The median first onset of effect is observed within seven days after injection. The effect of each treatment generally lasts approximately 3-4 months, however, it may last significantly longer or shorter. The period between each treatment session should be at least 10 weeks.
Post-stroke spasticity of the upper limb
Reconstituted Xeomin is injected using a suitable sterile needle (e.g. 26 gauge / 0.45 mm diameter / 37 mm length, for superficial muscles and a longer needle, e.g. 22 gauge / 0.7 mm diameter / 75 mm length, for deeper musculature).
Localisation of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful. Multiple injection sites may allow Xeomin to have more uniform contact with the innervation areas of the muscle and are especially useful when larger muscles are injected.
The exact dosage and number of injection sites should be tailored to the individual patient based on the size, number and location of muscles involved, the severity of spasticity, and the presence of local muscle weakness.
In the management of post-stroke spasticity of the upper limb the following initial doses (units) were administered in the pivotal clinical trial:
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In the pivotal clinical trial, the minimal and maximum total dose were 170 U and 400 U, respectively.
For repeated treatments dosing should be tailored to the individual patient's need. The recommended dose ranges per muscle are provided in the following table:
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The maximum total recommended dose is up to 400 units per treatment session.
Patients reported the onset of action 4 days after treatment. The maximum effect as an improvement of muscle tone was perceived within 4 weeks. In general, the treatment effect lasted 12 weeks. Reinjections should not be performed within intervals of less than 12 weeks..
All indications
If no treatment effect occurs within one month after the initial injection, the following measures should be taken:
- Clinical verification of the neurotoxin effect on the injected muscle: e.g. an electromyographic investigation in a specialised facility
- Analysis of the reason for non-response, e.g. poor isolation of the muscles intended to be injected, too low dose, poor injection technique, fixed contracture, too weak antagonist, possible development of antibodies
- Review of Botulinum neurotoxin type A treatment as an adequate therapy
- If no adverse reactions have occurred during the initial treatment, an additional course of treatment can be performed under the following conditions: 1) dose adjustment with regard to analysis of the most recent therapy failure, 2) EMG-guidance, 3) the recommended minimum interval between the initial and repeat treatment is followed
A treatment-naïve patient should be regarded as a primary non-responder in cases of first injection failure. It has not been investigated whether secondary non-response due to the development of antibodies is less frequent under Xeomin therapy than under treatment with conventional preparations containing the Botulinum toxin type A complex. In cases of non-response, alternative therapies should be considered.
Xeomin has not been studied in the paediatric population and is therefore not recommended in the paediatric age group until further data become available.
Hypersensitivity to the active substance Botulinum neurotoxin type A or to any of the excipients.
Generalised disorders of muscle activity (e.g. myasthenia gravis, Lambert-Eaton syndrome).
Presence of infection at the proposed injection site.
Side effects related to spread of Botulinum 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 “spasmodic torticollis”).
An anaphylactic reaction may occur rarely after injection of Botulinum neurotoxin type A (see section 4.8). Adrenaline and other medical aids for treating anaphylaxis should be available.
Prior to administering Xeomin the physician must familiarise himself/herself with the patient's anatomy and any alterations to the anatomy due to prior surgical procedures. Extra caution is required when injecting at sites close to sensitive structures such as the carotid artery and lung apices.
Xeomin should be used with caution:
• If bleeding disorders of any type occur
• In patients receiving anticoagulant therapy
• In patients suffering from amyotrophic lateral sclerosis or other diseases which result in peripheral neuromuscular dysfunction
• In targeted muscles which display pronounced weakness or atrophy.
The recommended single doses of Xeomin should not be exceeded and the intervals between injections should not be shortened.
The clinical effects of Botulinum neurotoxin type A may increase or decrease by repeated injections. The possible reasons for changes in clinical effects are different techniques of reconstitution, the chosen injection intervals, the injected muscles and marginally varying toxin activity resulting from the biological testing procedure employed or secondary non-response.
Too frequent dosing of Botulinum toxin may result in antibody formation which may lead to treatment resistance (see section 4.2).
Previously akinetic or sedentary patients should be reminded to gradually resume activities following the injection of Xeomin.
Xeomin contains albumin, a derivative of human blood. Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include careful selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. There are no reports of viral transmissions with albumin manufactured to European Pharmacopoeia specifications by established processes.
Blepharospasm
Because of the anticholinergic effect of Botulinum neurotoxin type A, Xeomin should be used with caution in patients at risk of developing an angle closure glaucoma.
In order to prevent ectropion, injections into the lower lid area should be avoided, and vigorous treatment of any epithelial defect is necessary. This may require protective drops, ointments, soft bandage contact lenses, or closure of the eye by patching or similar means.
Reduced blinking following Xeomin injection into the orbicularis muscle can lead to corneal exposure, persistent epithelial defects and corneal ulceration, especially in patients with cranial nerve disorders (facial nerve). Careful testing of corneal sensation should be performed in patients with previous eye operations.
Ecchymosis easily occurs in the soft tissues of the eyelid. Immediate gentle pressure at the injection site can limit that risk.
Spasmodic torticollis
Patients should be informed that injections of Xeomin for the management of spasmodic torticollis may cause mild to severe dysphagia with the risk of aspiration and dyspnoea. Medical intervention may be necessary (e.g. in the form of a gastric feeding tube) (see also section 4.8). Dysphagia can last for up to two to three weeks after injection, but a duration of up to five months has been reported in one case. 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 require bilateral injections into the sternocleidomastoid muscles are at greater risk. The occurrence of dysphagia is attributable to the spread of the pharmacological effect of Xeomin as the result of the neurotoxin spread into the oesophageal musculature.
Post-stroke spasticity of the upper limb
Xeomin as a treatment for focal spasticity has been studied in association with usual standard care regimens, and is not intended as a replacement for these treatment modalities. Xeomin is not likely to be effective in improving range of motion at a joint affected by a fixed contracture.
Theoretically, the effect of Botulinum neurotoxin may be potentiated by aminoglycoside antibiotics or other medicinal products that interfere with neuromuscular transmission, e.g. tubocurarine-type muscle relaxants.
Therefore, the concomitant use of Xeomin with aminoglycosides or spectinomycin requires special care. Peripheral muscle relaxants should be used with caution, if necessary reducing the starting dose of relaxant, or using an intermediate-acting substance such as vecuronium or atracurium rather than substances with longer lasting effects.
4-Aminochinolines may reduce the effect of Xeomin.
There are no adequate data from the use of Botulinum neurotoxin type A in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Therefore, Xeomin should not be used during pregnancy unless clearly necessary and unless the potential benefit justifies the risk.
It is not known whether Botulinum neurotoxin type A is excreted into the breast milk. Therefore, the use of Xeomin during lactation cannot be recommended.
No studies on the effects on the ability to drive and use machines have been performed. However, Xeomin may cause tiredness, muscle weakness, dizziness and visual disturbance, which could affect driving.
Due to the nature of the diseases being treated, the ability to drive and to operate machines may be reduced. Due to the latency of onset, some of the therapeutic and/or adverse effects of Xeomin, which may also interfere with the ability to drive and operate machinery. Consequently affected persons should avoid these tasks until their faculties are fully recovered.
Undesirable effects may occur from misplaced injections of Botulinum neurotoxin type A that temporarily paralyse nearby muscle groups. Large doses may cause paralysis in muscles distant from the injection site. Usually, undesirable effects are observed within the first week after treatment and are temporary in nature. They may be restricted to the area around the injection site (e.g. local pain, tenderness at the injection site, and injection site haemorrhage).
As is expected for any injection procedure, localized pain, inflammation, paraesthesia, hypoesthesia, tenderness, swelling/oedema, erythema, localized infection bleeding and/or bruising may be associated with the injection.
Needle-related pain and/or anxiety may result in vasovagal responses, including transient symptomatic hypotension and syncope.
Frequency by different indications
Based on clinical experience information on the frequency of adverse reactions for the individual indications is given below. The frequency categories are defined as follows: very common (
Blepharospasm
The following adverse reactions were reported with Xeomin:
Nervous system disorders
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Eye disorders
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Gastrointestinal disorders
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Skin and subcutaneous tissue disorders
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Musculoskeletal and connective tissue disorders
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Injury, poisoning and procedural complications
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Additionally, the following undesirable effects and accordingly their frequencies are known for the comparative compound containing conventional Botulinum toxin type A complex used in clinical trials with Xeomin. It is possible that these undesirable effects may also occur with Xeomin.
Nervous system disorders
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Eye disorders
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Skin and subcutaneous tissue disorders
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Musculoskeletal and connective tissue disorders
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General disorders and administration site conditions
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Spasmodic torticollis
The following adverse reactions were reported with Xeomin:
Nervous system disorders
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Eye disorders
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Respiratory, thoracic and mediastinal disorders
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Gastrointestinal disorders
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Skin and subcutaneous tissue disorders
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Musculoskeletal and connective tissue disorders
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General disorders and administration site conditions
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Additionally, the following undesirable effects and accordingly their frequencies are known for the comparative compound containing conventional Botulinum toxin type A complex used in clinical trials with Xeomin. It is possible that these undesirable effects may also occur with Xeomin.
Nervous system disorders
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Eye disorders
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Respiratory, thoracic and mediastinal disorders
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Gastrointestinal disorders
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Skin and subcutaneous tissue disorders
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Musculoskeletal and connective tissue disorders
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General disorders and administration site conditions
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The management of spasmodic torticollis may cause dysphagia with varying degrees of severity with the potential for aspiration which may require medical intervention. Dysphagia may persist for two to three weeks after injection, but has been reported in one case to last five months. Dysphagia appears to be dose-dependent. In clinical trials with Botulinum toxin type A complex it was reported that dysphagia occurs less frequently with total doses below 200 U per treatment session.
Post-stroke spasticity of the upper limb
The following adverse reactions were reported with Xeomin:
General disorders and administration site conditions
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Musculoskeletal and connective tissue disorders
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Gastrointestinal disorders
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Nervous system disorders
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Vascular disorders
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Respiratory, thoracic and mediastinal disorders
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Skin and subcutaneous tissue disorders
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Some of these undesirable effects may be disease related.
General
Localised allergic reactions like swelling, oedema, erythema, pruritus or rash have been rarely reported from post-marketing experience with Xeomin.
The following additional information is also based on publications on conventional preparations containing the Botulinum toxin type A complex.
Side effects related to spread of toxin distant from the site of administration have been reported very rarely (exaggerated muscle weakness, dysphagia, and aspiration pneumonitis with fatal outcome in some cases) (see section 4.4).
Dysphagia has been reported following injection to sites other than the cervical musculature.
The following other adverse events have been reported following administration of conventional Botulinum toxin type A complex: dysarthria, abdominal pain, hyperhidrosis, anorexia, hypoacusis, tinnitus, radiculopathy.
There have been rare reports of undesirable effects related to the cardiovascular system, such as arrhythmia and myocardial infarction, some with fatal outcomes following treatment with botulinum toxins. It remains unclear whether these deaths were induced by botulinum toxin or whether these were caused by pre-existing 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 conventional Botulinum toxin type A complex either alone or in combination with other agents known to cause similar reactions.
A case of peripheral neuropathy has been reported in a male after receiving four sets of injections of a conventional preparation containing the Botulinum toxin type A complex (for neck and back spasm, and severe pain) over an 11 week period.
Angle closure glaucoma has been reported very rarely following administration of conventional Botulinum toxin type A complex 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 Botulinum toxin injection has not been established.
A female patient developed brachial plexopathy two days after injection of a conventional preparation containing the Botulinum toxin type A complex for the treatment of cervical dystonia, with recovery after five months.
Erythema multiforme, urticaria, and psoriasis-like rash have been described with the use of conventional preparations containing the Botulinum toxin type A complex, but their causal relationship remains unclear.
Following injection of conventional Botulinum toxin type A complex, EMG showed increased jitter in some distant muscles which was not associated with muscle weakness or other types of electrophysiological abnormalities.
Symptoms of overdose:
Increased doses of Botulinum neurotoxin type A may result in pronounced neuromuscular paralysis distant from the injection site. Symptoms of overdose are not immediately apparent post-injection and may include general weakness, ptosis, diplopia, breathing, swallowing and speech difficulties, or paralysis of the respiratory muscles resulting in an aspiration pneumonia.
Measures in cases of overdose:
In case of an overdose the patient must be monitored medically for several days. If signs of intoxication appear, hospitalisation with general supportive measures is necessary. Intubation and assisted ventilation will become necessary until improvement if paralysis of the respiratory muscles occurs.
Pharmacotherapeutic group: Muscle relaxant, peripherally acting agent, ATC code: M03AX01
Botulinum neurotoxin type A blocks cholinergic transmission at the neuromuscular junction by inhibiting the release of acetylcholine. The nerve terminals of the neuromuscular junction no longer respond to nerve impulses, and secretion of the neurotransmitter is prevented (chemical denervation). Recovery of impulse transmission is re-established by the formation of new nerve terminals and motor endplates.
The mechanism of action by which Botulinum neurotoxin type A exerts its effects on cholinergic nerve terminals can be described by a three-step sequential process which includes the following steps:
a) binding to the cholinergic nerve terminals,
b) entry or internalisation into the nerve terminal,
c) inhibition of acetylcholine release by intracellular poisoning within the nerve terminal.
The heavy chain of the Botulinum neurotoxin type A binds with an exceptionally high selectivity and affinity to receptors only found on cholinergic terminals. After internalisation of the neuroto
