Dosage guidance:
Dosage form information: The tablet and capsule dosage forms are not bioequivalent when administered with food.
Spasticity associated with cerebral palsy: Limited data available (Ref): Dosing based on small open-label trials and clinical experience.
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no pediatric-specific dosage recommendations; use with caution (tizanidine is primarily renally eliminated); based on experience in adult patients, dosing adjustment suggested.
There are no pediatric-specific dosage recommendations; based on experience in adult patients, dosing adjustment suggested; use with caution.
(For additional information see "Tizanidine: Drug information")
Dosage guidance:
Dosage form information: Switching between capsules and tablets may alter effect as these preparations are not bioequivalent when administered with food.
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 (Ref). In general, muscle relaxants should be used temporarily (eg, for a few days or intermittently for a few days when needed; up to 4 weeks’ duration when necessary) (Ref).
Oral: Initial: 2 to 4 mg every 8 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) (Ref).
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]) (Ref).
Oral: Initial: 2 mg once daily usually at bedtime; may increase based on response and tolerability in increments of 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 (Ref). In the treatment of spasticity associated with stroke (eg, hemiplegic shoulder pain), some experts initiate therapy with 2 mg every 8 hours as needed (Ref). In the treatment of spasticity associated with ALS, some experts limit dose to 24 mg/day (Ref).
Discontinuation of therapy: Gradually taper total daily dose by 2 to 4 mg to reduce the risk of rebound symptoms (eg, hypertension, tachycardia, hypertonia), especially in patients receiving high doses (eg, ≥16 mg/day) for long periods (eg, ≥9 weeks) or in patients who have been receiving concomitant opioids (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: Oral:
CrCl ≥60 mL/minute: No dosage adjustment necessary (Ref).
CrCl ≥25 to <60 mL/minute: Initial: No specific dosage adjustment recommended (has not been studied); however, tizanidine is primarily renally eliminated; use with caution. Start at the low end of the dosing range and monitor for side effects with increased doses (Ref).
CrCl <25 mL/minute: Initial: 2 mg once daily; may increase based on response and tolerability by 2 mg per day (with a minimum of 1 to 4 days between dose increases). Use with caution; clearance reduced >50%. If higher doses are necessary, consider increasing the dose instead of increasing dosing frequency (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be significantly dialyzable (large Vd) (Ref).
Oral: Initial: 2 mg once daily; use with caution, as clearance in patients with severe kidney dysfunction is reduced >50%. Slowly increase based on tolerability and response in 2 mg increments. If higher doses are necessary, consider increasing the dose instead of increasing dosing frequency (Ref).
Peritoneal dialysis: Unlikely to be significantly dialyzable (large Vd) (Ref).
Oral: Initial: 2 mg once daily; use with caution, as clearance in patients with severe kidney dysfunction is reduced >50%. Slowly increase based on tolerability and response in 2 mg increments. If higher doses are necessary, consider increasing the dose instead of increasing dosing frequency (Ref).
CRRT: Unlikely to be significantly dialyzable (large Vd) (Ref).
Oral: Initial: 2 mg once daily; use with caution, as clearance is reduced in patients with kidney dysfunction. Slowly increase based on tolerability and response in 2 mg increments. If higher doses are necessary, consider increasing the dose instead of increasing dosing frequency (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Unlikely to be significantly dialyzable (large Vd) (Ref).
Oral: Initial: 2 mg once daily; use with caution, as clearance is reduced in patients with kidney dysfunction. Slowly increase based on tolerability and response in 2 mg increments. If higher doses are necessary, consider increasing the dose instead of increasing dosing frequency (Ref).
Use with caution; reduce dose during initial dose titration. If higher doses are necessary, increase dose instead of increasing dosing frequency. Monitor aminotransferases.
Asymptomatic, reversible increased liver enzymes (most notably alanine aminotransferase [ALT]) and severe hepatotoxicity have been reported (Ref). Resolution in patients with clinically significant increases in liver enzymes occurs upon discontinuation. In patients with severe hepatotoxicity, recovery has occurred within 1 to 2 months of discontinuation (Ref).
Mechanism: Non–dose-related; unknown, may be due to immunologic reaction (Ref).
Onset: Delayed; reported 2 to 4 months after initiation (Ref). Upon rechallenge, increases in ALT have been reported within 6 days (Ref).
Risk factors:
• Underlying hepatic impairment (Ref)
Reversible hypotension has been demonstrated in 7% to 12% of patients receiving tizanidine (Ref). Orthostatic hypotension has also been reported ((Ref). Hypotension may lead to asthenia, dizziness, syncope, or discontinuation (Ref).
Mechanism: Dose-related; related to the pharmacologic action (ie, alpha-2 adrenergic agonist) (Ref).
Onset: Rapid; occurs within 30 minutes to 6 hours (Ref).
Risk factors:
• Higher doses and rapid titration
• Concurrent CYP1A2 inhibitors (eg, ciprofloxacin is associated with a 10-fold and fluvoxamine with a 33-fold increase in tizanidine concentrations) (Ref)
• Concurrent use of medications that cause hypotension (Ref)
• Underlying hepatic impairment (Child-Pugh score ≥7) (Ref)
Non–life-threatening, reversible sedated state occurs in 24% to 50% of patients receiving a standard dose (≤36 mg/day) of tizanidine (Ref). Sedation leading to coma has occurred with tizanidine overdose (Ref).
Mechanism: Dose-related; related to the pharmacologic action (ie, alpha-2 adrenergic agonist) (Ref).
Onset: Rapid; may occur within 60 minutes (Ref).
Risk factors:
• Concurrent use of alcohol
• Concurrent CYP1A2 inhibitors (eg, ciprofloxacin is associated with a 10-fold and fluvoxamine with a 33-fold increase in tizanidine concentrations) (Ref)
• Concurrent CNS depressants (Ref)
• Underlying kidney impairment
Abrupt discontinuation of tizanidine has led to potentially life-threatening withdrawal syndrome, including possible dysthermia, hallucinations, hypertension, nausea, tremor, and tachycardia (Ref).
Mechanism: Dose- and time-related (ie, hypersecretion of catecholamines following cessation of alpha-2 agonism) (Ref).
Onset: Rapid; occurs within 12 to 24 hours of cessation (Ref).
Risk factors
• High doses (≥16 mg daily) (Ref).
• Prolonged use (≥9 weeks)
• Abrupt discontinuation (Ref)
• Concurrent cessation of other CNS depressants (eg, baclofen, benzodiazepines, opioids) (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adolescents and adults.
>10%:
Gastrointestinal: Xerostomia (49%)
Nervous system: Asthenia (41%; including fatigue) (table 1) , dizziness (16%) (table 2) , drowsiness (48%) (table 3)
Drug (Tizanidine) |
Placebo |
Dosage Form |
Number of Patients (Tizanidine) |
Number of Patients (Placebo) |
---|---|---|---|---|
41% |
16% |
Oral tablets |
264 |
261 |
Drug (Tizanidine) |
Placebo |
Dosage Form |
Number of Patients (Tizanidine) |
Number of Patients (Placebo) |
---|---|---|---|---|
16% |
4% |
Oral tablets |
264 |
261 |
Drug (Tizanidine) |
Placebo |
Dosage Form |
Number of Patients (Tizanidine) |
Number of Patients (Placebo) |
---|---|---|---|---|
48% |
10% |
Oral tablets |
264 |
261 |
1% to 10%:
Gastrointestinal: Constipation (4%), vomiting (3%)
Genitourinary: Urinary frequency (3%), urinary tract infection (10%)
Hepatic: Increased liver enzymes (most notably increased serum alanine aminotransferase) (6%) (table 4)
Drug (Tizanidine) |
Placebo |
Dosage Form |
Number of Patients (Tizanidine) |
Number of Patients (Placebo) |
---|---|---|---|---|
6% |
2% |
Oral tablets |
264 |
261 |
Infection: Infection (6%)
Nervous system: Delusion (≤3%), nervousness (3%), speech disturbance (3%), visual hallucination (≤3%)
Neuromuscular & skeletal: Dyskinesia (3%)
Ophthalmic: Amblyopia (≤3%), blurred vision (≤3%)
Respiratory: Flu-like symptoms (3%), pharyngitis (3%), rhinitis (3%)
Postmarketing:
Cardiovascular: Bradycardia (Ref), hypotension (Ref), orthostatic hypotension (Ref), syncope, ventricular tachycardia
Dermatologic: Exfoliative dermatitis, skin rash, Stevens-Johnson syndrome
Hepatic: Hepatitis (Ref), hepatotoxicity (Ref)
Hypersensitivity: Anaphylaxis, angioedema
Nervous system: Depression, hallucination, paresthesia, sedated state (Ref), seizure, tremor, withdrawal syndrome (Ref)
Neuromuscular & skeletal: Arthralgia, muscle spasm
Hypersensitivity (eg, anaphylaxis, angioedema) to tizanidine or any component of the formulation; concomitant use with strong CYP1A2 inhibitors.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Canadian labeling: Additional contraindications (not in US labeling): Patients requiring spasticity to maintain function (eg, maintenance of upright posture, balance in locomotion).
Disease-related concerns:
• Hepatic impairment: Use with caution 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.
Special populations:
• Older adults: Use with caution; clearance decreased fourfold in older adults (≥65 years of age); may increase risk of adverse effects and/or duration of effects. Older adults with severe renal impairment (CrCl <25 mL/minute) may have clearance reduced by >50% compared to healthy older adults.
Other warnings/precautions:
• 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.
Ontralfy Oral Solution: FDA approved December 2024; anticipated availability currently unknown. Information pertaining to this product within the monograph is pending revision. Ontralfy is indicated for the treatment of spasticity in adults. Consult the prescribing information for additional information.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Zanaflex: 2 mg [DSC], 4 mg [DSC], 6 mg [DSC]
Generic: 2 mg, 4 mg, 6 mg
Tablet, Oral:
Zanaflex: 4 mg
Generic: 2 mg, 4 mg
Yes
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
Tablets (tiZANidine HCl Oral)
2 mg (per each): $1.22
4 mg (per each): $1.46 - $1.47
Tablets (Zanaflex Oral)
4 mg (per each): $4.30
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 2 mg, 4 mg
Oral: May be taken with or without food but consistent administration with regard to meals is recommended (due to impact on absorption). 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 intact capsule under fasted conditions.
Oral: May be administered with or without food but consistent administration with regard to meals is recommended (due to impact on absorption). 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.
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).
Management of spasticity; reserve treatment with tizanidine for daily activities and times when relief of spasticity is most important (FDA approved in adults).
TiZANidine may be confused with nizatidine, tiaGABine.
Zanaflex may be confused with Xiaflex.
Tizanidine is identified in the Screening Tool of Older Person's Prescriptions (STOPP) criteria as a potentially inappropriate medication in older adults (≥65 years of age) with dementia or delirium (O’Mahony 2023).
Zanaflex capsules and Zanaflex tablets (or generic tizanidine tablets) are not interchangeable in the fed state.
Substrate of CYP1A2 (Major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor
Aldesleukin: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Alfuzosin: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alpha2-Agonists: May increase hypotensive effects of TiZANidine. Risk X: Avoid
Amifostine: Blood Pressure Lowering Agents may increase hypotensive effects of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider Therapy Modification
Amiodarone: May increase serum concentration of TiZANidine. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amisulpride (Oral): May increase hypotensive effects of Hypotension-Associated Agents. Risk C: Monitor
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may increase hypotensive effects of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor
Arginine: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Barbiturates: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Benperidol: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Beta-Blockers: May increase rebound hypertensive effects of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Alpha2-Agonists may increase AV-blocking effects of Beta-Blockers. Sinus node dysfunction may also be enhanced. 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. Risk D: Consider Therapy Modification
Blonanserin: CNS Depressants may increase CNS depressant effects 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 increase hypotensive effects of Hypotension-Associated Agents. Risk C: Monitor
Bradycardia-Causing Agents: May increase bradycardic effects of Bradycardia-Causing Agents. Risk C: Monitor
Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Brimonidine (Topical): May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Broccoli: May decrease serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May decrease hypotensive effects of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may increase hypotensive effects of Bromperidol. Risk X: Avoid
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects 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
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Cannabis: May decrease serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor
Ceritinib: Bradycardia-Causing Agents may increase bradycardic effects 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. Risk D: Consider Therapy Modification
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects 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 increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Ciprofloxacin (Systemic): May increase serum concentration of TiZANidine. Risk X: Avoid
CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
CYP1A2 Inducers (Moderate): May decrease serum concentration of TiZANidine. Risk C: Monitor
CYP1A2 Inhibitors (Moderate): May increase serum concentration of TiZANidine. Management: Avoid the use of tizanidine with moderate CYP1A2 inhibitors when possible. If combined, monitor closely for increased tizanidine toxicities (eg, hypotension, bradycardia, drowsiness). Tizanidine dose reduction or discontinuation may be necessary. Risk D: Consider Therapy Modification
CYP1A2 Inhibitors (Strong): May increase serum concentration of TiZANidine. Risk X: Avoid
CYP1A2 Inhibitors (Weak): May increase serum concentration of TiZANidine. Management: Avoid the use of tizanidine with weak CYP1A2 inhibitors when possible. If combined, monitor closely for increased tizanidine toxicities (eg, hypotension, bradycardia, drowsiness). Tizanidine dose reduction or discontinuation may be necessary. Risk D: Consider Therapy Modification
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Diazoxide Choline: May increase serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk X: Avoid
Diazoxide: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dinutuximab Beta: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
DULoxetine: Blood Pressure Lowering Agents may increase hypotensive effects of DULoxetine. Risk C: Monitor
Elranatamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Epcoritamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Etrasimod: May increase bradycardic effects of Bradycardia-Causing Agents. Risk C: Monitor
Famotidine: May increase serum concentration of TiZANidine. Risk C: Monitor
Fexinidazole: Bradycardia-Causing Agents may increase arrhythmogenic effects of Fexinidazole. Risk X: Avoid
Filgotinib: May increase serum concentration of CYP1A2 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Fingolimod: Bradycardia-Causing Agents may increase bradycardic effects of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider Therapy Modification
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
Glofitamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Herbal Products with Blood Pressure Lowering Effects: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Hypotension-Associated Agents: Blood Pressure Lowering Agents may increase hypotensive effects of Hypotension-Associated Agents. Risk C: Monitor
Iloperidone: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Ivabradine: Bradycardia-Causing Agents may increase bradycardic effects of Ivabradine. Risk C: Monitor
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lacosamide: Bradycardia-Causing Agents may increase AV-blocking effects of Lacosamide. Risk C: Monitor
Landiolol: Bradycardia-Causing Agents may increase bradycardic effects of Landiolol. Risk X: Avoid
Lemborexant: May increase CNS depressant effects 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
Leniolisib: May increase serum concentration of CYP1A2 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Levodopa-Foslevodopa: Blood Pressure Lowering Agents may increase hypotensive effects of Levodopa-Foslevodopa. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lormetazepam: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May decrease antihypertensive effects of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may increase orthostatic hypotensive effects of Metergoline. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Midodrine: May increase bradycardic effects of Bradycardia-Causing Agents. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mirtazapine: May decrease antihypertensive effects 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 increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Mosunetuzumab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Naftopidil: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nicergoline: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Nicorandil: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Nitroprusside: Blood Pressure Lowering Agents may increase hypotensive effects of Nitroprusside. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
Obinutuzumab: May increase hypotensive effects 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
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects 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
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification
OxyCODONE: CNS Depressants may increase CNS depressant effects 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
Ozanimod: May increase bradycardic effects of Bradycardia-Causing Agents. Risk C: Monitor
Pacritinib: May increase serum concentration of CYP1A2 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Pentoxifylline: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pholcodine: Blood Pressure Lowering Agents may increase hypotensive effects of Pholcodine. Risk C: Monitor
Phosphodiesterase 5 Inhibitors: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ponesimod: Bradycardia-Causing Agents may increase bradycardic effects of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider Therapy Modification
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Primaquine: May increase serum concentration of CYP1A2 Substrates (High risk with Inhibitors). Risk C: Monitor
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Prostacyclin Analogues: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Quinagolide: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Ritlecitinib: May increase serum concentration of CYP1A2 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Serotonin/Norepinephrine Reuptake Inhibitor: May decrease therapeutic effects of Alpha2-Agonists. Risk C: Monitor
Silodosin: May increase hypotensive effects of Blood Pressure Lowering Agents. Risk C: Monitor
Siponimod: Bradycardia-Causing Agents may increase bradycardic effects of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider Therapy Modification
Suvorexant: CNS Depressants may increase CNS depressant effects 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
Talquetamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Tarlatamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Teclistamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Tobacco (Smoked): May decrease serum concentration of TiZANidine. Risk C: Monitor
Tricyclic Antidepressants: May decrease antihypertensive effects 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 increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects 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
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
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.
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.
Oral contraceptives may decrease the clearance of tizanidine; concomitant use of oral contraception is not recommended by the manufacturer. Consult drug interactions database for details related to management of patients taking tizanidine with CYP1A2 inhibitors (weak).
Information related to use of tizanidine in pregnancy is limited (Eleftheriou 2014).
LFTs at baseline and during use as clinically appropriate (including 1 month after maximum dose achieved); renal function; blood pressure; signs/symptoms of hypotension; mental alertness and hallucinations.
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.
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%)
Altered kidney function: 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.
Older adult: Younger subjects cleared drug 4 times faster than elderly subjects.