Tizanidine Hydrochloride

Pronunciation

Pronunciation: tye-ZAN-i-deen HYE-droe-KLOR-ide
Class: Skeletal muscle relaxant

Trade Names

Tizanidine Hydrochloride
- Tablets 2 mg
- Tablets 4 mg

Zanaflex
- Tablets 2 mg
- Tablets 4 mg
- Capsules 2 mg
- Capsules 4 mg
- Capsules 6 mg

Apo-Tizanidine (Canada)
Gen-Tizanidine (Canada)

Pharmacology

An alpha-2 adrenergic receptor agonist that may reduce spasticity by increasing presynaptic inhibition of motor neurons.

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Pharmacokinetics

Absorption

Well absorbed; absolute bioavailability is about 40% because of extensive first-pass hepatic metabolism. T max is 1 h (tablets and capsules in fasted state); food increases T max (1 h and 25 min for tablets; 3 to 4 h for capsules); food increases C max of tablets 30% and reduces C max of capsules 20%. Administration of capsule contents sprinkled on applesauce increases C max and AUC 15% to 20% and decreases T max 15 min compared with administration of intact capsule.

Distribution

Tizanidine is widely distributed. Vd is about 2.4 L/kg. About 30% is bound to plasma proteins.

Metabolism

About 95% of dose is metabolized (CYP1A2); metabolites are not known to be active.

Elimination

The half-life is about 2 to 2.5 h.

Peak

1 to 2 h.

Duration

3 to 6 h.

Special Populations

Renal Function Impairment

Cl is reduced more than 50% in elderly patients with renal function impairment (CrCl less than 25 mL/min) compared with healthy subjects; this may lead to longer duration of clinical effects.

Hepatic Function Impairment

Effect of hepatic impairment on the pharmacokinetics have not been evaluated. Avoid or use with extreme caution.

Elderly

Younger subjects cleared drug 4 times faster than elderly subjects.

Gender

Effect of gender on the pharmacokinetics have not been evaluated.

Race

Effect of race on the pharmacokinetics have not been evaluated.

Indications and Usage

Acute and intermittent management of increased muscle tone associated with spasticity.

Contraindications

Coadministration of ciprofloxacin or fluvoxamine; hypersensitivity to any component of the product.

Dosage and Administration

Adults

PO Initiate therapy with a 4 mg dose, increasing the dose gradually in 2 to 4 mg increments to optimum effect. The dose can be repeated at 6- to 8-h intervals as needed (max, 3 doses in 24 h not to exceed 36 mg/day).

General Advice

  • Administer consistently with or without food. Advise health care provider if administration consistency cannot be maintained because a change in dose may be needed.
  • Do not switch between tablets and capsules. Tablets and capsules are not equivalent when administered with food.
  • Capsule may be opened and the contents sprinkled on applesauce and then immediately consumed. However, administration of capsule contents sprinkled on applesauce is not bioequivalent to administration of intact capsule under fasting conditions. Do not switch between intact capsules and capsule content sprinkled on food unless directed by health care provider.

Storage/Stability

Store at controlled room temperature (59° to 86°F).

Drug Interactions

ACE inhibitors (eg, lisinopril)

Pharmacologic effects of ACE inhibitors may be increased, possibly resulting in severe hypotension.

Acetaminophen

The time to reach acetaminophen peak concentrations may be delayed.

Alcohol

Plasma levels of tizanidine may be elevated, increasing the adverse reactions.

Antihypertensive agents

Use with caution; do not administer with other alpha-2 adrenergic agonists (eg, clonidine).

Ciprofloxacin, fluvoxamine

Coadministration with tizanidine is contraindicated. Tizanidine plasma concentrations may be elevated, increasing the risk of adverse reactions (eg, hypotension, sedation).

CYP1A2 inhibitors (eg, acyclovir, antiarrhythmic agents [eg, amiodarone, mexiletine, propafenone, verapamil], cimetidine, famotidine, fluoxetine, hormonal contraceptives, quinolone antibiotics [eg, norfloxacin], ticlopidine, zileuton)

Tizanidine plasma levels may be elevated, increasing pharmacologic effects and adverse reactions.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypotension (33%); bradycardia (10%).

CNS

Somnolence (92%); asthenia (78%); dizziness (45%); dyskinesia, nervousness, speech disorder (3%); anxiety, depression, paresthesia (at least 1%).

Dermatologic

Rash, skin ulcer, sweating (at least 1%).

EENT

Amblyopia, pharyngitis, rhinitis (3%).

GI

Dry mouth (88%); constipation (4%); vomiting (3%); abdomen pain, diarrhea, dyspepsia (at least 1%).

Genitourinary

UTI (10%); urinary frequency (3%).

Lab Tests

Abnormal LFTs (3%).

Musculoskeletal

Back pain, myasthenia (at least 1%).

Miscellaneous

Infection (6%); flu syndrome (3%); fever (at least 1%).

Precautions

Monitor

Monitor transaminase levels before starting therapy, during the first 6 mo (eg, 1, 3, 6 mo), and periodically thereafter during long-term therapy. Monitor patients with CrCl less than 25 mL/min for onset or increase in severity of common adverse reactions (eg, dry mouth, dizziness, somnolence).


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Use with caution because Cl may be decreased 4-fold.

Renal Function

Use with caution in patients with renal function impairment (CrCl less than 25 mL/min). Reduce dose during initial titration; if higher doses are required, increase individual doses rather than dosing frequency. Closely monitor for onset or increase in severity of common adverse reactions (eg, asthenia, dizziness, dry mouth, somnolence).

Hepatic Function

Avoid or use with caution.

Hazardous Tasks

Dose-related sedation, interfering with daily activities, commonly occurs. Drowsiness may be noted within 0.5 h of dosing and peaks at 1.5 h following dose.

Bioequivalence

Tablets and capsules are bioequivalent to each other under fasted conditions, but not under fed conditions.

CV

Reduced pulse rate and BP may occur.

Chronic use

Clinical experience with long-term use of single doses of tizanidine at 8 to 16 mg or total daily doses of 24 to 36 mg is limited.

Discontinuation of treatment

Decrease dose slowly to minimize risk of withdrawal, rebound hypertension, tachycardia, and hypertonia, especially in patients who have received high doses for prolonged periods.

Hallucinosis/Psychotic-like symptoms

Hallucinations, delusions, and psychosis in association with hallucinations may occur.

Hepatic toxicity

Hepatocellular liver injury may occur.

Hypotension

Dose-related hypotension may occur, starting within 1 h of administration and peaking 2 to 3 h after administration. Bradycardia, light-headedness/dizziness, orthostatic hypotension, and syncope (rarely) have been reported.

Posture/balance/function

Use with caution when spasticity is utilized to sustain posture, balance in locomotion, or increased function.

Overdosage

Symptoms

Bradycardia, confusion, coma, depressed cardiac function, hypotension, lethargy, respiratory depression, somnolence.

Patient Information

  • Advise patient that there is limited experience with tizanidine in regard to duration of use and the higher doses required to reduce muscle tone.
  • Advise patient to review the patient information leaflet carefully before starting therapy, and to read and check for new information each time the medication is refilled.
  • Review dosing schedule with patient.
  • Advise patient that medication is started at a low dose and gradually increased as tolerated until max benefit is achieved.
  • Instruct patient to take prescribed dose at 6- to 8-h intervals as needed for spasticity, to a max of 3 doses in a 24-h period.
  • Advise patient to take tizanidine consistently with or without food. Caution patient not to change from tablets to capsules, or from capsules to tablets, without discussing with health care provider because dosing changes may be required.
  • Advise patient that if medication needs to be discontinued, it will be slowly withdrawn unless safety concerns (eg, rash) require a more rapid withdrawal. Caution patient not to stop taking the medication abruptly or decrease the dose unless advised by health care provider because of risk of developing withdrawal symptoms (eg, hypertension, rapid heart rate).
  • Instruct patient to avoid alcohol and other CNS depressant medications while taking tizanidine.
  • Instruct patient to get up slowly from a lying or sitting position and to avoid sudden position changes to prevent postural hypotension. Instruct patient to lie or sit down if they experience dizziness, light-headedness, and/or faintness when standing.
  • Advise patient to report frequent episodes of dizziness and/or faintness with position changes to health care provider. Caution patient that hot tubs and hot showers or baths may make dizziness and light-headedness worse.
  • Advise patient to take sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
  • Advise patient that drug may cause drowsiness and/or dizziness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
  • Advise patient to notify health care provider if any of the following occur: dark urine, excessive drowsiness, pain below right side of chest, unexplained appetite loss or flu-like symptoms, yellowing of skin or eyes.

Copyright © 2009 Wolters Kluwer Health.

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