Clinical experience is limited. In one case, where an adult patient ingested 400mg Tisalud, recovery was uneventful. This patient received mannitol and furosemide
Symptoms
Nausea, vomiting, hypotension, bradycardia, QT prolongation, dizziness, miosis, respiratory distress, coma, restlessness, somnolence.
Treatment
General supportive measures are indicated and an attempt should be made to remove ingested substance from the gastro-intestinal tract using gastric lavage or by repeated administration of high doses of activated charcoal. The patient should be well hydrated as forced diuresis is expected to accelerate the elimination of Tisalud. Further treatment should be symptomatic.
Not applicable.
The adverse effects are classified below by system organ class according to the following convention:
Very common (>1/10)
Common (>1/100 to <1/10)
Uncommon (>1/1,000 to ≤1/100)
Rare (>1/10,000 to ≤1/1,000)
Very rare, including isolated reports (<1/10,000)
Not known (cannot be estimated from the available data)
| Immune system disorders | |
| Not known: | Hypersensitivity reactions |
| Psychiatric disorders | |
| Rare: | Hallucinations, insomnia, sleep disorders |
| Not known: | Anxiety disorders, confusional state |
| Nervous system disorders | |
| Common: | Somnolence, dizziness |
| Not known: | Headache, ataxia, dysarthria |
| Eye disorders | |
| Not known: | Accommodation disorder |
| Cardiac disorders | |
| Common: | Bradycardia, tachycardia |
| Not known: | QT prolongation has been reported in post-marketing surveillance |
| Vascular disorders | |
| Common: | Hypotension,, rebound hypertension |
| Gastrointestinal disorders | |
| Common: | Dry mouth |
| Rare: | Nausea, gastrointestinal disorder |
| Not known: | Abdominal pain, vomiting |
| Hepato-biliary disorders | |
| Rare: | Increases in hepatic serum transaminases |
| Very rare: | Hepatitis, hepatic failure |
| Skin and subcutaneous tissue disorders | |
| Not known: | Pruritus, rash |
| Musculoskeletal and connective tissue disorders | |
| Rare: | Muscular weakness |
| General disorders and administration site conditions | |
| Common | Fatigue |
| Not known: | Absence of appetite |
| Investigations | |
| Common: | Blood pressure decrease |
| Rare: | Transaminase increase |
* The hallucinations are self-limiting, without evidence of psychosis, and have invariably occurred in patients concurrently taking potentially hallucinogenic substances, e.g. anti-depressants.
With low doses, such as those recommended for the relief of painful muscle spasms, somnolence, fatigue, dizziness, dry mouth, blood pressure decrease, nausea, gastrointestinal disorder and transaminase increase have been reported, usually as mild and transient adverse reactions..
With the higher doses recommended for the treatment of spasticity, the adverse reactions reported with low doses are more frequent and more pronounced, but seldom severe enough to require discontinuation of treatment.
In addition, the following adverse reactions may occur: confusional state, hypotension, bradycardia, muscular weakness, insomnia, sleep disorder, hallucination, hepatitis.
Withdrawal syndrome
Rebound hypertension and tachycardia have been observed after sudden withdrawal of Tisalud, when it had been used chronically, and/or in high daily dosages, and/or concomitantly with antihypertensive drugs. In extreme cases, rebound hypertension might lead to cerebrovascular accident.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard
Acute toxicity
Tisalud possesses a low order of acute toxicity. Signs of overdose were seen after single doses > 40mg/kg in animals and are related to the pharmacological action of the substance.
Repeat dose toxicity
The toxic effects of Tisalud are mainly related to its pharmacological action. At doses of 24 and 40mg/kg per day in subchronic and chronic rodent studies, the α2-agonist effects resulted in central nervous system stimulation, e.g. motor excitation, aggressiveness, tremor and convulsions.
Signs related to centrally mediated muscle relaxation, e.g. sedation and ataxia, were frequently observed at lower dose levels in subchronic and chronic oral studies with dogs. Such signs, related to the myotonolytic activity of the substance, were noted at 1 to 4mg/kg per day in a 13 week dog study, and at 1.5mg/kg per day in a 52-week dog study.
Prolongation of the QT interval and bradycardia were noted in chronic toxicity studies in dogs at doses of 1.0mg/kg per day and above.
Retinal atrophy and corneal opacity have been observed in chronic toxicity studies in the rat. The no observed adverse effect load in the rat was below 1mg/kg/day.
Slight increases in hepatic serum transaminases were observed in a number of toxicity studies at higher dose levels. They were not consistently associated with histopathological changes in the liver.
Mutagenicity
Various in vitro assays as well as in vivo assays produced no evidence of mutagenic potential of Tisalud.
Carcinogenicity
No evidence for carcinogenicity was demonstrated in two long-term dietary studies in mice (78 weeks) and rats (104 weeks), at dose levels up to 9mg/kg per day in rats and up to 16mg/kg per day in mice. At these dose levels, corresponding to the maximum tolerated dose, based on reductions in growth rate, no neoplastic or pre-neoplastic pathology, attributable to treatment, was observed.
Reproductive toxicity
No embryotoxicity or teratogenicity occurred in pregnant rats and rabbits at dose levels up to 30mg/kg per day of Tisalud. However, doses of 10-100mg/kg per day in rats were maternally toxic and resulted in developmental retardation of foetuses as seen by lower foetal body weights and retarded skeletal ossification.
In female rats, treated prior to mating through lactation or during late pregnancy until weaning of the young, a dose-dependent (10 and 30mg/kg per day) prolongation of gestation time and dystocia occurred, resulting in an increased foetal mortality and delayed development. These effects were attributed to the pharmacological effect of Tisalud. No developmental effects occurred at 3mg/kg per day although sedation was induced in the treated dams.
Passage of Tisalud and/or its metabolites into milk of rodents is known to occur.
Treatment of spasticity associated with multiple sclerosis or with spinal cord injury or disease.
Pharmacotherapeutic group: Musculo-skeletal system; muscle relaxants; centrally acting agents; other centrally acting agents
ATC code: M03B X02
Tisalud is a centrally acting skeletal muscle relaxant. Its principal site of action is the spinal cord, where the evidence suggests that, by stimulating presynaptic alpha2-receptors, it inhibits the release of excitatory aminoacids that stimulate N-methyl-D-aspartate (NMDA) receptors. Polysynaptic signal transmission at spinal interneuron level, which is responsible for excessive muscle tone, is thus inhibited and muscle tone reduced. Tisalud has no direct effect on skeletal muscle, the neuromuscular junction or on monosynaptic spinal reflexes. In addition to its muscle-relaxant properties, Tisalud also exerts a moderate central analgesic effect.
In humans, Tisalud reduces pathologically increased muscle tone, including resistance to passive movements and alleviates painful spasms and clonus.
Absorption
Tisalud is rapidly absorbed, reaching peak plasma concentration in approximately 1 hour after dosing.
Distribution
Tisalud is only about 30% bound to plasma proteins and, in animal studies, was found to readily cross the bloodbrain barrier. Mean steady-state volume of distribution (VSS) following i.v. administration is 2.6 L/kg.
Biotransformation
Although Tisalud is well absorbed, first pass metabolism limits plasma availability to 34% of that of an intravenous dose. Tisalud undergoes rapid and extensive metabolism in the liver. Tisalud is mainly metabolized by cytochrome P450 1A2 in vitro.
Elimination
The metabolites are primarily excreted via the renal route (approximately 70% of the administered dose) and appear to be inactive. Renal excretion of the parent compound is approximately 53% after a single 5 mg dose and 66% after dosing with 4 mg three times daily. The elimination half-life of Tisalud from plasma is 2-4 hours in patients.
Linearity
Tisalud has linear pharmacokinetics over the dose range 4 to 20 mg. The low intraindividual variation in pharmacokinetic parameters (Cmax and AUC) enables reliable prediction of plasma levels following oral administration.
Characteristics in special patient populations
The pharmacokinetic parameters of Tisalud are not affected by gender.
In patients with renal insufficiency (creatinine clearance < 25 mL/min), maximal mean plasma levels were found to be twice as high as in normal volunteers, and the terminal half-life was prolonged to approximately 14 hours, resulting in much higher (approximately 6-fold on average) AUC values.
Effect of food
Concomitant food intake has no clinically significant influence on the pharmacokinetic profile of Tisalud tablets.
CYP inhibitors
Concomitant use of Tisalud with CYP1A2 inhibitors is not recommended.
Hypotension
Hypotension may occur during treatment with Tisalud and also as a result of drug interactions with CYP1A2 inhibitors and/or antihypertensive drugs. Severe manifestations of hypotension such as loss of consciousness and circulatory collapse have also been observed.
Withdrawal syndrome
Rebound hypertension and tachycardia have been observed after sudden withdrawal of Tisalud, when it had been used chronically, and/or in high daily dosages, and/or concomitantly with antihypertensive drugs. In extreme cases, rebound hypertension might lead to cerebrovascular accident. Tisalud should not be stopped abruptly, but rather gradually.
Renal insufficiency
In patients with renal insufficiency (creatinine clearance < 25 mL/min), it is recommended to start treatment at 2 mg once daily. Dosage increases should be done in small steps according to tolerability and efficacy. If efficacy has to be improved, it is advisable to increase first the once daily dose before increasing the frequency of administration.
Cardiovascular, hepatic or renal disorders
Caution is required in patients with cardiovascular disorders, coronary artery disease or renal or hepatic disorders. Regular clinical laboratory and ECG monitoring is recommended during treatment with Tisalud.
Hepatic dysfunction
Since hepatic dysfunction has been reported in association with Tisalud but rarely at daily doses up to 12mg, it is recommended that liver function tests should be monitored monthly for the first four months in patients receiving doses of 12mg and higher and in patients who develop clinical symptoms suggestive of hepatic dysfunction, such as unexplained nausea, anorexia or tiredness. Treatment with Tisalud should be discontinued if serum levels of SGPT (serum glutamic-pyruvic transaminase) and/or SGOT (serum glutamic-oxaloacetic transaminase) are persistently above three times the upper limit of the normal range. Tisalud should be discontinued in patients with symptoms compatible with hepatitis or where jaundice occurs.
This medicinal product contains lactose anhydrous. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Patients experiencing somnolence, dizziness or any signs or symptoms of hypotension should refrain from activities requiring a high degree of alertness, e.g. driving a vehicle or operating machines.
Posology
The effect of Tisalud on spasticity is maximal within 2-3 hours of dosing and it has a relatively short duration of action. The timing and frequency of dosing should therefore be tailored to the individual, and Tisalud should be given in divided doses, up to 3-4 times daily, depending on the patient's needs. There is considerable variation in response between patients so careful titration is necessary. Care should be taken not to exceed the dose producing the desired therapeutic effect.
It is usual to start with a single dose of 2mg increasing by 2mg increments at no less than half-weekly intervals. The optimum therapeutic response is generally achieved with a daily dose of between 12 and 24mg, administered in 3 or 4 equally spaced doses. Single doses should not exceed 12mg. The total daily dose should not exceed 36mg.
Adverse events may occur at therapeutic doses but these can be minimised by slow titration so that in the large majority of patients they are not a limiting factor.
Discontinuing therapy
If therapy needs to be discontinued, particularly in patients who have been receiving high doses for long periods, the dose should be decreased slowly.
Elderly
Experience in the elderly is limited and use of Tisalud is not recommended unless the benefit of treatment clearly outweighs the risk. Pharmacokinetic data suggest that renal clearance in the elderly may in some cases be significantly decreased. Caution is therefore indicated when using Tisalud in elderly patients.
Paediatric population
Experience with Tisalud in patients under the age of 18 years is limited. Tisalud is not recommended for use in this population.
Renal impairment
In patients with renal insufficiency (creatinine clearance < 25 ml/min) treatment should be started with 2mg once daily with slow titration to achieve the effective dose. Dosage increases should be in increments of no more than 2mg according to tolerability and effectiveness. If efficacy has to be improved, it is advisable to slowly increase the once-daily dose before increasing the frequency of administration. Renal function should be monitored as appropriate in these patients.
Hepatic impairment
Tisalud is contraindicated in patients with significantly impaired hepatic function.
Method of administration
For oral use
No special requirements.
