Note: Patients more sensitive to sedating and other CNS adverse effects (eg, older adults, patients with organ impairment) may better tolerate a reduced dose, less frequent administration, and/or more gradual titration (Chou 2022). 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 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) (Chou 2022; Knight 2022; 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 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 (Gelber 2001; Nair 2014; manufacturer's labeling). In the treatment of spasticity associated with stroke (eg, hemiplegic shoulder pain), some experts initiate therapy with 2 mg every 8 hours as needed (Creutzfeld 2022). In the treatment of spasticity associated with ALS, some experts limit dose to 24 mg/day (Galvez-Jimenez 2022).
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 (Suárez-Lledó 2018; manufacturer's labeling).
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 (expert opinion).
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 (expert opinion).
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 (Wagstaff 1997; expert opinion; manufacturer's labeling).
Hemodialysis, intermittent (thrice weekly): Unlikely to be significantly dialyzable (large Vd) (expert opinion).
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 (Kitabata 2005; expert opinion; manufacturer's labeling).
Peritoneal dialysis: Unlikely to be significantly dialyzable (large Vd) (expert opinion).
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 (expert opinion; manufacturer's labeling).
CRRT: Unlikely to be significantly dialyzable (large Vd) (expert opinion).
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 (expert opinion; manufacturer's labeling).
PIRRT (eg, sustained, low-efficiency diafiltration): Unlikely to be significantly dialyzable (large Vd) (expert opinion).
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 (expert opinion; manufacturer's labeling).
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.
(For additional information see "Tizanidine: Pediatric drug information")
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.
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; 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; clearance is decreased. Refer to adult dosing.
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
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 2 mg, 4 mg
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.
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.
Spasticity: Management of spasticity; reserve treatment with tizanidine for daily activities and times when relief of spasticity is most important.
Muscle spasm and/or musculoskeletal pain (adjunctive therapy)
TiZANidine may be confused with nizatidine, tiaGABine.
Zanaflex may be confused with Xiaflex.
Zanaflex capsules and Zanaflex tablets (or generic tizanidine tablets) are not interchangeable in the fed state.
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 idiosyncratic hypersensitivity (Ref).
Onset: Varied; ranges from 2 to 14 weeks after initiation (Ref). Upon rechallenge, increases in ALT have been noted 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: Dizziness (16%) (table 1) , drowsiness (48%) (table 2)
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 |
Neuromuscular & skeletal: Asthenia (41%) (table 3)
Drug (Tizanidine) |
Placebo |
Dosage Form |
Number of Patients (Tizanidine) |
Number of Patients (Placebo) |
---|---|---|---|---|
41% |
16% |
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%) (Khan 2012)
Neuromuscular & skeletal: Dyskinesia (3%)
Ophthalmic: Amblyopia (≤3%), blurred vision (≤3%)
Respiratory: Flu-like symptoms (3%), pharyngitis (3%), rhinitis (3%)
Frequency not defined:
Hypersensitivity: Angioedema
Nervous system: Fatigue
Neuromuscular & skeletal: Muscle spasm
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
Nervous system: Depression, paresthesia, sedated state (Ref), seizure, withdrawal syndrome (Ref)
Neuromuscular & skeletal: Arthralgia, tremor
Concomitant therapy with potent CYP1A2 inhibitors (eg, ciprofloxacin, fluvoxamine).
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.
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.
Substrate of CYP1A2 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
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 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 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): May enhance the CNS depressant effect of CNS Depressants. 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. 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
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). 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. 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. 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
Daridorexant: May enhance the CNS depressant effect 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: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. 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
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. 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: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination
Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect 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
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect 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
Herbal Products with Blood Pressure Lowering Effects: 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 CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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. 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 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
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
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
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect 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 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
Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
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. Risk C: Monitor therapy
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
Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect 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 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
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect 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 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
Serotonin/Norepinephrine Reuptake Inhibitors: May diminish the therapeutic 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. If combined, consider obtaining a cardiology consult regarding patient monitoring. 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
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
Valerian: 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
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.
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).
It is not known if tizanidine is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
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.
Monitor LFTs at baseline and during use (including 1 month after maximum dose achieved) or if hepatic injury suspected; BP (including prior to dose increase); renal function; mental alertness.
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%)
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.
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): $3.98
4 mg (per each): $5.04
6 mg (per each): $7.56
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): $3.76
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