Brand name: Zanaflex
Drug class: Centrally Acting Skeletal Muscle Relaxants
VA class: MS200
Chemical name: 5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothiadiazol-4-amine monohydrochloride
Molecular formula: C₉H₈ClN₅S•HCl
CAS number: 64461-82-1

Medically reviewed by Drugs.com on Aug 15, 2024. Written by ASHP.

Introduction

Skeletal muscle relaxant; centrally acting α₂-adrenergic agonist.

Uses for tiZANidine

Spasticity

Management of spasticity associated with cerebral or spinal injury, alone or in conjunction with other standard therapies (e.g., baclofen).

tiZANidine Dosage and Administration

General

• Individualize dosage according to the patient's requirements and response using the lowest dosage that produces optimum response without adverse effects.

Administration

Oral Administration

Clinically important differences (e.g., increased adverse effects, delayed or more rapid onset of activity) may be apparent when switching administration of capsules or tablets between fed and/or fasting states, switching between capsules and tablets in fed state, or switching between administration of intact capsule and sprinkling capsule contents on applesauce. Be thoroughly familiar with possible pharmacokinetic changes associated with these conditions. (See Absorption under Pharmacokinetics.)

Dosage

Available as tizanidine hydrochloride; dosage expressed in terms of tizanidine.

Adults

Spasticity

Oral

Initially, 4 mg; single doses <8 mg not effective in clinical trials, but 4-mg dose used to minimize the incidence of common dose-related adverse effects (e.g., orthostatic hypotension).

Repeat 4-mg dose every 6–8 hours as needed for a maximum of 3 doses in 24 hours.

Increase dosage gradually in increments of 2–4 mg daily over a period of 2–4 weeks until optimum therapeutic effects are obtained with tolerable adverse effects. (See Limited Experience with Long-term Use of Higher Dosages under Cautions.)

Prescribing Limits

Adults

Spasticity

Oral

Maximum 36 mg in a 24-hour period.

Special Populations

Renal Impairment

Initiate with caution in patients with renal impairment (Cl_cr <25 mL/minute). In these patients, use smaller individual doses during dosage titration; if higher doses are needed, increase the amount of each individual dose rather than increasing the frequency of dosing.

Cautions for tiZANidine

Contraindications

• Concomitant therapy with ciprofloxacin or fluvoxamine. (See Specific Drugs under Interactions.)

• Known hypersensitivity to tizanidine or any ingredient in the formulation.

Warnings/Precautions

Warnings

Limited Experience with Long-term Use of Higher Dosages

Only limited clinical experience with long-term use of tizanidine at single doses of 8–16 mg or total daily dosages of 24–36 mg. Therefore, only adverse effects with a relatively high incidence were likely to be identified in clinical studies. (See Dosage and Administration.)

Hypotension

Hypotension, occasionally associated with bradycardia, orthostatic effects, dizziness, and, rarely, syncope, reported. Hypotensive effect is dose related.

Minimize risk of marked hypotension by careful dosage titration; observe patients for manifestations of hypotension prior to dosage adjustment. Patients moving from supine to upright position may be at increased risk for hypotension and orthostatic effects.

Use caution in patients receiving concomitant antihypertensive therapy and avoid use with other α₂-adrenergic agonists (e.g., clonidine). Because clinically important hypotension reported with concurrent use of either fluvoxamine or ciprofloxacin, these drugs are contraindicated in patients receiving tizanidine. (See Interactions.)

Risk of Liver Injury

Liver injury (most often hepatocellular) reported occasionally. Elevations (i.e., >3 times ULN, or 2 times ULN if baseline levels were elevated) of ALT or AST reported in about 5% of tizanidine-treated patients in controlled studies. In most cases, resolved rapidly upon drug discontinuance without residual problems. In patients with elevated aminotransferase concentrations, nausea, vomiting, anorexia, and jaundice occasionally reported. Death associated with liver failure reported rarely.

Monitor serum aminotransferase concentrations prior to and during the first 6 months of treatment (e.g., at baseline and at 1, 3, and 6 months) and periodically thereafter based on clinical status.

Avoid tizanidine or use only with extreme caution in patients with hepatic impairment. (See Hepatic Impairment under Cautions.)

Sedation

Dose-related sedation, sometimes severe. May interfere with daily activity.

Hallucinations/Psychotic-like Symptoms

Hallucinations (formed, visual) or delusions reported in 3% of tizanidine-treated patients in 2 controlled studies; all cases reported within first 6 weeks of therapy. Psychoses associated with hallucinations reported in at least 1 patient.

Potential Interaction with Fluvoxamine or Ciprofloxacin

In pharmacokinetic studies, substantial increases in serum tizanidine concentrations observed during concurrent administration of fluvoxamine or ciprofloxacin (potent CYP1A2 inhibitors); potentiated hypotensive and sedative effects also observed. Concurrent administration of fluvoxamine or ciprofloxacin contraindicated. (See Interactions.)

Potential Interaction with Other CYP1A2 Inhibitors

Potential drug interactions with other CYP1A2 inhibitors; ordinarily should avoid concurrent use. If combined use is necessary, use drugs with caution. (See Interactions.)

General Precautions

Cardiovascular Effects

Potential for prolongation of the QT interval and bradycardia based on animal studies.

Pulse rate reduction associated with decreases in BP reported.

Ocular Effects

Dose-related retinal degeneration and corneal opacities observed in animal studies. No reports of corneal opacities or retinal degeneration in clinical studies.

Use in Women Taking Oral Contraceptives

Concurrent use of tizanidine and oral contraceptives may substantially reduce the clearance of tizanidine; ordinarily should avoid concomitant use. If clinically necessary, reduce initial tizanidine dosage and titration rate. (See Specific Drugs under Interactions.)

Discontinuance of Therapy

Possible rebound manifestations with abrupt withdrawal of therapy, including hypertension, tachycardia, hypertonia, tremor, and anxiety.

If therapy is to be discontinued, decrease dosage gradually, particularly in patients who have been receiving high dosages for prolonged periods, to minimize the risk of withdrawal and rebound symptoms.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether tizanidine is distributed into milk. However, because it is lipid-soluble, tizanidine might be expected to pass into milk. Use caution in nursing women.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Clearance is decreased 4-fold; use with caution.

Hepatic Impairment

Tizanidine undergoes extensive first-pass metabolism in the liver; hepatic impairment is likely to substantially affect the drug's pharmacokinetics. Avoid use or use only with extreme caution in patients with hepatic impairment. (See Risk of Liver Injury under Cautions.)

Renal Impairment

Clearance is reduced by >50% in patients with Cl_cr <25 mL/minute. Use with caution in patients with renal impairment. Monitor closely for onset or increased severity of adverse effects (e.g., dry mouth, somnolence, asthenia, dizziness) that may indicate potential overdosage. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Dry mouth, somnolence, asthenia (weakness, fatigue, and/or tiredness), dizziness.

Drug Interactions

Extensively metabolized, mainly by CYP1A2.

Drugs Affecting Hepatic Microsomal Enzymes

CYP1A2 inhibitors: Potential pharmacokinetic interaction (decreased plasma clearance of tizanidine). Ordinarily avoid concomitant use; if concomitant use is necessary, use with caution. (See Specific Drugs under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Not likely to affect metabolism of CYP substrates.

Specific Drugs

tiZANidine Pharmacokinetics

Absorption

Bioavailability

Essentially completely absorbed following oral administration of capsules and tablets; peak plasma concentrations attained in about 1 hour.

Commercially available capsules and tablets are bioequivalent under fasting conditions, but not under nonfasting conditions.

Food

Tablets: Food increases the mean peak plasma concentration by about 30%, increases the median time to peak plasma concentration from about 60 minutes to 85 minutes, and increases the extent of absorption by about 30%.

Capsules: Food decreases the mean peak plasma concentration by 20% and increases the median time to peak plasma concentration from about 1 hour to 3 hours, and increases the extent of absorption by about 10%. When given with food, the amount of tizanidine absorbed from the capsules about 80% of the amount absorbed from the tablet.

Administration of the capsule contents sprinkled on applesauce is not bioequivalent to intact capsule under fasting conditions and results in a 15–20% increase in peak plasma concentration and AUC and a 15-minute decrease in median lag time and time to achieve peak plasma concentration compared with administration of intact capsule while fasting.

Distribution

Plasma Protein Binding

About 30%.

Elimination

Metabolism

Undergoes extensive first-pass hepatic metabolism. Metabolized mainly by CYP1A2.

Elimination Route

Recovered in urine (60%) and feces (20%) following administration of single or multiple radiolabeled doses.

Half-life

About 2.5 hours.

Stability

Storage

Oral

Capsules and Tablets

25°C (may be exposed to 15–30°C).

Actions

• Centrally acting α₂-adrenergic agonist with myotonolytic effects on skeletal muscle.

• Exact mechanism in reducing muscle tone and spasm frequency is not clear. Reportedly decreases the frequency and amplitude of muscle spasms (tonic reflexes) that arise in response to muscle stretching in patients with various spinal cord lesions. Appears to reduce spasticity by increasing presynaptic inhibition of motor neurons, leading to reduced facilitation of spinal motor neurons and a resultant decrease in muscle tone.

• Greatest effects on polysynaptic pathways, with no important effect on monosynaptic spinal reflexes. The drug does not have direct effects on skeletal muscle fibers or the neuromuscular junction.

• Shown to have antinociceptive effects in animals, and some reports have suggested that it may improve pain associated with muscle spasm.

• Structurally and pharmacologically related to clonidine and other α₂-adrenergic agonists; however, tizanidine has only one-tenth to one-fiftieth of clonidine's antihypertensive potency.

• Importance of advising patients that clinical experience with long-term or high-dose tizanidine therapy is limited.

• Risk of marked orthostatic hypotension; importance of exercising caution when moving from a supine to a fixed upright position.

• Risk of sedation, which may be additive when taken in conjunction with alcohol or other CNS depressants; importance of exercising caution when performing activities requiring alertness, including driving a motor vehicle or operating machinery.

• Importance of advising patients of potential changes in absorption profile and resulting changes in efficacy and adverse effect profile when taken with food. (See Pharmacokinetics.)

• Importance of not discontinuing abruptly because of potential for rebound hypertension and tachycardia.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses, and of informing clinicians or pharmacists whenever any drug is added or discontinued. Importance of not taking tizanidine concomitantly with either ciprofloxacin or fluvoxamine.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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Frequently asked questions

• What is Miderizone used for?

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