Active ingredients: Tizanidine
SIRDALUD 2 mg tablets
SIRDALUD 4 mg tablets
SIRDALUD 6 mg tablets
Why is Sirdalud used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Muscle relaxant with central action
THERAPEUTIC INDICATIONS
Painful muscle spasms:
- associated with static and functional disorders of the spine (cervical and lumbar arthritic syndromes, stiff neck, back pain, etc.);
- consequent to surgical interventions (herniated disc, osteoarthritis of the hip, etc.).
Spasticity resulting from neurological disorders:
ex. multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, cerebral vascular accidents.
Contraindications When Sirdalud should not be used
Severe impairment of liver function.
Concomitant use of tizanidine with strong cytochrome P1A2 inhibitors such as fluvoxamine or ciprofloxacin is contraindicated (see "Interactions). Hypersensitivity to tizanidine or to any of the excipients.
Precautions for use What you need to know before taking Sirdalud
Inhibitors of cytochromes P
The concomitant use of Sirdalud with moderate cytochrome P1A2 inhibitors is not recommended (see "Interactions").
Care should be taken when Sirdalud is administered with drugs known to prolong the QT interval (see "Undesirable Effects").
Hypotension
Hypotension may occur during treatment with Sirdalud and as a consequence of interaction with cytochrome P1A2 inhibitors and / or antihypertensive drugs (see "Undesirable effects" and "Interactions"). Severe manifestations of hypotension with loss of consciousness have also been reported. and circulatory collapse.
Discontinuation syndrome
Rebound hypertension and tachycardia have been observed after abrupt discontinuation of Sirdalud, when used chronically, and / or at high daily doses, and / or concomitantly with antihypertensive drugs. In extreme cases, rebound hypertension could lead to cerebrovascular accident (see "Interactions" and "Undesirable effects"). Sirdalud should not be discontinued abruptly but gradually (see "Dose, method and time of administration" and "Undesirable effects" ").
C.impaired liver function
Cases of hepatic impairment have been reported in association with tizanidine treatment, although these episodes have rarely occurred at doses up to 12 mg / day. Therefore, in the case of patients treated with doses equal to or greater than 12 mg / day or in the case of patients presenting clinical symptoms of hepatic dysfunction (such as nausea of unknown origin, anorexia, asthenia), it is recommended to carry out evaluation tests. liver function monthly for the first 4 months of therapy. Treatment with SIRDALUD should be discontinued if serum SGPT or SGOT levels are consistently tripled above the upper limit of the normal range.
Renal impairment
In patients with renal impairment (creatinine clearance normal renal function. Therefore it is recommended to start therapy with 2 mg once daily (see "Dose, method and time of administration").
Cardiocirculatory and coronary insufficiency
Caution is advised in patients with cardiovascular and coronary insufficiency. If treatment with SIRDALUD is started in these patients, it will be advisable to carry out normal diagnostic laboratory tests at regular intervals together with regular electrocardiographic control.
In such patients, however, the dosage of the drug must be adequately adjusted.
Interactions Which drugs or foods can modify the effect of Sirdalud
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Concomitant use of medicinal products known to inhibit cytochrome P1A2 activity may increase plasma levels of tizanidine.
Increased plasma levels of tizanidine may lead to overdose symptoms such as QT prolongation (c) (see "Overdose"). Concomitant administration of medicinal products known to induce CYP1A2 activity may decrease plasma levels of tizanidine. Decreased plasma levels of tizanidine may reduce the therapeutic effect of Sirdalud.
Interactions observed that lead to a contraindication
The concomitant use of Sirdalud with fluvoxamine or ciprofloxacin, both of which are inhibitors of cytochrome P450 1A2 for humans, is contraindicated (see "Contraindications"). A much higher blood concentration of Sirdalud has been reported, caused by fluvoxamine or ciprofloxacin. This can cause clinically important and prolonged hypertension, drowsiness, dizziness and decreased psychomotor ability (see "Precautions for use").
Interactions observed that do not recommend concomitant use
The concomitant use of Sirdalud with other cytochrome P1A2 inhibitors such as some antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, some fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives and tactile "use"). The concomitant use of tizanidine (in high doses) and other medicinal products that can cause QT prolongation (c) (including but not limited to cisapride, amitriptyline and azithromycin) is not recommended (see "Precautions for use").
Observed interactions to be considered
Antihypertensives
Concomitant use of Sirdalud with antihypertensives, including diuretics, may occasionally lead to hypotension (see "Precautions for use") and bradycardia. Rebound hypertension and tachycardia have been observed in some patients after abrupt discontinuation of Sirdalud when administered with antihypertensive drugs. In extreme cases, rebound hypertension could lead to cerebrovascular accident (see "Precautions for use" and "Undesirable effects")
Rifampicin
Concomitant administration of Sirdalud and rifampicin results in a 50% decrease in tizanidine concentrations. Therefore, the therapeutic effect of Sirdalud may be reduced during treatment with rifampicin, which in some patients may be of clinical significance. Long-term concomitant administration should be avoided and if considered, careful attention may be required. dose adjustment (increase).
Cigarette smoke
Administration of Sirdalud to male smokers (> 10 cigarettes per day) results in an approximately 30% decrease in systemic exposure to tizanidine. Long-term therapy with Sirdalud in heavy male smokers may require higher doses than average doses.
Alcohol
During therapy with Sirdalud, alcohol consumption should be minimized or avoided as it may increase potential adverse events (e.g. sedation and hypotension). Sirdalud may increase the depressant effect of alcohol on the central nervous system. Intended interactions to be considered Sedatives, hypnotics (eg benzodiazepines or baclofen) and other medicinal products such as antihistamines may also enhance the sedative action of tizanidine.
Sirdalud should be avoided when using another alpha-2 adrenergic agonist (such as clonidine) due to the potential additive hypotensive effect.
Warnings It is important to know that:
Fertility, pregnancy and breastfeeding
Pregnancy
Ask your doctor or pharmacist for advice before taking any medicine.
Since no controlled studies have been performed in pregnant women, tizanidine should not be administered during pregnancy unless the benefit clearly outweighs the potential risk.
Feeding time
Tizanidine should not be taken by women who are breastfeeding.
Fertility
No impairment of fertility was observed in male rats at a dose of 10 mg / kg / day and in female rats at a dose of 3 mg / kg / day. Fertility was reduced in male rats treated with 30 mg / kg / day and in female rats treated with 10 mg / kg / day. Effects on maternal behavior and clinical signs including marked sedation, weight loss and ataxia were observed at these doses.
Effects on ability to drive and use machines
Patients who experience somnolence, dizziness or any signs or symptoms of hypotension should refrain from performing activities that require a high degree of alertness, such as driving or operating machinery. This phenomenon may be aggravated when the drug is taken in combination with alcohol.
Important information about some of the ingredients: Sirdalud contains lactose: in case of ascertained intolerance to sugars, contact your doctor before taking the medicine.
Dosage and method of use How to use Sirdalud: Dosage
Sirdalud exhibits a narrow therapeutic index and high inter-patient variability in plasma concentrations of tizanidine which necessitate major dose adjustments to provide for patient needs.
A low starting dose can minimize the risk of side effects. The dose should be carefully increased according to the needs of the individual patient.
Painful muscle spasms
The usual dose is 2 to 4 mg two to three times a day. In severe cases, an additional administration of 1 tablet of 2 or 4 mg is recommended, preferably at bedtime to minimize sedation.
Spasticity resulting from neurological disorders
Dosage should be adjusted to the individual needs of the patient. The starting dose should not exceed 6 mg daily divided into three administrations. Then gradually increase by 2-4 mg every three to six days. In most patients, the optimal therapeutic response is generally achieved with a dose of 12-24 mg divided into 3 or 4 daily administrations.
It is recommended not to exceed the maximum daily dose of 36 mg. During the course of treatment, it is advisable to ascertain whether a reduction in dosage can be made.
Pediatric population
Experience in patients below 18 years of age is limited, therefore the administration of SIRDALUD in this population is not recommended.
Senior citizens
Experience with the use of Sirdalud in the elderly is limited. Therefore it is recommended to start treatment with the lowest dose and to gradually increase the dose according to tolerability and efficacy.
Patients with renal impairment
In patients with renal impairment (creatinine clearance <25 ml / min) it is recommended to start treatment with 2 mg once daily. The dose increase should be gradual according to tolerability and efficacy. If it is necessary to increase the therapeutic effect, it is recommended to increase the once daily dose first before increasing the frequency of administration (see "Precautions for use").
Patients with hepatic impairment
The use of Sirdalud in patients with severe hepatic impairment is contraindicated (see "Contraindications").
Although Sirdalud is extensively metabolised in the liver, limited data is available in this population. Its use has been associated with reversible abnormalities in liver function tests (see "Precautions for use" and "Undesirable effects"). Sirdalud should be used with caution in patients with moderate hepatic impairment and any treatment should start with the lowest dose. Subsequently, dose increases should be made with caution and according to the patient's tolerability. Discontinuation of treatment If treatment with Sirdalud has to be discontinued, the dosage should be decreased slowly, particularly in patients treated with high doses over a longer period of time, to avoid or minimize the risk of rebound hypertension and tachycardia (see " Precautions for "use")
Overdose What to do if you have taken too much Sirdalud
In the few reported cases of overdose, healing occurred without significant consequences, including one patient who ingested 400 mg of Sirdalud.
Symptoms
Nausea, vomiting, hypotension, QT interval prolongation (c), dizziness, miosis, respiratory distress, coma, agitation, somnolence.
Treatment
It is recommended to favor the elimination of the ingested drug through repeated administration of high doses of activated charcoal. Forced diuresis is indicated to accelerate the elimination of the drug. Further treatments must be symptomatic.
In case of accidental ingestion / intake of an overdose of Sirdalud, notify your doctor immediately or go to the nearest hospital.
If you have any questions about the use of Sirdalud, ask your doctor or pharmacist.
Side Effects What are the side effects of Sirdalud
Like all medicines, Sirdalud can cause side effects, although not everybody gets them.
Adverse drug reactions from clinical trials are listed by MedDRA system organ class. Within each system organ class, adverse drug reactions are listed by frequency, with the most frequent first. Within each frequency class, adverse drug reactions are presented in descending order of severity. In addition, for each adverse reaction the corresponding frequency is also indicated using the CIOMS III convention: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1 / 10,000, <1/1000); very rare (<1 / 10,000), not known (cannot be estimated from the available data).
Adverse drug reactions
Psychiatric disorders
Common: Insomnia, sleep disturbances
Nervous system disorders
Very common: Somnolence, dizziness
Cardiac pathologies
Uncommon: Bradycardia
Vascular pathologies
Common: Hypotension
Gastrointestinal disorders
Very common: Gastrointestinal disturbances, dry mouth
Common: Nausea
Musculoskeletal and connective tissue disorders
Very common: Muscle weakness
General disorders and administration site conditions
Very common: Fatigue
Diagnostic tests
Common: Drop in blood pressure, increase in transaminases
At low doses, such as those recommended for the resolution of painful muscle spasms, somnolence, fatigue, dizziness, dry mouth, drop in blood pressure, nausea, gastrointestinal disturbances and elevated transaminases have been reported as mild and transient.
At higher doses, recommended for the treatment of spasticity, side effects reported at low doses are more frequent and more pronounced, but rarely severe enough to require discontinuation of treatment. In case elevated transaminase values are not reported. to normal within 4-6 weeks, treatment with SIRDALUD should be discontinued.
In addition, the following side effects may occur: hypotension, bradycardia, muscle weakness, insomnia, sleep disturbances, hallucinations, hepatitis.
Post-marketing adverse drug reactions (frequency not known)
The following adverse drug reactions have been reported during the marketing phase of Sirdalud through spontaneous reports and case reports in the literature. Since these reactions were reported on a voluntary basis from a population of uncertain size and subject to confounding factors, it is not possible to estimate their frequency in a realistic way (which is therefore reported as unknown) or to establish a causal relationship with drug exposure. Adverse drug reactions are listed by MedDRA system organ class.
Psychiatric disorders: Hallucinations, confusional state
Nervous system disorders: Vertigo
Vascular disorders: Syncope
Eye disorders: Blurred vision
Hepatobiliary disorders: Hepatitis, liver failure
General disorders and administration site conditions: Asthenia, withdrawal syndrome
Discontinuation syndrome
Rebound hypertension and tachycardia have been observed after abrupt discontinuation of Sirdalud. In extreme cases, rebound hypertension could lead to cerebrovascular accident (see "Precautions for use" and "Interactions")
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet please inform your doctor or pharmacist.
Expiry and Retention
Expiry: see the expiry date indicated on the package.
WARNING: Do not use the medicine after the expiry date indicated on the package.
The expiry date indicated refers to the product in intact packaging, correctly stored.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Keep this medicine out of the reach and sight of children.
COMPOSITION
SIRDALUD 2 mg tablets
One tablet contains:
Active ingredient: tizanidine hydrochloride 2.29 mg equal to 2.00 mg of tizanidine base
Excipients: anhydrous colloidal silica, stearic acid, microcrystalline cellulose, anhydrous lactose
SIRDALUD 4 mg tablets
One tablet contains:
Active ingredient: 4.58 mg tizanidine hydrochloride equal to 4.00 mg of tizanidine base
Excipients: anhydrous colloidal silica, stearic acid, microcrystalline cellulose, anhydrous lactose.
SIRDALUD 6 mg tablets
One tablet contains:
Active ingredient: tizanidine hydrochloride. 6.86 mg equal to 6.00 mg of tizanidine base
Excipients: anhydrous colloidal silica, stearic acid, microcrystalline cellulose, anhydrous lactose.
PHARMACEUTICAL FORM AND CONTENT
SIRDALUD 2 mg tablets 15 tablets
SIRDALUD 2 mg tablets 20 tablets
SIRDALUD 4 mg tablets 30 tablets
SIRDALUD 6 mg tablets 30 tablets
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
SIRDALUD 2 - 4 - 6 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
SIRDALUD 2 mg tablets
One tablet contains:
Active principle:
tizanidine hydrochloride ........................... 2.29 mg
equal to 2.00 mg of tizanidine base
SIRDALUD 4 mg tablets
One tablet contains:
Active principle:
tizanidine hydrochloride ........................... 4.58 mg
equal to 4.00 mg of tizanidine base
SIRDALUD 6 mg tablets
One tablet contains:
Active principle:
tizanidine hydrochloride ........................... 6.86 mg
equal to 6.00 mg of tizanidine base
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Painful muscle spasms:
- associated with static and functional disorders of the spine (cervical and lumbar arthritic syndromes, stiff neck, back pain, etc.);
- consequent to surgical interventions (herniated disc, osteoarthritis of the hip, etc.).
Spasticity resulting from neurological disorders:
ex. multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, cerebral vascular accidents.
04.2 Posology and method of administration
Sirdalud exhibits a narrow therapeutic index and high inter-patient variability in plasma concentrations of tizanidine which necessitate major dose adjustments to provide for patient needs.
A low starting dose can minimize the risk of side effects. The dose should be carefully increased according to the needs of the individual patient.
Painful muscle spasms
The usual dose is 2 to 4 mg two to three times a day. In severe cases, an additional administration of 1 tablet of 2 or 4 mg is recommended, preferably at bedtime to minimize sedation.
Spasticity resulting from neurological disorders
Dosage should be adjusted to the individual needs of the patient.The starting dose should not exceed 6 mg daily divided into three administrations. Then gradually increase by 2-4 mg every three to six days.
In most patients, the optimal therapeutic response is generally achieved with a dose of 12-24 mg divided into 3 or 4 daily administrations.
It is recommended not to exceed the maximum daily dose of 36 mg.
During the course of treatment, it is advisable to ascertain whether a reduction in dosage can be made.
Pediatric population
Experience in patients below 18 years of age is limited and therefore the administration of SIRDALUD in this population is not recommended.
Senior citizens
Experience with the use of Sirdalud in the elderly is limited. Therefore it is recommended to start treatment with the lowest dose and to gradually increase the dose according to tolerability and efficacy.
Patients with renal impairment
In patients with renal impairment (creatinine clearance
Patients with hepatic impairment
The use of Sirdalud in patients with severe hepatic impairment is contraindicated (see 4.3).
Although Sirdalud is extensively metabolised in the liver, limited data is available in this population (see 5.2). Its use has been associated with reversible abnormalities in liver function tests (see 4.4 and 4.8). Sirdalud should be used with caution in patients with moderate hepatic impairment and any treatment should start with the lowest dose. Subsequently, dose increases should be made with caution and according to the patient's tolerability.
Discontinuation of treatment
If treatment with Sirdalud has to be discontinued, the dosage should be slowly tapered particularly in patients treated with high doses over a longer period of time to avoid or minimize the risk of rebound hypertension and tachycardia (see 4.4).
04.3 Contraindications
Severe impairment of hepatic function (see 5.2).
Concomitant use of tizanidine with strong cytochrome P1A2 inhibitors such as fluvoxamine or ciprofloxacin is contraindicated (see 4.5).
Hypersensitivity to tizanidine or to any of the excipients.
04.4 Special warnings and appropriate precautions for use
Inhibitors of cytochromes P
Concomitant use of Sirdalud with moderate cytochrome P1A2 inhibitors is not recommended (see 4.5).
Care should be taken when Sirdalud is administered with drugs known to prolong the QT interval (see 4.5).
Hypotension
Hypotension may occur during treatment with Sirdalud and as a consequence of interaction with cytochrome P1A2 inhibitors and / or antihypertensive drugs (see 4.8 and 4.5).
Severe manifestations of hypotension with loss of consciousness and circulatory collapse have also been reported.
Discontinuation syndrome
Rebound hypertension and tachycardia have been observed after abrupt discontinuation of Sirdalud, when used chronically, and / or at high daily doses, and / or concomitantly with antihypertensive drugs. In extreme cases, rebound hypertension could lead to cerebrovascular accident (see 4.5 and 4.8). Sirdalud should not be stopped abruptly but gradually (see 4.2 and 4.8).
Impaired liver function
Cases of hepatic impairment have been reported in association with tizanidine treatment, although these episodes rarely occurred at doses up to 12 mg / day. Therefore, in the case of patients treated with doses equal to or greater than 12 mg / day or in the case of patients presenting clinical symptoms of hepatic dysfunction (such as nausea of unknown origin, anorexia, asthenia), it is recommended to carry out evaluation tests. liver function monthly for the first 4 months of therapy. Treatment with SIRDALUD should be discontinued if serum SGPT or SGOT levels are consistently tripled above the upper limit of the normal range.
Renal impairment
In patients with renal impairment (creatinine clearance normal renal function. Therefore it is recommended to start therapy with 2 mg once daily (see 4.2 and 5.2).
Cardiocirculatory and coronary insufficiency
Caution is advised in patients with cardiovascular and coronary insufficiency. If treatment with SIRDALUD is started in these patients, it will be advisable to carry out normal diagnostic laboratory tests at regular intervals together with regular electrocardiographic control.
In such patients, however, the dosage of the drug must be adequately adjusted.
Sirdalud contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Concomitant use of medicinal products known to inhibit cytochrome P1A2 activity may increase plasma levels of tizanidine (see 5.2). Increased plasma levels of tizanidine may lead to overdose symptoms such as QT prolongation (c) (see 4.9).
Concomitant administration of medicinal products known to induce CYP1A2 activity may decrease the plasma levels of tizanidine (see 5.2). Decreased plasma levels of tizanidine may reduce the therapeutic effect of Sirdalud.
Interactions observed that lead to a contraindication
Concomitant use of Sirdalud with fluvoxamine or ciprofloxacin, both of which are inhibitors of human cytochrome P450 1A2, is contraindicated (see 4.3). Concomitant use of Sirdalud with fluvoxamine and ciprofloxacin results in a 33-fold increase in the AUC of tizanidine by fluvoxamine and 10-fold by ciprofloxacin. This can cause clinically important and prolonged hypertension, somnolence, dizziness and decreased psychomotor ability (see 4.4).
Interactions observed that do not recommend concomitant use
The concomitant use of Sirdalud with other cytochrome P1A2 inhibitors such as some antiarrhythmics (amiodarone, mexiletine, propafenone), cimetidine, some fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives and ticlopid are not recommended.
Concomitant use is not recommended of tizanidine (in high doses) and other medicinal products that can cause QT prolongation (c) (including but not limited to cisapride, amitriptyline and azithromycin) (see 4.4).
Observed interactions to be considered
Antihypertensives
Concomitant use of Sirdalud with antihypertensive agents, including diuretics, may occasionally result in hypotension (see 4.4) and bradycardia. Rebound hypertension and tachycardia have been observed in some patients after abrupt discontinuation of Sirdalud when administered with antihypertensive drugs. extreme cases rebound hypertension could result in cerebrovascular accident (see 4.4 and 4.8).
Rifampicin
Concomitant administration of Sirdalud and rifampicin results in a 50% decrease in tizanidine concentrations. Therefore, the therapeutic effect of Sirdalud may be reduced during treatment with rifampicin, which in some patients may be of clinical significance. Long-term concomitant administration should be avoided and if considered, careful attention may be required. dose adjustment (increase).
Cigarette smoke
Administration of Sirdalud to male smokers (> 10 cigarettes per day) results in an approximately 30% decrease in systemic exposure to tizanidine. Long-term therapy with Sirdalud in heavy male smokers may require higher doses than average doses.
Alcohol
During therapy with Sirdalud, alcohol consumption should be minimized or avoided as it may increase potential adverse events (e.g. sedation and hypotension). Sirdalud may increase the depressant effect of alcohol on the central nervous system.
Intended interactions to be considered
Sedatives, hypnotics (eg benzodiazepines or baclofen) and other medicines such as antihistamines may also increase the sedative action of tizanidine.
Sirdalud should be avoided when using another alpha-2 adrenergic agonist (such as clonidine) due to the potential additive hypotensive effect.
04.6 Pregnancy and lactation
Pregnancy
Animal studies indicate increased pre- and postnatal mortality at maternally toxic doses.
As no controlled studies have been performed in pregnant women, tizanidine should not be administered during pregnancy unless the benefit clearly outweighs the potential risk.
Pregnancy
In rats, only small amounts of tizanidine are excreted in the milk. As no human data are available, Sirdalud should not be administered to breastfeeding women.
Fertility
No impairment of fertility was observed in male rats at a dose of 10 mg / kg / day and in female rats at a dose of 3 mg / kg / day. Fertility was reduced in male rats treated with 30 mg / kg / day and in female rats treated with 10 mg / kg / day. Effects on maternal behavior and clinical signs including marked sedation, weight loss and ataxia were observed at these doses.
04.7 Effects on ability to drive and use machines
Patients who experience somnolence, dizziness or any signs or symptoms of hypotension should refrain from performing activities that require a high degree of alertness, such as driving or operating machinery.
The phenomenon can worsen when the drug is taken in association with alcohol.
04.8 Undesirable effects
Adverse drug reactions from clinical trials (Table 1) are listed by MedDRA system organ class. Within each system organ class, adverse drug reactions are listed by frequency, with the most frequent first. Within each frequency class, adverse drug reactions are presented in descending order of severity. In addition, for each adverse reaction the corresponding frequency is also indicated using the CIOMS III convention: very common (≥ 1/10); common (≥ 1/100,
Table 1 - Adverse drug reactions
At low doses, such as those recommended for the resolution of painful muscle spasms, somnolence, fatigue, dizziness, dry mouth, drop in blood pressure, nausea, gastrointestinal disturbances, and transaminase elevations have been reported as moderate and transient.
At higher doses, recommended for the treatment of spasticity, side effects reported at low doses are more frequent and more pronounced, but rarely severe enough to require discontinuation of treatment. In case elevated transaminase values are not reported. to normal within 4-6 weeks, treatment with SIRDALUD should be discontinued.
In addition, the following side effects may occur: hypotension, bradycardia, muscle weakness, insomnia, sleep disturbances, hallucinations, hepatitis.
Post-marketing adverse drug reactions (frequency not known)
The following adverse drug reactions have been reported during the marketing phase of Sirdalud through spontaneous reports and case reports in the literature. Since these reactions were reported on a voluntary basis from a population of uncertain size and subject to confounding factors, it is not possible to estimate their frequency in a realistic way (which is therefore reported as unknown) or to establish a causal relationship with drug exposure. Adverse drug reactions are listed by MedDRA system organ class.
Psychiatric disorders: Hallucinations, confusional state
Nervous system disorders: dizziness
Vascular disorders: syncope
Eye disorders: blurred vision
Hepatobiliary disorders: hepatitis, liver failure
General disorders and administration site conditions: asthenia, withdrawal syndrome
Discontinuation syndrome
After abrupt discontinuation of Sirdalud, rebound hypertension and tachycardia were observed. In extreme cases, rebound hypertension could result in cerebrovascular accident (see 4.4 and 4.5).
04.9 Overdose
In the few reported cases of overdose, healing occurred without significant consequences, including one patient who ingested 400 mg of Sirdalud.
Symptoms
Nausea, vomiting, hypotension, QT interval prolongation (c), dizziness, miosis, respiratory distress, coma, agitation, somnolence.
Treatment
It is recommended to favor the elimination of the ingested drug through repeated administration of high doses of activated charcoal. Forced diuresis is indicated to accelerate the elimination of the drug. Further treatments must be symptomatic.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: centrally acting muscle relaxant.
ATC code: M03BX02.
Mechanism of action: Tizanidine is a centrally acting muscle relaxant. The main site of action is the spinal cord where, through the stimulation of presynaptic alpha2 receptors, it seems to exert an inhibitory effect on the release of excitatory amino acids that stimulate the N-methyl-D-aspartate (NMDA) receptors. transmission of the polysynaptic signal at the level of the spinal interneuron, responsible for excessive muscle tone, with reduction of muscle tone. In addition to its muscle relaxant properties, tizanidine also exerts a moderate central analgesic effect.
Pharmacodynamic properties: SIRDALUD is effective both in forms of acute muscle spasticity (painful muscle spasms of various etiology) and in chronic muscle spasticity of spinal and cerebral origin. The drug reduces resistance to passive movements, relieves spasms and clonus, and can improve voluntary strength.
The antispastic activity (measured by the Ashworth score and the pendulum test) and adverse effects (heart rate and blood pressure) of Sirdalud are related to the plasma concentration of tizanidine.
05.2 Pharmacokinetic properties
Absorption and bioavailability
Tizanidine is rapidly and almost completely absorbed: maximum plasma concentration is reached within approximately 1 hour of oral administration. The mean absolute bioavailability of the tablet is approximately 34% (CV 38%) due to marked first pass metabolism. The mean maximum plasma concentration (Cmax) of tizanidine is 12.3 ng / ml (CV 10%) and 15.6 ng / ml (CV13%) after single and repeated administration of 4 mg doses, respectively.
Concomitant food intake does not significantly affect the pharmacokinetic profile of tizanidine (administered as 4 mg tablets). Although the Cmax value is approximately 1/3 higher after administration of the tablet under fed conditions, it is not considered to be of clinical relevance, nor is the effect on the extent of absorption (AUC) significant.
Distribution
After i.v. the mean steady-state volume of distribution was 2.6 l / kg (CV 21%). Plasma protein binding is 30%.
Biotransformation / Metabolism
The drug is metabolised rapidly and to a large extent (approximately 95%) by the liver. Tizanidine is mainly metabolised by cytochrome P450 1A2 in vitro. The metabolites appear to be practically inactive.
Elimination
The mean elimination half-life of tizanidine from the systemic circulation is 2-4 hours. Excretion occurs mainly via the kidneys (approximately 70% of the dose) in the form of metabolites. Unchanged drug is excreted only in small amounts via the kidney (approximately 4.5%).
Linearity
Tizanidine has linear pharmacokinetics over the dose range of 1 to 20 mg.
Characteristics in particular patient populations
Patients with renal impairment
In patients with renal impairment (creatinine clearance
Patients with hepatic impairment
No specific studies have been conducted in this population. Since tizanidine is extensively metabolised in the liver by the CYP1A2 enzyme, hepatic impairment may increase its systemic exposure. Sirdalud is contraindicated in patients with severe hepatic impairment (see 4.3).
Senior citizens
Pharmacokinetic data in this population are limited.
Gender and ethnicity
Gender has no clinically significant effect on the pharmacokinetics of tizanidine. The impact of ethnic and race sensitivity on the pharmacokinetics of tizanidine has not been studied.
Clinical studies
No recent clinical data are available on the approved indications of Sirdalud.
05.3 Preclinical safety data
Acute toxicity
Tizanidine demonstrated low acute toxicity. Signs of overdose were found, attributable to the pharmacological effect of the drug.
Chronic and subchronic toxicity
In a 13-week toxicity study in rats, daily doses of 1.7 - 8 - 40 mg / kg were administered with the diet. The greatest effects observed were related to central nervous system stimulation (eg motor excitation, aggression, tremors and convulsions) and occurred mainly at higher doses.
In two studies in dogs lasting 13 and 52 weeks, daily doses of 0.3 - 1 - 3 mg / kg (in capsules) and 0.15 - 0.45 - 1.5 mg / kg were administered, respectively. kg. Electrocardiographic changes and central nervous system effects observed at doses ≥1 mg / kg represent exaggerated pharmacological effects. The transient increase in SGPT, observed at daily doses ≥1 mg / kg, was not related to histopathological changes: this increase however indicates that the liver is a potential target organ.
Mutagenesis
In vitro, in vivo and cytogenesis tests did not reveal any potential mutagenic effects of tizanidine.
Carcinogenesis
Toxicity studies conducted in rats and mice, to which daily doses up to 9 and 16 mg / kg were administered with the diet, respectively, did not reveal any potential carcinogenic effects of tizanidine.
Reproductive toxicity
Reproduction studies conducted in rats at a dose of 3 mg / kg / day and in rabbits at a dose of 30 mg / kg / day showed no evidence of teratogenicity. Prolongation of the duration of pregnancy was observed in female rats at doses of 10 and 30 mg / kg / day. There was an increase in the loss of fetuses and pups and there was developmental delay. At these doses, the mothers showed marked signs of muscle relaxation and sedation.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Anhydrous colloidal silica, stearic acid, microcrystalline cellulose, anhydrous lactose.
06.2 Incompatibility
None.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
None.
06.5 Nature of the immediate packaging and contents of the package
Lithographed box containing PVC / PVDC / aluminum blisters of: SIRDALUD 2 mg tablets 15 tablets of 2 mg
SIRDALUD 2 mg tablets 20 tablets of 2 mg
SIRDALUD 4 mg tablets 30 tablets of 4 mg
SIRDALUD 6 mg tablets 30 tablets of 6 mg
06.6 Instructions for use and handling
None.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Farma S.p.A.
Largo Umberto Boccioni, 1 - 21040 Origgio (VA)
08.0 MARKETING AUTHORIZATION NUMBER
SIRDALUD 2 mg tablets - 15 tablets A.I.C. n. 025852056
SIRDALUD 2 mg tablets - 20 tablets A.I.C. n. 025852068
SIRDALUD 4 mg tablets - 30 tablets A.I.C. n. 025852029
SIRDALUD 6 mg tablets - 30 tablets A.I.C. n. 025852031
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
SIRDALUD 2 mg tablets: 18.06.1993 / 01.07.2008
SIRDALUD 4 mg tablets: 18.06.1993 / 01.07.2008
SIRDALUD 6 mg tablets: 18.06.1993 / 01.07.2008
10.0 DATE OF REVISION OF THE TEXT
Determination of June 28, 2011
