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TiZANidine

Pronunciation

Pronunciation

(tye ZAN i deen)

Index Terms

  • Sirdalud
  • Tizanidine HCl

Dosage Forms

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

Capsule, Oral:

Zanaflex: 2 mg, 4 mg, 6 mg

Generic: 2 mg, 4 mg, 6 mg

Tablet, Oral:

Zanaflex: 4 mg [scored]

Generic: 2 mg, 4 mg

Brand Names: U.S.

  • Zanaflex

Pharmacologic Category

  • Alpha2-Adrenergic Agonist

Pharmacology

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.

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 2-3 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

2.4 L/kg

Metabolism

Extensively hepatic via CYP1A2 to inactive metabolites

Excretion

Urine (60%); feces (20%)

Onset of Action

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

Time to Peak

Fasting state: Capsule, tablet: 1 hour

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

Duration of Action

Single dose (8 mg): 3-6 hours

Half-Life Elimination

~2.5 hours

Protein Binding

~30%

Special Populations: 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.

Special Populations: Hepatic Function Impairment

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

Special Populations: Elderly

Younger subjects cleared drug 4 times faster than elderly subjects.

Use: Labeled Indications

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

Use: Unlabeled

Acute low back pain

Contraindications

Concomitant therapy with ciprofloxacin or fluvoxamine (potent CYP1A2 inhibitors)

Dosing: Adult

Spasticity: Oral: Initial: 2 mg up to 3 times daily (at 6- to 8-hour intervals) as needed; may titrate to optimal effect in 2-4 mg increments per dose (with a minimum of 1-4 days between dose increases); maximum: 36 mg daily. Note: Single doses >16 mg have not been studied.

Discontinuation of therapy: Gradually taper dose by 2-4 mg daily.

Dosing: Geriatric

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

Dosing: Renal Impairment

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

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.

Administration

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.

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

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

Drug Interactions

ACE Inhibitors: TiZANidine may enhance the hypotensive effect of ACE Inhibitors. Monitor therapy

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

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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. Consider therapy modification

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

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

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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. Consider therapy modification

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

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

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

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

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

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

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 patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. 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. Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. 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 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Avoid combination

CYP1A2 Inhibitors (Strong): May increase the serum concentration of TiZANidine. Management: Tizanidine use with ciprofloxacin or fluvoxamine is contraindicated. If use with another strong inhibitor cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on response. Monitor closely. Avoid combination

CYP1A2 Inhibitors (Weak): May increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

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

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. 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. Monitor therapy

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

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

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

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

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

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

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

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

Iobenguane I 123: Alpha2-Agonists may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

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

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

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

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

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

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

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

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

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

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

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. 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. Consider therapy modification

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

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

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

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. Consider therapy modification

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

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

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

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

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

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

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

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

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. 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. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

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

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

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

Tricyclic Antidepressants: May diminish the antihypertensive effect of Alpha2-Agonists. Consider therapy modification

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

Adverse Reactions

Frequency percentages below reported during multiple-dose studies, unless specified otherwise.

>10%:

Cardiovascular: Hypotension (16% to 33%)

Central nervous system: Somnolence (48%), dizziness (16%)

Gastrointestinal: Xerostomia (49%)

Neuromuscular & skeletal: Weakness (41%)

1% to 10%:

Cardiovascular: Bradycardia (12% to 10%)

Central nervous system: Nervousness (3%), speech disorder (3%), visual hallucinations/delusions (3%), anxiety (1%), depression (1%), fever (1%)

Dermatologic: Rash (1%), skin ulcer (1%)

Gastrointestinal: Constipation (4%), vomiting (3%), abdominal pain (1%), diarrhea (1%), dyspepsia (1%)

Genitourinary: UTI (10%), urinary frequency (3%)

Hepatic: Liver enzymes increased (3% to 5%)

Neuromuscular & skeletal: Dyskinesia (3%), back pain (1%), myasthenia (1%), paresthesia (1%)

Ocular: Blurred vision (3%)

Respiratory: Pharyngitis (3%), rhinitis (3%)

Miscellaneous: Infection (6%), flu-like syndrome (3%), diaphoresis (1%)

<1%, frequency not defined, and postmarketing experience (limited to important or life-threatening): Abnormal dreams, abnormal thinking, abscess, adrenal insufficiency, allergic reaction, anemia, angina pectoris, arrhythmia, carcinoma (including skin), cholelithiasis, deafness, dementia, depersonalization, dyslipidemia, gastrointestinal hemorrhage, glaucoma, heart failure, hepatomegaly, hemiplegia, hepatic failure, hepatitis, hepatoma, herpes infections, hypercholesterolemia, hyperglycemia, hypokalemia, hyponatremia, hypoproteinemia, hypothyroidism, intestinal obstruction, jaundice, leukopenia, leukocytosis, MI, migraine, neuralgia, optic neuritis, orthostatic hypotension, palpitation, paralysis, psychotic-like symptoms, pulmonary embolus, purpura, respiratory acidosis, retinal hemorrhage, seizure, sepsis, suicide attempt, syncope, thrombocythemia, thrombocytopenia, ventricular extrasystoles, ventricular tachycardia, vertigo

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 (20-28 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.

Monitoring Parameters

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

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry mouth, fatigue, or loss of strength and energy. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), severe dizziness, passing out, confusion, hallucinations, mood changes, behavioral changes, bradycardia, abnormal movements, or back pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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