Tizanidine

Pharmacologic Category

Alpha2-Adrenergic Agonist

Dosing: Adult

Note: Patients more sensitive to sedating and other CNS adverse effects (eg, those who are older, debilitated, or with organ impairment) may better tolerate a reduced dose, less frequent administration, and/or more gradual titration. Switching between capsules and tablets may alter effect as these preparations are not bioequivalent when administered with food; see Pharmacodynamics/Kinetics.

Muscle spasm and/or musculoskeletal pain (adjunctive therapy) (off-label use):

Note: For skeletal muscle spasm and/or pain (eg, low back pain, neck pain) with muscle spasm, usually in combination with nonsteroidal anti-inflammatory drugs and/or acetaminophen (ACP [Chou 2017]; Pareek 2009; van Tulder 2003). In general, muscle relaxants should be used temporarily (eg, for a few days or intermittently for a few days when needed) (APS 2016).

Oral: Initial: 2 to 4 mg every 6 to 12 hours as needed and/or at bedtime; some may benefit by scheduling doses initially. May increase based on response and tolerability up to a maximum dose of 24 mg/day (eg, 4 to 8 mg every 8 hours as needed) (Chou 2019; Knight 2020; Pareek 2009; van Tulder 2003).

Spasticity:

Note: For muscle spasticity due to neurologic injury or disease (eg, multiple sclerosis, stroke, spinal cord injury, traumatic brain injury, amyotrophic lateral sclerosis [ALS]) (Ashworth 2012; Chou 2004; Lindsay 2016; Nair 2014; Otero-Romero 2016; Shakespeare 2003; Taricco 2006).

Oral: Initial: 2 mg once daily usually at bedtime; may increase based on response and tolerability by 2 to 4 mg per day (with a minimum of 1 to 4 days between dose increases) up to a maximum dose of 36 mg/day in 3 or 4 divided doses. In treatment of spasticity associated with ALS, some experts limit dose to 24 mg/day (Galvez-Jimenez 2019).

Discontinuation of therapy: Gradually taper dose by 2 to 4 mg daily to reduce the risk of rebound symptoms (eg, hypertension, tachycardia, hypertonia), especially in patients receiving high doses (eg, ≥20 mg/day) for long periods (eg, ≥9 weeks) or in patients who have been receiving concomitant opioids.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Use with caution; clearance is decreased. Refer to adult dosing.

Dosing: Renal Impairment: Adult

CrCl ≥25 mL/minute: No dosage adjustment provided in manufacturer's labeling; however, caution may be needed as creatinine clearance decreases.

CrCl <25 mL/minute: Use with caution; clearance reduced >50%. During initial dose titration, use reduced doses. If higher doses are necessary, increase dose instead of increasing dosing frequency.

Dosing: Hepatic Impairment: Adult

Avoid use in hepatic impairment; if used, reduce dose during initial dose titration. If higher doses are necessary, increase dose instead of increasing dosing frequency. Monitor aminotransferases.

Dosing: Pediatric

Note:The tablet and capsule dosage forms are not bioequivalent when administered with food.

Spasticity associated with cerebral palsy: Limited data available (Dai 2008; Dai 2016; Kliegman 2016; Patel 2005): Dosing based on small open label trials and clinical experience; tizanidine was used in combination with adjunct botulinum toxin therapy

Initial dose:

Children 2 to <10 years: Oral: 1 mg at bedtime, titrate as needed

Children ≥10 years and adolescents: Oral: 2 mg at bedtime, titrate as needed

Titration and maintenance dose: Children ≥2 years and Adolescents: Oral: Titrate initial dose upward to reported effective range of: 0.3 to 0.5 mg/kg/day in 3 to 4 divided doses; maximum daily dose: 24 mg/day.Note: In adults, when discontinuation of therapy is necessary, doses are gradually tapered by 2 to 4 mg daily.

Dosing: Renal Impairment: Pediatric

There are no pediatric specific dosage recommendations; use with caution; based on experience in adult patients, dosing adjustment suggested.

Dosing: Hepatic Impairment: Pediatric

There are no pediatric specific dosage recommendations; based on experience in adult patients, dosing adjustment suggested.

Calculations

• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)
• Creatinine Clearance by Jelliffe
• Creatinine Clearance by Sanaka
• Glomerular Filtration Rate by Abbreviated MDRD
• Glomerular Filtration Rate by Abbreviated MDRD (SI units)
• Glomerular Filtration Rate by MDRD
• Glomerular Filtration Rate by MDRD (IDMS-Traceable SCr)
• Glomerular Filtration Rate by MDRD (SI units)
• Glomerular Filtration Rate Estimate in African Americans by AASK Equation

Use: Labeled Indications

Spasticity: Management of spasticity; reserve treatment with tizanidine for daily activities and times when relief of spasticity is most important.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Muscle spasm and/or musculoskeletal pain (adjunctive therapy)Level of Evidence [B]

Data from multiple double-blind, randomized, controlled trials are supportive of the use of tizanidine (either alone or in combination with co-analgesics) in the treatment of skeletal muscle spasm and/or musculoskeletal pain Ref.

Administration: Oral

Capsules may be opened and contents sprinkled on food; however, extent of absorption is increased up to 20% relative to administration of the capsule under fasted conditions.

Administration: Pediatric

Oral: May be taken with or without food but should be consistent with regards to administration. Capsules may be opened and contents sprinkled on food (eg, applesauce); however, extent of absorption is increased up to 20% relative to administration of the capsule under fasted conditions.

Dietary Considerations

Administration with food compared to administration in the fasting state results in clinically-significant differences in absorption and other pharmacokinetic parameters. Patients should be consistent and should not switch administration of the tablets or the capsules between the fasting and nonfasting state. In addition, switching between the capsules and the tablets in the fed state will also result in significant differences. Opening capsule contents to sprinkle on applesauce compared to swallowing intact capsules whole will also result in significant absorption differences. Patients should be consistent with regards to administration.

Storage/Stability

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to relax muscles.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Dry mouth

• Fatigue

• Loss of strength and energy

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.

• Severe dizziness

• Passing out

• Confusion

• Sensing things that seem real but are not

• Mood changes

• Behavioral changes

• Slow heartbeat

• Chills

• Sore throat

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Other safety concerns:

Contraindications

Concomitant therapy with ciprofloxacin or fluvoxamine (potent CYP1A2 inhibitors)

Warnings/Precautions

Concerns related to adverse effects:

• Hepatic effects: Potential for hepatotoxicity; monitor aminotransferases prior to and during use or if hepatic injury is suspected.

• Hypersensitivity reactions: Hypersensitivity reactions, including anaphylaxis, angioedema, respiratory compromise, and urticaria have been reported with use. Patients with signs and symptoms of allergic reactions should discontinue therapy.

• Hypotension: Significant hypotension and syncope may occur; use with caution in patients at risk for severe hypotensive effects (eg, patients taking concurrent medications which may predispose to hypotension). Minimize effects by titrating dose and monitoring for signs and symptoms of hypotension prior to dose increase.

• Sedation: Sedation may occur; use with caution in patients at risk for sedative effects (eg, patients taking concurrent CNS depressants); patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Visual hallucinations: Use has been associated with visual hallucinations or delusions; use caution in patients with psychiatric disorders. Consider discontinuation of therapy if hallucinations occur.

Disease-related concerns:

• Hepatic impairment: Use not recommended in patients with hepatic impairment; potential for effects likely due to extensive hepatic metabolism of tizanidine.

• Renal impairment: Use with caution in patients with renal impairment. Clearance decreased significantly in patients with severe impairment (CrCl <25 mL/minute); dose reductions recommended.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.

Special populations:

• Elderly: Use with caution; clearance decreased fourfold in the elderly; may increase risk of adverse effects and/or duration of effects. Elderly with severe renal impairment (CrCl <25 mL/minute) may have clearance reduced by >50% compared to healthy elderly subjects.

Other warnings/precautions:

• Abrupt withdrawal: Withdrawal resulting in rebound hypertension, tachycardia, and hypertonia may occur upon discontinuation; doses should be decreased slowly, particularly in patients taking concomitant opioids or receiving high doses (20 to 28 mg daily) for prolonged periods (≥9 weeks).

• Food: Food alters absorption profile relative to administration under fasting conditions. In addition, bioequivalence between capsules and tablets is altered by food; capsules and tablets are bioequivalent under fasting conditions, but not under nonfasting conditions.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Since elderly commonly have renal function of CrCl <30 mL/minute, creatinine clearance should be estimated before dosing this medication. Low doses should be started initially because of the possibility of CNS effects.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Breast-Feeding Considerations

Excretion in breast milk is unknown, but expected due to lipid solubility.

Briggs' Drugs in Pregnancy & Lactation

• Tizanidine

Adverse Reactions

>10%:

Cardiovascular: Hypotension (16% to 33%)

Central nervous system: Drowsiness (48% to 92%), dizziness (16% to 45%)

Gastrointestinal: Xerostomia (49% to 88%)

Neuromuscular & skeletal: Asthenia (41% to 78%)

1% to 10%:

Cardiovascular: Bradycardia (2% to 10%)

Central nervous system: Nervousness (3%), speech disturbance (3%), delusion (≤3%), visual hallucination (≤3%)

Gastrointestinal: Constipation (4%), vomiting (3%)

Genitourinary: Urinary tract infection (10%), urinary frequency (3%)

Hepatic: Abnormal hepatic function tests (6%)

Infection: Infection (6%)

Neuromuscular & skeletal: Dyskinesia (3%)

Ophthalmic: Blurred vision (3%)

Respiratory: Flu-like symptoms (3%), pharyngitis (3%), rhinitis (3%)

Frequency not defined:

Central nervous system: Drug withdrawal, sedated state

Hypersensitivity: Hypersensitivity reaction

<1%, postmarketing, and/or case reports: Anaphylaxis, arthralgia, depression, exfoliative dermatitis, fatigue, hepatitis, hepatotoxicity, muscle spasm, paresthesia, seizure, skin rash, Stevens-Johnson syndrome, syncope, tremor, ventricular tachycardia

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects

Substrate of CYP1A2 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions Open Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Amiodarone: May increase the serum concentration of TiZANidine. Risk C: Monitor therapy

Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: TiZANidine may enhance the hypotensive effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Risk X: Avoid combination

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Beta-Blockers: Alpha2-Agonists may enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Levobunolol; Metipranolol. Risk D: Consider therapy modification

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Exceptions are discussed in separate monographs. Risk D: Consider therapy modification

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Ciprofloxacin (Systemic): May increase the serum concentration of TiZANidine. Risk X: Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP1A2 Inducers (Moderate): May decrease the serum concentration of TiZANidine. Risk C: Monitor therapy

CYP1A2 Inhibitors (Moderate): May increase the serum concentration of TiZANidine. Management: If combined use cannot be avoided, initiate tizanidine in adults at 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Exceptions: Ciprofloxacin (Systemic). Risk D: Consider therapy modification

CYP1A2 Inhibitors (Strong): May increase the serum concentration of TiZANidine. Risk X: Avoid combination

CYP1A2 Inhibitors (Weak): May increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk D: Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Fexinidazole [INT]: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole [INT]. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Risk D: Consider therapy modification

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy

Lisinopril: TiZANidine may enhance the hypotensive effect of Lisinopril. Risk C: Monitor therapy

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mirtazapine: May diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding concurrent use. If the combination cannot be avoided, monitor for decreased effects of alpha2-agonists if mirtazapine is initiated/dose increased, or increased effects if mirtazapine is discontinued/dose decreased. Risk D: Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Risk D: Consider therapy modification

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May diminish the antihypertensive effect of Alpha2-Agonists. Risk C: Monitor therapy

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. Risk D: Consider therapy modification

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Tobacco (Smoked): May decrease the serum concentration of TiZANidine. Risk C: Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Tricyclic Antidepressants: May diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding this combination. If used, monitor for decreased effects of the alpha2-agonist. Exercise great caution if discontinuing an alpha2-agonist in a patient receiving a TCA. Risk D: Consider therapy modification

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Food Interactions

The tablet and capsule dosage forms are not bioequivalent when administered with food. Food increases both the time to peak concentration and the extent of absorption for both the tablet and capsule. However, maximal concentrations of tizanidine achieved when administered with food were increased by 30% for the tablet, but decreased by 20% for the capsule. Under fed conditions, the capsule is approximately 80% bioavailable relative to the tablet. Management: Administer with or without food, but keep consistent.

Genes of Interest

• Cytochrome P450 1A2
• Potassium Voltage-Gated Channel, Isk-Related Family, Member 1
• Voltage-Gated Sodium Channel 5A

Monitoring Parameters

Monitor liver function (aminotransferases) at baseline and 1 month after maximum dose achieved or if hepatic injury suspected; blood pressure; renal function

Advanced Practitioners Physical Assessment/Monitoring

May cause hypotension; monitor blood pressure periodically. Do not discontinue medication abruptly; can cause hypertension and tachycardia.

Nursing Physical Assessment/Monitoring

May cause hypotension; monitor blood pressure periodically. Do not discontinue medication abruptly; can cause hypertension and tachycardia.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Zanaflex: 2 mg, 4 mg, 6 mg

Generic: 2 mg, 4 mg, 6 mg

Tablet, Oral:

Zanaflex: 4 mg

Zanaflex: 4 mg [DSC] [scored]

Generic: 2 mg, 4 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Generic: 2 mg, 4 mg

Anatomic Therapeutic Chemical (ATC) Classification

• M03BX02

Generic Available (US)

Yes

Pricing: US

Capsules (tiZANidine HCl Oral)

2 mg (per each): $1.22 - $2.71

4 mg (per each): $3.43 - $3.44

6 mg (per each): $5.15

Capsules (Zanaflex Oral)

2 mg (per each): $3.45

4 mg (per each): $4.37

6 mg (per each): $6.56

Tablets (tiZANidine HCl Oral)

2 mg (per each): $1.22

4 mg (per each): $0.09 - $1.47

Tablets (Zanaflex Oral)

4 mg (per each): $3.25

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Mechanism of Action

An alpha2-adrenergic agonist agent which decreases spasticity by increasing presynaptic inhibition; effects are greatest on polysynaptic pathways; overall effect is to reduce facilitation of spinal motor neurons.

Pharmacodynamics/Kinetics

Onset: Single dose (8 mg): Peak effect: 1 to 2 hours

Duration: Single dose (8 mg): 3 to 6 hours

Absorption: Tablets and capsules are bioequivalent under fasting conditions, but not under nonfasting conditions.

Tablets administered with food: Peak plasma concentration is increased by ~30%; time to peak increased by 25 minutes; extent of absorption increased by ~30%.

Capsules administered with food: Peak plasma concentration decreased by 20%; time to peak increased by 2 to 3 hours; extent of absorption increased by ~10%.

Capsules opened and sprinkled on applesauce are not bioequivalent to administration of intact capsules under fasting conditions. Peak plasma concentration and AUC are increased by 15% to 20%; time to peak decreased by 15 minutes.

Distribution: IV: 2.4 L/kg

Protein binding: ~30%

Metabolism: Extensively hepatic via CYP1A2 to inactive metabolites

Bioavailability: ~40% (extensive first-pass metabolism)

Half-life elimination: ~2.5 hours

Time to peak, serum:

Fasting state: Capsule, tablet: 1 hour

Fed state: Capsule: 3 to 4 hours, Tablet: 1.5 hours

Excretion: Urine (60%); feces (20%)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Clearance is reduced more than 50% in elderly patients with renal function impairment (creatinine clearance <25 mL/minute) compared with healthy subjects; this may lead to longer duration of clinical effects.

Hepatic function impairment: Extensively metabolized in the liver and significant effects are expected; use not recommended in patients with hepatic impairment.

Geriatric: Younger subjects cleared drug 4 times faster than elderly subjects.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Frequent occurrence of xerostomia (normal salivary flow resumes upon discontinuation) has been reported. Rare occurrence of Stevens-Johnson syndrome has also been reported.

Effects on Bleeding

No information available to require special precautions

Index Terms

Sirdalud; Tizanidine HCl

FDA Approval Date

November 27, 1996

References

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Brand Names: International

KaiLaiTong (CN); Mio-Relax (CO); Musant (BG); Musrel (LK); Myores (ID); Myos-Nor (CO); Myoxyl (LK); Phardex (ID); Rekan (EG); Relentus (BD); Remus (BD); Sirdalud (AE, AR, AT, BB, BE, BF, BH, BJ, BM, BR, BS, BZ, CH, CI, CL, CO, CR, CY, CZ, DE, DK, DO, EE, EG, ES, ET, FI, FR, GH, GM, GN, GR, GT, GY, HK, HN, ID, IL, IN, IQ, IR, IT, JM, JO, KE, KR, KW, LB, LR, LT, LU, LV, LY, MA, ML, MR, MT, MU, MW, MX, NE, NG, NI, NL, NO, OM, PA, PE, PH, PL, PR, PT, PY, QA, RU, SA, SC, SD, SE, SI, SK, SL, SN, SR, SV, SY, TH, TN, TR, TT, TW, TZ, UA, UG, VE, VN, YE, ZA, ZM, ZW); Sirdalud MR (CH, MX, NL); Sirdalud Retard (DK, FI); Sirdalum (UY); Spaslax (TW); Stidine (TW); Ternelin (JP); Tilax (QA); Tizadin (BD); Tizalin (TW); Tizalud (UA); Tizan (TH); Tizanac (BD); Tizarid (KR); Tizigesic (LK); Tizyl (EG); Tonolyte 2 (TH); Tonolyte 4 (TH); Zanaflex (IE); Zita (PK); Zitanid (ID)

Last Updated 5/2/20