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Tizanidine Hydrochloride

(British Approved Name Modified, US Adopted Name, rINNM)

Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Tizanidine HydrochlorideSynonyms: AN-021; DS-103-282; DS-103-282-ch; Tizanidina, hidrocloruro de
BAN: Tizanidine Hydrochloride [BANM]
USAN: Tizanidine Hydrochloride
INN: Tizanidine Hydrochloride [rINNM (en)]
INN: Hidrocloruro de tizanidina [rINNM (es)]
INN: Tizanidine, Chlorhydrate de [rINNM (fr)]
INN: Tizanidini Hydrochloridum [rINNM (la)]
INN: Тизанидина Гидрохлорид [rINNM (ru)]
Chemical name: 5-Chloro-N-(2-imidazolin-2-yl)-2,1,3-benzothiadiazol-4-ylamine hydrochloride
Molecular formula: C9H8ClN5S,HCl =290.2
CAS: 51322-75-9 (tizanidine); 64461-82-1 (tizanidine hydrochloride)
ATC code: M03BX02

Pharmacopoeias. In Japan and US.

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Tizanidine Hydrochloride). Store in airtight containers.

Adverse Effects and Precautions

Tizanidine hydrochloride may cause drowsiness; patients affected should not drive or operate machinery. Other adverse effects include dry mouth, fatigue, dizziness or vertigo, muscle pain and weakness, insomnia, anxiety, headache, bradycardia, nausea, and gastrointestinal disturbances. Hallucinations have occurred on rare occasions. Many adverse effects have been found to be dose related and slow titration of doses appears to reduce the frequency of occurrence. Hypotension may occur.

Increases in liver enzymes and rarely acute hepatitis have been associated with tizanidine and it is contra-indicated in patients with severe hepatic dysfunction. In the UK it is recommended that liver function should be monitored monthly in all patients for the first 4 months and in those who develop symptoms suggestive of hepatic dysfunction; similarly, in the United States of America baseline assessment and monitoring at 1, 3, and 6 months is advised. Treatment should be stopped if liver enzymes are persistently raised. Caution is required in the elderly and in patients with renal insufficiency.

Interactions

Tizanidine is metabolised by the cytochrome P450 isoenzyme C YP1A2 and use with ciprofloxacin or fluvoxamine, both potent inhibitors of this isoenzyme, is contra-indicated. Use with other more moderate inhibitors of CYP1A2 (such as other quinolone antibacterials, cimetidine, and antiarrhythmics such as amiodarone, mexiletine, propafenone, and verapamil) should be avoided unless clinically necessary.

The CNS effects of tizanidine may be enhanced by alcohol or other CNS depressants. There may be an additive hypotensive effect when tizanidine is used in patients receiving antihypertensive therapy; bradycardia may also be enhanced if given with beta blockers or digoxin. Caution should be exercised when tizanidine is given with drugs known to increase the QT interval. The clearance of tizanidine has been reported to be lower in women receiving hormonal contraceptives.

Antibacterials

In a study of healthy subjects, ciprofloxacin, an inhibitor of the cytochrome P450 isoenzyme CYP1A2, was reported to elevate the plasma concentrations of tizanidine thereby potentiating its hypotensive and sedative effects.

Antidepressants

In a study in 10 healthy subjects^wvoxam-ine, a potent inhibitor of the cytochrome P450 isoenzyme CYP1A2, was reported to increase tizanidine’s peak plasma concentrations and elimination half-life 12-fold and 3-fold, respectively. An increased incidence of adverse effects associated with tizanidine such as hypotension, bradycardia, drowsiness, and dizziness was noted in these subjects.

A 70-year-old woman receiving fluvoxamine 150 mg daily and other medications developed bradycardia, dry mouth, urinary retention, and a low body temperature when given tizanidine 3 mg daily; the patient improved when tizanidine was stopped. In a retrospective survey of medical records, the authors reported adverse effects associated with tizanidine in 6 of 23 patients also receiving fluvoxamine.

Antiepileptics

For reference to an interaction between tizanidine andphenytoin.

Cardiovascular drugs

Severe hypotension, occurring 2 hours after treatment with tizanidine, has been reported in a patient receiving antihypertensives, including lisinopril, and other medications. The patient improved after tizanidine and antihypertensives were stopped; they were later resumed without lisinopril, and caused no problems.

Oral contraceptives

Mean peak plasma concentrations after a single 4-mg dose of tizanidine were 3 times greater in 15 women using an oral contraceptive containing ethinylestradiol and gestodene than in controls; the elimination half-life was not, however, significantly different. The effect appeared to be due to inhibition of the cytochrome P450 isoenzyme CYP1A2 by the contraceptive, resulting in reduced presystemic metabolism of tizanidine. Because the therapeutic range of tizanidine is narrow, care should be exercised if it is given to patients taking oral contraceptives.

Pharmacokinetics

Tizanidine is well absorbed from the gastrointestinal tract and peak plasma concentrations occur about 1 to 2 hours after oral doses. It is about 30% bound to plasma proteins. Tizanidine undergoes extensive first-pass metabolism in the liver mainly via the cytochrome P450 isoenzyme CYP1A2 and is excreted mainly in the urine as inactive metabolites. Elimination half-lives of 2 to 4 hours have been reported.

Uses and Administration

Tizanidine hydrochloride is a centrally acting skeletal muscle relaxant. It is an a2-adrenergic agonist structurally related to clonidine and acts mainly at spinal and supraspinal levels to inhibit excitatory interneurones. It is used for the symptomatic relief of spasticity associated with multiple sclerosis or with spinal cord injury or disease. It is also used in the symptomatic treatment of painful muscle spasm associated with musculoskeletal conditions.

Tizanidine hydrochloride is given orally, usually in divided doses; doses are expressed in terms of the base. Tizanidine hydrochloride 1.14mg is equivalent to about 1 mg of tizanidine. The usual initial daily dose in the UK in the management of spasticity is the equivalent of 2 mg of the base given as a single dose. The dose may be increased thereafter according to response in steps of 2 mg at intervals of at least 3 to 4 days, usually up to 24 mg daily given in 3 or 4 divided doses.

A similar schedule, with an initial daily dose of 4 mg, increased as required in steps of 2 to 4 mg, is used in the USA. The maximum recommended dose is 36 mg daily. Maintenance doses have been given in some countries in the form of modified-release preparations. For dosage in renal impairment, see below.

In the treatment of painful muscle spasm tizanidine hydrochloride is given in doses equivalent to 2 to 4 mg of the base three times daily.

Administration in renal impairment

In the UK, licensed product information recommends that in patients with renal insufficiency, treatment with tizanidine hydrochloride should be started with the equivalent of 2 mg of the base once daily; thereafter it advises a slow increase in the once-daily dose before increasing the frequency of administration. Similar recommendations are made in the United States of America.

Headache

Results from an open-label study and a later controlled study suggested that tizanidine might be of value in the prophylaxis of chronic daily headache. However, an earlier controlled study failed to show any significant advantage over placebo in the treatment of chronic tension-type headache. In another study tizanidine was also effective when given with a long-acting NSAID as part of a detoxification regimen for patients with chronic daily headaches induced by analgesic overuse.

Premedication

The value of tizanidine as a premedicant is being studied.A dose of tizanidine 12 mg appears to have sedative and sympatholytic effects comparable with clonidine 150micrograms.

Spasticity

The efficacy of tizanidine for spasticity associated with cerebral and spinal disorders has been shown in several placebo-controlled studies and in comparative studies it has produced similar improvements in muscle tone to baclofen or diazepam. Carefully titrated doses of tizanidine and baclofen used together may have additive beneficial effects but use with benzodiazepines is not recommended because of potential interactions. It was considered that tizanidine might have the advantage of being better tolerated than baclofen.

Preparations

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Tizanidine Tablets.

Proprietary Preparations

Argentina: Sirdalud;

Austria; Sirdalud;

Belgium: Sirdalud;

Brazil: Sirdalud;

Canada: Zanaflex;

Chile: Sirdalud;

Czech Republic: Sirdalud;

Denmark: Sirdalud;

Finland: Sirdalud;

Germany; Sirdalud;

Greece: Sirdalud;

Hungary: Sirdalud;

India: Sirdalud;

Indonesia: Myores; Sirdalud; Zitanid;

Ireland: Zanaflex;

Italy: Sirdalud;

Mexico: Sirdalud;

Netherlands: Sirdalud;

Philippines: Sirdalud; Ternelax;

Poland: Sirdalud;

Portugal: Sirdalud;

Russia: Sirdalud;

Spain: Sirdalud;

Switzerland: Sirdalud;

Thailand: Sirdalud; Tizan;

Turkey: Sirdalud;

United Kingdom (UK): Zanaflex;

United States of America (US and USA): Zanaflex;

Venezuela: Sirdalud.

Multi-ingredient

India: Kinectine-MR; Movon-MR; Niciflex-T; Nicip T; Nimulid MR; Valus-XT ; Vorth-XTt; Zerodol-MR

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