·         Painful muscle spasms.

·         Spasticity due to multiple sclerosis.

·         Spasticity due to spinal cord injuries.

·         Spasticity due to brain injury.

The therapeutic range of Sirdalud is narrow and the tizanidine levels in plasma vary a lot between individuals. Therefore an adjustment of the dosage in accordance with the patient´s needs is important.

 

A small initial dose of 2 mg three times daily may decrease the risk of undesirable effects. The increasing of the dose is to be carefully adjusted in accordance with the individual needs of the patient.

 

Alleviation of painful muscular spasms

A common dose is 2 – 4 mg tablet x 3/day. In severe cases an additional dose of 2 – 4 mg can be taken, preferably in the evening in order to minimise possible daytime somnolence.

 

Spasticity caused by neurological disorders

The initial dosage should not exceed 6 mg/day divided into three doses. The dosage can gradually be increased by 2 - 4mg twice a week or at one week intervals. The optimal therapeutic response is normally achieved with daily doses of 12 – 24 mg administered as 3 - 4 doses at equivalent intervals. The maximum dose of 36 mg/day should not be exceeded.

 

Paediatric population

There is very little experience of the use in patients under the age of 18, and Sirdalud is not recommended for use in this age group.

 

Geriatric population

There is only little experience of the use of Sirdalud in the treatment of geriatric patients. Therefore a treatment initiation at the lowest possible dose and increasing of that dose in small increments in accordance with tolerability and effect are recommended.

 

Patients with renal insufficiency

An initiation of the treatment by 2 mg once daily is recommended in patients with renal insufficiency (creatinine clearance < 25 ml/min). Increasing of the dose is to be carried out in small increments in accordance with tolerability and effect. If the effect needs to be enhanced, the once daily dose should preferably first be increased before adding the amount of dosing events per day (see section 4.4 Special warnings and precautions for use).

 

Patients with hepatic insufficiency

The use of Sirdalud in patients with severe hepatic insufficiency is contraindicated (see section 4.3 Contraindications).

 

Sirdalud is extensively metabolised by the liver, and there is only little information about the metabolism in the patient group concerned (see section 5.2 Pharmacokinetic properties). The use of Sirdalud has been supposed to be associated with deviations from the normal results in hepatic function tests, the results of which, however, in most of the patients have returned to normal after cessation of the treatment (see section 4.4 Special warnings and precautions for use and 4.8 Undesirable effects). Caution is to be followed in the use of Sirdalud in patients with moderate hepatic insufficiency, and the treatment should be initiated at the lowest dose. After initiation the dose is to be cautiously increased in accordance with the tolerability of the patient.

 

Interruption of the treatment

If a treatment with Sirdalud must be discontinued, the dosing is to be decreased step-wisely in order to avoid or minimise the risk of rebound hypertension and tachycardia, particularly in patients having received high doses during a longer period of time (see section 4.4 Special warnings and precautions for use).

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • Significantly worsened hepatic function (see 5.2 Pharmacokinetics). • Simultaneous use of tizanidine with potent CYP1A2 inhibitors, such as fluvoxamine or ciprofloxacin, is contraindicated (see 4.5 Interaction with other medicinal products and other forms of interactions).

CYP inhibitors

Concomitant use of Sirdalud with moderate or potent CYP1A2 inhibitors is not recommended (see section 4.5 Interaction with other medicinal products and other forms of interaction).

 

Caution is to be followed in the administration of Sirdalud together with medicines causing QT prolongation (see section 4.5 Interaction with other medicinal products and other forms of interaction).

 

Hypotension

Hypotension may occur during a treatment with Sirdalud (see section 4.8 Undesirable effects) and also as a result of drug interactions with CYP1A2 inhibitors and/or antihypertensive drugs (see section 4.5 Interaction with other medicinal products and other forms of interaction). 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 Sirdalud, 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 disturbances of the cerebral circulation. Sirdalud should not be stopped abruptly, but rather gradually (see sections 4.2 Posology and method of administration, 4.5 Interaction with other medicinal products and other forms of interaction and section 4.8 Undesirable effects).

 

Hepatic insufficiency

Since hepatic insufficiency has been reported in connection with the use of tizanidine it is recommended that liver function tests should be undertaken before the treatment is started in order to exclude patients with severe hepatic insufficiency or some hepatic disease. Function tests once a month during the first 4 months should also be performed in all patients, and particularly in patients developing clinical symptoms indicating hepatic dysfunction such as unexplainable nausea, anorexia or tiredness. Sirdalud treatment has to be stopped if the serum ALAT and ASAT values are continuously three times more than the upper limit of the reference range.

 

Renal insufficiency

In patients with renal insufficiency (creatinine clearance < 25 ml/min) the systemic exposure to tizanidine may increase even up to six times the exposure in patients with a normal renal function. Therefore a start of the treatment with 2 mg once daily is recommended (see section 4.2 Posology and method of administration and section 5.2 Pharmacokinetic properties).

 

The Sirdalud tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Concomitant administration of drugs known to inhibit the activity of CYP1A2 may increase

the plasma levels of tizanidine (see section 5.2 Pharmacokinetic properties).

 

The increased plasma levels of tizanidine may result in overdose symptoms, such as QT(c) prolongation (see also section 4.9 Overdose). A concomitant use of tizanidine (at high doses) and other products potentially prolonging the QT(c) is not recommended.

 

A concomitant use of medicinal products increasing the CYP1A2 activity may decrease the plasma concentration of tizanidine (see section 5.2 Pharmacokinetic properties). Decreased tizanidine levels in plasma may decrease the therapeutic effect of Sirdalud.

 

Interactions posing a contraindication

The use of Sirdalud simultaneously with fluvoxamine or ciprofloxacin, both CYP450 1A2 inhibitors in human beings, is contraindicated. Concomitant use of tizanidine with fluvoxamine or ciprofloxacin resulted in a 33-fold and 10-fold increase in tizanidine AUC (see section 4.3 Contraindications), respectively. Clinically significant, long term reduction of blood pressure connected with sleepiness, dizziness and lowered psycho-motoric performance ability may occur (see section 4.4 Special warnings and precautions for use).

 

Concomitant use not recommended due to interactions noted

Co-administration of Sirdalud simultaneously with other CYP 1A2 inhibitors, such as some rhythmic disorder drugs (amiodarone, mexiletine, propaphenone), cimetidine, some fluoroquinolones (enoxacin, pefloxacin, norfloxacin), rofecoxib, oral contraceptives and ticlopidine is not recommended (see section 4.4 Special warnings and precautions for use).

 

A concomitant use of Sirdalud and medicinal products associated with a known prolongation of the QT interval is not recommended (e.g. cisapride, amitriptyline and azithromycin) (see section 4.4 Special warnings and precautions for use).

 

Known interactions which have to be considered

Antihypertensives

Concomitant use of Sirdalud with antihypertensives, including diuretics and beta-blocking agents, may occasionally cause hypotension (see section 4.4 Special warnings and precautions for use) and bradycardia. In some patients rebound hypertension and tachycardia have been observed upon abrupt discontinuation of a treatment with Sirdalud when concomitantly used with antihypertensive drugs. In extreme cases, rebound hypertension might lead to disturbances of the cerebral circulation (see section 4.4 Special warnings and precautions for use and section 4.8 Undesirable effects).

 

Rifampicin

A concomitant use of Sirdalud and rifampicin causes a 50 % decrease in the blood level of tizanidine. Therefore the therapeutic effect of Sirdalud may be decreased during a treatment with rifampicin, which may be of clinical importance to some patients. A prolonged concomitant treatment should be avoided, and if a concomitant treatment is considered, a careful determination (addition) of the dose is needed.

 

Smoking

The administration of Sirdalud in smoking men (> 10 cigarettes daily) causes a decrease of about 30 % in the systemic exposure to tizanidine. A long-term treatment with Sirdalud in male heavy smokers may require doses above the common ones. There is no information available on female smokers, but dosage adjustments are not required.

 

Alcohol

The use of alcohol should be decreased to a minimum or completely avoided during a treatment with Sirdalud, since alcohol may increase the possible undesirable effects (e.g. sedation or hypotension). Sirdalud may potent the CNS depressing effects of alcohol.

 

Expected interactions to be notified

Sedatives, hypnotics (e.g. benzodiazepines or baclofen) and other substances, like antihistamines, may increase the sedative effects of tizanidine.

 

A concomitant use of Sirdalud and other alpha-2 adrenergic agonists (like clonidine) and digoxin should be avoided due to a potential additive hypotensive effect.

Pregnancy

Increased pre- and postnatal mortality has been shown in animal studies performed at maternally toxic doses and due to the prolonged gestation time (see section 5.3 Preclinical safety data).

 

As controlled studies have not been undertaken as regards pregnant women, tizanidine should not be used during pregnancy if the benefits do not clearly exceed the risks.

 

Lactation

The excretion in breast-milk has not been studied in breast-feeding mothers. Even though it is uncertain whether the medicine is excreted in breast-milk, small amount may be excreted on basis of the physico-chemical properties and structure of the drug substance. Based on available preclinical data (see section 5.3 Preclinical safety data), the estimated amount a human infant may receive would be 0.7 % of the adult dose, if the mother receives a treatment with tizanidine. Due to the lack of information in human beings, Sirdalud should not be given to breast-feeding mothers.

 

Fertility

There is no information regarding human beings. Animal studies have shown decreased fertility in rats at high doses (see section 5.3 Preclinical safety information).

Patients experiencing somnolence, dizziness or any signs or symptoms of hypotension should refrain from functions requiring particular alertness during Sirdalud treatment, such as driving or working with machinery.

Adverse reactions observed in clinical trials (Table 1) are ranked according to the system organ classes of MedDRA. Under each system organ heading the adverse effects have been ranked according to frequency, the most frequent first. Within each frequency grouping, the adverse reactions are ranked in order of decreasing seriousness. In addition every adverse reaction has been classified in accordance with the CIOMS III classification: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000) very rare (< 1/10,000).

 

 

Table 1 Undesirable effects

Psychiatric disorders
	Common:	Insomnia, sleep disorders
Nervous system disorders
	Very common:	Somnolence, dizziness
Cardiac disorders
	Uncommon:	Bradycardia
Vascular disorders
	Common:	Hypotension
Gastrointestinal disorders
	Very common:	Gastrointestinal disorders, dry mouth
	Common:	Nausea
Musculoskeletal and connective tissue disorders
	Very common:	Muscular weakness
General disorders and administration site conditions
	Very common:	Fatigue
Investigations
	Common:	Blood pressure decrease, increased transaminases

 

With low doses, such as those recommended for the relief of painful muscle spasms, somnolence, fatigue, dizziness, dry mouth, blood pressure decrease, nausea, gastrointestinal disorders and increased transaminases 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: hypotension, bradycardia, muscular weakness, insomnia, sleep disorders, hallucinations and hepatitis.

 

Undesirable effects observed after market introduction (frequency not known)

The following adverse reactions of Sirdalud have been reported in spontaneous reports and literature after introduction on the market. Since the reporting of this kind of adverse reactions is voluntary and the reports originate from a population of uncertain size and depend on different circumstances, it is not possible to reliably assess their frequency (therefore the frequency is classified as not known) or to show a causal relationship between the reactions and the exposure to the drug substance. The adverse reactions have been grouped in accordance with the system organ classes of MedDRA.

 

Psychiatric disorders: Hallucinations, state of confusion

Nervous system disorders: Dizziness

Vascular disorders: Syncope

Eye disorders: Blurred vision

Hepatobiliary disorders: Hepatitis, hepatic insufficiency

General disorders: Asthenia, withdrawal syndrome due to discontinuation of treatment.

 

Withdrawal syndrome

Rebound hypertension and tachycardia have been observed after sudden withdrawal of Sirdalud, 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 disturbances of the cerebral circulation (see section 4.4 Special warnings and precautions for use and section 4.5 Interaction with other medicinal products and other forms of interaction).

 

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

 

To report any side effect(s):

·         Saudi Arabia

-          The National Pharmacovigilance Center (NPC):

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

•    Other GCC States:

-  Please contact the relevant competent authority.

4.9 Overdose

Only a few reports exist as regards overdosage of Sirdalud products. All the patients, also one patient administered 400 mg Sirdalud who had been reported as having taken a Sirdalud overdose as the only drug, recovered without any complications.

 

Signs and symptoms: Nausea, vomiting, hypotonia, QT(c) prolongation, dizziness, somnolence, miosis, restlessness, respiratory distress, coma.

 

Treatment: It is recommended that the drug is removed by repeatedly administering large amounts of medicinal charcoal. It is assumed that intensified diuresis will speed up Sirdalud's elimination. Further treatment should be in accordance with the symptoms.

Pharmacotherapeutic group: Muscle relaxants, centrally acting agents. ATC code M03BX02.

 

Tizanidine is a centrally affecting skeletal muscle relaxant. Its main point of effect is located in the spinal cord where, based on studies, by stimulating presynaptic alpha₂-receptors it inhibits the release of amino acids stimulating N-methyl-D-aspartate (NMDA) receptors. In this way the transmission of polysynaptic signals causing excess muscle tone at the spinal interneuron level and muscle tone is reduced. In addition to its muscle relaxing properties tizanidine has reasonable central analgesic effects.

Sirdalud is effective both for sudden painful muscle spasms and chronic spasticity of a spinal or cerebral origin. It reduces resistance to passive movements, alleviates spasms and clonus and may increase voluntary strength.

 

The antispasmodic effect (when measured by the Ashworth scale and the pendulum test) and the undesirable effects (pulse and blood pressure) of Sirdalud are dependent on the tizanidine levels in plasma.

Absorption

Tizanidine is absorbed rapidly and almost completely. The peak plasma concentration is achieved approximately within 1 hour of the administration of the drug. The average absolute bioavailability is approximately 34% (coefficient of variation: 38 %) due to extensive first-pass metabolism. The mean maximum concentration (C_max) of tizanidine in plasma is 12.3 ng/ml (coefficient of variation: 10 %) after a single dose of 4 mg and 15.6 ng/ml (coefficient of variation: 13 %) after repeated doses of 4 mg.

 

A concomitant ingestion of food has no relevant impact on the pharmacokinetic profile of tizanidine (using 4 mg tablets). Even though C_max is increased by about 1/3 when the tablet is taken with food, this probably is of no clinical importance nor does it have any significant effect on the absorption (AUC).

 

Distribution

The average distribution volume at steady-state (V_ss) after iv administration is 2.6 l/kg (coefficient of variation: 21 %). Binding to plasma proteins is 30%.

 

Biotransformation

The drug has been shown to be rapidly and extensively metabolized by the liver (about 95 %). Tizanidine metabolises in vitro mainly via cytochrome P450 1A2. Metabolites appear to be inactive.

 

Elimination

Tizanidine is eliminated from the systemic circulation and the average terminal half-life is 2 - 4 hours. Metabolites are mainly secreted via kidneys (approx. 70% of the dosage). Only very little (approx. 4.5 %) of the medicinal substance is secreted in an unchanged format via the kidneys.

 

Linearity

The pharmacokinetics of tizanidine is linear at doses of 1-20 mg.

 

Typical properties in specific patient groups

In patients with renal insufficiency (creatinine clearance < 25 ml/min), the average peak concentration in plasma is twice as high as in healthy volunteers and the terminal half-life is approx. 14 hours which (on average about 6 times prolonged) clearly increases the AUC value (see section 4.4 Special warnings and precautions for use).

 

Patients with hepatic insufficiency

No particular studies have been performed in this patient group. Since tizanidine is extensively metabolised in the liver by the CYP1A2 enzyme, a decrease in the hepatic function may increase the systemic exposure to tizanidine. The use of Sirdalud is contraindicated in patients with severe hepatic insufficiency (see section 4.3 Contraindications).

 

Elderly patients

There is only little pharmacokinetic data available from this patient group.

 

Effects of sex and ethnic background

The sex of the patient has no clinically significant impact on the pharmacokinetics of tizanidine. The impact of ethnic background and race on the pharmacokinetics of tizanidine have not been studied.

Acute toxicity

The acute toxicity of tizanidine is of a low order. Signs of overdosage have been seen and they were related to the drug’s pharmacological action.

 

Chronic and sub-chronic toxicity

The amount given in food in a peroral toxicity test undertaken with rats lasting for 13 weeks was 1, 7, 8 and 40 mg/kg/day. The most important findings were connected with central nervous system stimulation, for example motor stimulation, aggressiveness, trembling and convulsions, and they were mainly experienced only when using larger doses.

 

In a study undertaken with dogs lasting 13 weeks the doses given were 0.3, 1 and 3 mg/kg/day in capsules and in a study lasting 52 weeks the doses given were 0.15, 0.45 and 1.5 mg/kg/day. The ECG variations and the central nervous system effects found when the daily doses were 1 mg/kg or more are connected with the emphasised pharmacological effects of the drug. No histopathological findings were connected with the temporary increase of the serum ALAT value using 24-hour doses of 1 mg/kg or above but it fits with the view that the liver is a potential target organ.

 

Mutagenicity

The in vitro and in vivo tests and cytogenetic tests did not show any possible mutagenicity of tizanidine.

 

Carcinogenicity

In the peroral toxicity tests the dose given to the rats was a maximum of 9 mg/kg/day, whereas the mice were given a dose of 16 mg/kg/day. The results achieved as regards both of the species did not indicate that tizanidine would have any carcinogenic potential.

 

Reproductive toxicity

No decrease in fertility was seen at doses of 10 mg/kg/day in male rats or at doses of 3 mg/kg/day in female rats. The fertility was impaired in male rats at doses of 30 mg/kg/day and in female rats at doses of 10 mg/kg/day. At these doses behavioural effects and clinical symptoms, like a remarkable sedation, decreased body weight and ataxia, were also seen in the mother rats.
Reproduction studies were performed in rats at doses of 3 mg/kg/day and in rabbits at doses of 30 mg/kg/day. In these studies no evidence of teratogenicity was seen. Daily doses of 10 and 30 mg/kg lengthened the gestation period in female rats. Pre- and postnatal mortality was also increased, and delayed development notified. At these doses the mother rats showed remarkable symptoms of muscle relaxation and sedation.

 

Lactation

Preclinical studies in rats indicate that the medicinal substance would be excreted in breast milk to a small extent. The radioactivity measured in rat milk was slightly higher than the radioactivity in plasma, and the milk:plasma ratio of the systemic exposure was 1.8. A possible explanation for this phenomenon is non-ionic, passive diffusion.

Silica, colloidal anhydrous; stearic acid, microcrystalline cellulose, anhydrous lactose.

NA

2 years

Keep out of the reach and sight of children.

Store below 30 ^oC.

Blister packages of PVC/PE/PVDC/aluminium foil.

Package sizes of 30 tablets.

No special requirements.