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  • CLASSES

    Muscle Relaxants, Centrally Acting, Plain

    DEA CLASS

    Rx

    DESCRIPTION

    Oral muscle relaxant; structure related to clonidine; pharmacology mediated by alpha2-receptors and may cause significant orthostasis with initial dosing; efficacy similar to baclofen in treating spasticity.

    COMMON BRAND NAMES

    Zanaflex

    HOW SUPPLIED

    Tizanidine/Tizanidine Hydrochloride/Zanaflex Oral Cap: 2mg, 4mg, 6mg
    Tizanidine/Tizanidine Hydrochloride/Zanaflex Oral Tab: 2mg, 4mg

    DOSAGE & INDICATIONS

    For the acute and intermittent management of increased muscle tone associated with spasticity (including spasticity related to multiple sclerosis or spinal cord injury).
    NOTE: Because of its short duration, tizanidine should be reserved for activities and times when spasticity control is most important. Use tizanidine with caution when spasticity is beneficial to obtain increased function or to sustain posture and balance during movement.
    Oral dosage
    Adults

    2 mg PO is the recommended starting dose. The dose can be repeated at 6—8 hour intervals, as needed, to a maximum of three doses in 24 hours. Gradually increase the dose by 2—4 mg at each dose, with 1—4 days in between dose increases until satisfactory reduction in muscle tone is achieved. In geriatric patients, individual doses should be reduced during titration. If a geriatric patient requires higher doses, increase individual doses, rather than dosing frequency. Maximum daily dosage is 36 mg/day PO. Single doses greater than 16 mg have not been studied. Due to the potential for hepatotoxicity, monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected. If therapy needs to be discontinued, decrease the dose slowly (2 to 4 mg/day), particularly in patients who have been receiving high doses for long periods (e.g., 20 to 36 mg/day for >= 9 weeks), to minimize the risk of withdrawal and rebound hypertension, tachycardia and hypertonia.

    MAXIMUM DOSAGE

    Adults

    36 mg/day PO.

    Elderly

    36 mg/day PO. Maximum doses of tizanidine should be used cautiously in elderly patients; drug clearance may be substantially decreased.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Because of potential hepatotoxicity, tizanidine should be used with caution in patients with any hepatic impairment. Individual doses should be reduced during dose titration. If higher doses are required, increase individual doses rather than dosing frequency.

    Renal Impairment

    CrCl < 25 ml/min: Individual doses should be reduced during dose titration. If higher doses are required, increase individual doses rather than dosing frequency. Monitor closely for side effects; tizanidine clearance is reduced > 50% in renally impaired patients.
     
    Intermittent hemodialysis
    It is not known whether tizanidine is removed by hemodialysis; it appears that no supplemental dosage is needed following hemodialysis.

    ADMINISTRATION

    Oral Administration

    Tizanidine should be administered consistently with or without food. Once the formulation has been selected and the decision has been made whether to take with or without food, this regimen should not be altered. Instruct patients that changing whether tizanidine is taken with or without food may result in increased adverse events or delayed or more rapid onset of action.

    STORAGE

    Zanaflex:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Tizanidine is contraindicated in patients with known hypersensitivity to tizanidine or its ingredients.
     
    Tizanidine should be used with caution where spasticity is utilized to obtain increased function or to sustain posture and balance during movement.

    Hypotension

    Tizanidine is a central-acting alpha2-adrenergic agonist which is structurally and pharmacologically related to clonidine. Although tizanidine has a lower propensity to lower blood pressure than clonidine (2—10% of the antihypertensive potency in animal models), it can result in significant hypotension in some patients, especially with higher doses. Caution is advised when tizanidine is to be used in patients at risk for developing hypotension including patients who are receiving concurrent antihypertensive therapy (see Drug Interactions).

    Renal failure, renal impairment

    Tizanidine should be used with caution in patients with renal impairment (CrCl < 25 ml/min) or renal failure, as clearance is reduced by more than 50%. In these patients, during titration, the individual doses should be reduced. If higher doses are required, individual doses should be increased rather than dosing frequency. These patients should be monitored closely for the onset or increase in severity of the common adverse events (dry mouth, somnolence, asthenia and dizziness) as potential indicators of excessive overdose.

    Hepatic disease

    Due to the potential for hepatotoxicity, monitoring of aminotransferase levels is recommended recommended at baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected. Tizanidine should be used with caution in patients with hepatic impairment or hepatic disease. Tizanidine has not been studied in patients with hepatic disease.

    Driving or operating machinery

    Tizanidine can cause drowsiness and sedation. Patients receiving tizanidine should be advised to avoid driving or operating machinery until the effects of the drug are known.

    Psychosis

    Tizanidine use has been associated with hallucinations; tizanidine should be used with caution in patients with psychosis.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Use tizanidine with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation.

    Abrupt discontinuation

    Abrupt discontinuation of tizanidine may result in withdrawal adverse reactions including rebound hypertension, tachycardia, and hypertonia. To minimize the risk of withdrawal, particularly in patients who have been receiving high doses for long periods of time (e.g., 20 to 28 mg/day for 9 weeks or longer) or who may be on concomitant treatment with narcotics, decrease the dose slowly (2 to 4 mg/day).

    Labor, obstetric delivery, pregnancy

    There are no adequate or well-controlled studies of tizanidine in human pregnancy to inform regarding drug-associated fetal risks. Tizanidine should be given to pregnant women only if clearly needed. Reproduction studies performed in rats at a dose of 3 mg (base)/kg, equal to the maximum recommended human dose (MHRD) on a mg/m2 basis, and in rabbits at 30 mg (base)/kg, 16 times the MRHD on a mg/m2 basis, did not show evidence of teratogenicity. Tizanidine at doses that are equal to and up to 8 times the MRHD on a mg/m2 basis increased gestation duration in rats. Prenatal and postnatal pup loss was increased and developmental retardation occurred. Post-implantation loss was increased in rabbits at doses of 1 mg (base)/kg or greater, equal to or greater than 0.5 times the MRHD on a mg/m2 basis. The effect of tizanidine on labor and obstetric delivery in humans is unknown.

    Breast-feeding

    It is not known whether tizanidine is excreted into human breast milk, although as a lipid soluble drug, it might be expected to pass into breast milk. The effect of this exposure is not known and because of the possibility for serious adverse events in a nursing infant (e.g., sedation, hypotension, hepatic injury, and hallucinations/psychotic-like symptoms) the use of tizanidine during breast-feeding is not recommended. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children

    The safety and efficacy of tizanidine are not established in children or adolescents less than 18 years of age.

    Geriatric

    Tizanidine should be used with caution in geriatric patients because the older adult is more at risk for reduced clearance and increased risk for side effects than younger adult patients. The drug is substantially excreted by the kidney. Younger adult patients exhibit renal drug clearance rates that are 4-times faster than those of the older adult. In elderly patients with renal impairment (creatinine clearance less than 25 mL/minute), tizanidine clearance is reduced by more than 50% compared to healthy geriatric subjects. A prolonged time of effect is expected. During titration, the individual doses for the older adult should be reduced. If higher doses are required, individual doses should be increased rather than increasing the frequency of dosing. Geriatric patients should be monitored closely for the onset or increase in severity of the common adverse events (e.g., dry mouth, somnolence, asthenia and dizziness) as potential indicators of excessive dosage. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of medications in residents of long-term care facilities. According to the OBRA guidelines, most muscle relaxants are poorly tolerated by older adults due to anticholinergic side effects, sedation, and/or weakness. However, periodic use (e.g., once every three months) for no more than 7 days may be appropriate when other interventions or alternative medications are not effective or indicated. Chronic use in individuals with complications due to multiple sclerosis, spinal cord injuries, cerebral palsy, and other select conditions may be indicated, although close monitoring is warranted. Abrupt discontinuation of some muscle relaxants may cause or predispose individuals to seizures or hallucinations.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 2.0-10.0
    Stevens-Johnson syndrome / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    hypotension / Rapid / 16.0-67.0
    cystitis / Delayed / 0.1-10.0
    elevated hepatic enzymes / Delayed / 6.0-6.0
    constipation / Delayed / 4.0-4.0
    dyskinesia / Delayed / 3.0-3.0
    excitability / Early / 3.0-3.0
    hallucinations / Early / 3.0-3.0
    blurred vision / Early / 3.0-3.0
    hepatitis / Delayed / 0-1.0
    hypercholesterolemia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    hyperlipidemia / Delayed / 0-1.0
    anemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    QT prolongation / Rapid / Incidence not known
    depression / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    drowsiness / Early / 48.0-92.0
    xerostomia / Early / 49.0-88.0
    weakness / Early / 41.0-78.0
    asthenia / Delayed / 41.0-78.0
    fatigue / Early / 41.0-78.0
    dizziness / Early / 16.0-45.0
    infection / Delayed / 6.0-6.0
    influenza / Delayed / 3.0-3.0
    vomiting / Early / 3.0-3.0
    pharyngitis / Delayed / 3.0-3.0
    rhinitis / Early / 3.0-3.0
    increased urinary frequency / Early / 3.0-3.0
    leukocytosis / Delayed / 0-1.0
    syncope / Early / Incidence not known
    tremor / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    arthralgia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Acetaminophen: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Butalbital: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Codeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Dextromethorphan: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Concurrent use of tizanidine and CNS depressants like dichloralphenazone can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Diphenhydramine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Guaifenesin; Phenylephrine: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Oxycodone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone or oxycodone; naloxone is initiated in a patient taking a skeletal muscle relaxant, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage and titrate to clinical response; reduced initial doses of oxycodone; naltrexone, aspirin, ASA; oxycodone, and ibuprofen; oxycodone are also recommended. If a decision is made to start treatment with acetaminophen; oxycodone extended-release tabIets, start with 1 tablet PO every 12 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Pentazocine: (Moderate) Concurrent use of tizanidine and CNS depressants like pentazocine can cause additive CNS depression. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Propoxyphene: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Pseudoephedrine: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acetaminophen; Tramadol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Acrivastine; Pseudoephedrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Acyclovir: (Minor) Caution is advised when administering tizanidine with acyclovir. Tizanidine is primarily metabolized by CYP1A2; acyclovir is a weak inhibitor of CYP1A2. Taking these drugs together may increase the serum concentration of tizanidine, which could result in hypotension, bradycardia, or excessive drowsiness.
    Albuterol: (Minor) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Albuterol; Ipratropium: (Minor) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Alfentanil: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Alfuzosin: (Major) Alfuzosin should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. The manufacturer warns that the QT effect of alfuzosin should be considered prior to administering the drug to patients taking other medications known to prolong the QT interval.
    Aliskiren: (Moderate) Aliskiren can enhance the effects of tizanidine on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Aliskiren; Amlodipine: (Moderate) Aliskiren can enhance the effects of tizanidine on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Aliskiren can enhance the effects of tizanidine on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Aliskiren can enhance the effects of tizanidine on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Aliskiren; Valsartan: (Moderate) Aliskiren can enhance the effects of tizanidine on blood pressure if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly. Blood pressure and electrolytes should be routinely monitored in patients receiving aliskiren.
    Alprazolam: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Ambrisentan: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
    Amiloride: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Amiodarone: (Major) Tizanidine administration may result in QT prolongation and should be coadministered cautiously and with close monitoring with drugs that carry a possible risk for QT prolongation and torsade de pointes, such as amiodarone. Also, tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with CYP1A2 inhibitors, such as amiodarone, as concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs.
    Amitriptyline: (Minor) Tizanidine should be used cautiously and with close monitoring with tricyclic antidepressants. Tizanidine administration may result in QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Amitriptyline; Chlordiazepoxide: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. (Minor) Tizanidine should be used cautiously and with close monitoring with tricyclic antidepressants. Tizanidine administration may result in QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Amobarbital: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Tizanidine should be used cautiously and with close monitoring with clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Tizanidine administration may result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Tizanidine should be used cautiously and with close monitoring with clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Tizanidine administration may result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Anagrelide: (Major) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including tizanidine, could lead to increases in the serum concentrations of these drugs and, thus, adverse effects. Patients receiving anagrelide and tizanidine concomitantly should be monitored for increased toxicity of tizanidine. In addition, tizanidine and anagrelide are both associated with QT prolongation; coadministration may increase the risk of QT prolongation and TdP.
    Angiotensin II receptor antagonists: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Angiotensin-converting enzyme inhibitors: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Anxiolytics; Sedatives; and Hypnotics: (Moderate) Concurrent use of tizanidine and CNS depressants such as certain sedatives or hypnotics can cause additive CNS depression. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Apomorphine: (Major) Apomorphine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. In one study, a single mean dose of 5.2 mg (range 2-10 mg) prolonged the QT interval by about 3 msec. However, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    Arformoterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Aripiprazole: (Moderate) Tizanidine may cause QT prolongation. QT prolongation has also occurred during therapeutic use of aripiprazole and following overdose. Coadministration increases the risk for QT prolongation and torsade de pointes. In addition, concurrent use can cause additive CNS depression.
    Arsenic Trioxide: (Major) Avoid coadministration of tizanidine and arsenic trioxide. Tizanidine administration may result in QT prolongation. If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. QT prolongation should be expected with the administration of arsenic trioxide. Tizanidine administration may result in QT prolongation. Torsade de pointes (TdP) and complete atrioventricular block have been reported.
    Artemether; Lumefantrine: (Major) Coadministration of tizanidine and artemether; lumefantrine should be avoided. Consider ECG monitoring if tizanidine must be used with or after artemether; lumefantrine treatment. Tizanidine administration may result in QT prolongation. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration may result in additive effects.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect such as tizanidine.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone or oxycodone; naloxone is initiated in a patient taking a skeletal muscle relaxant, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage and titrate to clinical response; reduced initial doses of oxycodone; naltrexone, aspirin, ASA; oxycodone, and ibuprofen; oxycodone are also recommended. If a decision is made to start treatment with acetaminophen; oxycodone extended-release tabIets, start with 1 tablet PO every 12 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Atenolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Atenolol; Chlorthalidone: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including skeletal muscle relaxants.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including skeletal muscle relaxants.
    Azithromycin: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), azithromycin and tizanidine should be used together cautiously. Tizanidine administration may result in QT prolongation. There have been case reports of QT prolongation and TdP with the use of azithromycin in postmarketing reports. Concurrent use may increase the risk of QT prolongation.
    Bacitracin: (Minor) Tizanidine, which has skeletal muscle relaxant properties, should be used cautiously in patients receiving systemic bacitracin. If bacitracin is administered parenterally during surgery, there may be increased skeletal muscle relaxation, and postoperative use may reinstate neuromuscular blockade.
    Baclofen: (Moderate) Concurrent use of tizanidine and CNS depressants, such as baclofen, can cause additive CNS depression.
    Barbiturates: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Bedaquiline: (Major) Tizanidine should be used cautiously and with close monitoring with bedaquiline. Coadministration of bedaquiline with other QT prolonging drugs like tizanidine may result in additive or synergistic prolongation of the QT interval. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Belladonna; Opium: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bendroflumethiazide; Nadolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Benzodiazepines: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Beta-adrenergic blockers: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Betaxolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Tizanidine should be used cautiously and with close monitoring with metronidazole. Tizanidine administration may result in QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Tizanidine should be used cautiously and with close monitoring with metronidazole. Tizanidine administration may result in QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Bisoprolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Brimonidine; Timolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Brompheniramine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding skeletal muscle relaxants.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Brompheniramine; Pseudoephedrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Budesonide; Formoterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Buprenorphine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of tizanidine and buprenorphine is necessary. Buprenorphine and tizanidine have been associated with QT prolongation and have a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of tizanidine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of tizanidine and buprenorphine is necessary. Buprenorphine and tizanidine have been associated with QT prolongation and have a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of tizanidine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buspirone: (Moderate) Concurrent use of tizanidine and CNS depressants like buspirone can cause additive CNS depression.
    Butabarbital: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as tizanidine, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
    Carbetapentane; Chlorpheniramine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding skeletal muscle relaxants.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding skeletal muscle relaxants.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding skeletal muscle relaxants.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding skeletal muscle relaxants.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding skeletal muscle relaxants.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding skeletal muscle relaxants.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding skeletal muscle relaxants.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding skeletal muscle relaxants.
    Carbetapentane; Pyrilamine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding skeletal muscle relaxants.
    Carbidopa; Levodopa; Entacapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as tizanidine, due to the possibility of additive sedation.
    Carbinoxamine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Carbinoxamine; Phenylephrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Carbinoxamine; Pseudoephedrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Carteolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Carvedilol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Central-acting adrenergic agents: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Ceritinib: (Major) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and tizanidine; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Tizanidine is also associated with QT prolongation.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorcyclizine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlordiazepoxide: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Chlordiazepoxide; Clidinium: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Chloroquine: (Major) Tizanidine should be used cautiously and with close monitoring with chloroquine. Tizanidine administration may result in QT prolongation. Chloroquine administration is associated with an increased risk of QT prolongation and torsades de pointes (TdP). The need to coadminister chloroquine with drugs known to prolong the QT interval should be done with a careful assessment of risks versus benefits and should be avoided when possible.
    Chlorpheniramine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpheniramine; Codeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpheniramine; Dextromethorphan: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpheniramine; Phenylephrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Chlorpromazine: (Major) Tizanidine should be used cautiously and with close monitoring with chlorpromazine. Tizanidine administration may result in QT prolongation. Agents that prolong the QT interval could lead to torsade de pointes when combined with a phenothiazine, and therefore are generally not recommended for combined use. Phenothiazines have been associated with a risk of QT prolongation and/or torsade de pointes (TdP). This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine.
    Cimetidine: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors, such as cimetidine, as concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ciprofloxacin: (Severe) The concurrent use of tizanidine and ciprofloxacin is contraindicated due to the risk of tizanidine toxicity, including hypotension, bradycardia, and sedation. Tizanidine is a CYP1A2 substrate, and ciprofloxacin is a strong inhibitor of CYP1A2. In a trial of healthy volunteers, coadministration of ciprofloxacin increased the AUC of tizanidine by 10-fold. Subjects also experienced a significant decrease in blood pressure, increased drowsiness, and increased psychomotor impairment. In addition, both tizanidine and ciprofloxacin are associated with QT prolongation; coadministration would increase the risk of QT prolongation and torsade de pointes (TdP).
    Cisapride: (Severe) Because of the potential for torsade de pointes (TdP), use of cisapride with tizanidine is contraindicated. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Tizanidine administration may result in QT prolongation.
    Citalopram: (Major) Avoid coadministration of citalopram and tizanidine. Both drugs are associated with QT prolongation. If concurrent therapy is considered essential, ECG monitoring is recommended.
    Clarithromycin: (Major) Tizanidine should be used cautiously and with close monitoring with clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Tizanidine administration may result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Clemastine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Clomipramine: (Minor) Tizanidine should be used cautiously and with close monitoring with tricyclic antidepressants. Tizanidine administration may result in QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Clonazepam: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Clorazepate: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Clozapine: (Major) Tizanidine should be used cautiously and with close monitoring with clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tizanidine administration may result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Codeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Codeine; Guaifenesin: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Tizanidine should be used cautiously and with close monitoring with promethazine. Tizanidine administration may result in QT prolongation. Promethazine carries a possible risk of QT prolongation.
    Codeine; Promethazine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Tizanidine should be used cautiously and with close monitoring with promethazine. Tizanidine administration may result in QT prolongation. Promethazine carries a possible risk of QT prolongation.
    COMT inhibitors: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as tizanidine, due to the possibility of additive sedation.
    Crizotinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tizanidine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tizanidine administration may also result in QT prolongation.
    Cyclizine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Cyclobenzaprine: (Moderate) Tizanidine be used cautiously with cyclobenzaprine. Tizanidine administration may result in QT prolongation. Cyclobenzaprine is structurally similar to tricyclic antidepressants. Tricyclic antidepressants have been reported to prolong the QT interval, especially when given in excessive doses (or in overdosage settings). Cyclobenzaprine is associated with a possible risk of QT prolongation and torsades de pointes (TdP), particularly in the event of acute overdose.
    Cyproheptadine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. The use of ritonavir could result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Dasatinib: (Major) Tizanidine should be used cautiously with dasatinib. Tizanidine administration may result in QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Cautious dasatinib administration is recommended to patients who have or may develop QT prolongation such as patients taking drugs that lead to QT prolongation.
    Daunorubicin: (Moderate) Daunorubicin should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Acute cardiotoxicity can occur during the administration of daunorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Degarelix: (Major) Both tizanidine and degarelix can cause QT prolongation. Tizanidine should be used cautiously and with close monitoring with degarelix. Prescribers need to weigh the potential benefits and risks of degarelix use in patients with prolonged QT syndrome or in patients taking other drugs that may prolong the QT interval.
    Desipramine: (Minor) Tizanidine should be used cautiously and with close monitoring with tricyclic antidepressants. Tizanidine administration may result in QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Deutetrabenazine: (Moderate) For patients taking a deutetrabenazine dosage more than 24 mg/day with tizanidine, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Tizanidine administration may result in QT prolongation. Additionally, concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as tizanidine, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dexchlorpheniramine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Dexmedetomidine: (Moderate) Due to the anesthetic effects of dexmedetomidine, concurrent use with other CNS depressants, such as skeletal muscle relaxants, could result in additive sedative effects and possibly prolong recovery from anesthesia.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Dextromethorphan; Promethazine: (Moderate) Tizanidine should be used cautiously and with close monitoring with promethazine. Tizanidine administration may result in QT prolongation. Promethazine carries a possible risk of QT prolongation.
    Dextromethorphan; Quinidine: (Major) Quinidine and dextromethorphan; quinidine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Diazepam: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Dienogest; Estradiol valerate: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Dimenhydrinate: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Diphenhydramine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Diphenhydramine; Ibuprofen: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Diphenhydramine; Naproxen: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Diphenhydramine; Phenylephrine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Disopyramide: (Major) Tizanidine should be used cautiously and with close monitoring with disopyramide. Tizanidine administration may result in QT prolongation. Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Dofetilide: (Severe) Because of the potential for torsades de pointes (TdP), coadministration of tizanidine and dofetilide is contraindicated. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Tizanidine administration may result in QT prolongation.
    Dolasetron: (Major) Tizanidine should be used cautiously and with close monitoring with dolasetron. Tizanidine administration may result in QT prolongation. Dolasetron has been associated with a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Use of dolasetron injection for the prevention of chemotherapy-induced nausea and vomiting is contraindicated because the risk of QT prolongation is higher with the doses required for this indication; when the injection is used at lower doses (i.e., those approved for post-operative nausea and vomiting) or when the oral formulation is used, the risk of QT prolongation is lower and caution is advised.
    Dorzolamide; Timolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Doxazosin: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Doxepin: (Minor) Tizanidine should be used cautiously and with close monitoring with tricyclic antidepressants. Tizanidine administration may result in QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Doxorubicin: (Moderate) Doxorubicin should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Doxylamine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Doxylamine; Pyridoxine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Dronabinol, THC: (Moderate) Concomitant use of dronabinol with other CNS depressants, like tizanidine, can potentiate the effects of dronabinol on respiratory depression.
    Dronedarone: (Severe) Because of the potential for torsades de pointes (TdP), coadministration of tizanidine and dronedarone is contraindicated. Tizanidine administration may result in QT prolongation. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Tizanidine administration may result in QT prolongation. According to the revised 2001 labeling for droperidol, any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. If tizanidine and droperidol are coadministered, use extreme caution. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data.
    Drospirenone; Estradiol: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Drospirenone; Ethinyl Estradiol: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Efavirenz: (Major) Although data are limited, coadministration of efavirenz and tizanidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Although data are limited, coadministration of efavirenz and tizanidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs.
    Eliglustat: (Major) Tizanidine should be used cautiously and with close monitoring with eliglustat. Tizanidine administration may result in QT prolongation. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Tizanidine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Tizanidine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Entacapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as tizanidine, due to the possibility of additive sedation.
    Epirubicin: (Moderate) Epirubicin should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Acute cardiotoxicity can occur during the administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Eplerenone: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Epoprostenol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Eribulin: (Major) If eribulin and tizanidine must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both eribulin and tizanidine have been associated with QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Erythromycin: (Major) Tizanidine should be used cautiously and with close monitoring with erythromycin. Tizanidine administration may result in QT prolongation. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Erythromycin; Sulfisoxazole: (Major) Tizanidine should be used cautiously and with close monitoring with erythromycin. Tizanidine administration may result in QT prolongation. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Escitalopram: (Moderate) Tizanidine should be used cautiously and with close monitoring with escitalopram. Both tizanidine and escitalopram have been associated with QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Esmolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Estazolam: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Estradiol; Levonorgestrel: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Estradiol; Norethindrone: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Estradiol; Norgestimate: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethanol: (Major) Concurrent use of tizanidine and CNS depressants can cause additive CNS depression. It is best to limit the use of alcohol during treatment, due to additive drowsiness and dizziness. Additionally, ethanol increases the AUC and Cmax of tizanidine by about 20% and 15%, respectively, resulting in an increase in side effects associated with tizanidine.
    Ethinyl Estradiol: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Desogestrel: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Etonogestrel: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Levonorgestrel: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Norelgestromin: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Norethindrone: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Norgestimate: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ethinyl Estradiol; Norgestrel: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ezogabine: (Major) Tizanidine should be used cautiously and with close monitoring with ezogabine. Both ezogabine and tizanidine have been associated with QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Famotidine: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors. Famotidine is a weak CYP1A2 inhibitor. Concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Famotidine; Ibuprofen: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors. Famotidine is a weak CYP1A2 inhibitor. Concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Fentanyl: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Fingolimod: (Major) Tizanidine should be used cautiously and with close monitoring with fingolimod. Tizanidine administration may result in QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Tizanidine should be used cautiously and with close monitoring with flecainide. Tizanidine administration may result in QT prolongation. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Major) Fluconazole should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Fluoxetine: (Major) Fluoxetine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Fluoxetine; Olanzapine: (Major) Fluoxetine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration increases the risk for QT prolongation and torsade de pointes. (Moderate) Tizanidine should be used cautiously and with close monitoring with olanzapine. Tizanidine administration may result in QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP).
    Fluphenazine: (Major) Tizanidine is primarily metabolized by CYP1A2. The presystemic availability of tizanidine has been shown to be substantially increased by coadministration with CYP1A2 inhibitors. Average increases in tizanidine AUC of 10-fold and 33-fold have been reported following administration of strong CYP1A2 inhibitors. These increases in tizanidiine concentrations have been associated with significant hypotensive and sedative effects. The use of potent CYP1A2 inhibitors with tizanidine is contraindicated. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors, as concurrent use could lead to substantial increases in tizanidine blood concentrations. In addition, tizanidine administration may result in QT prolongation. Caution and close monitoring is recommended when administering tizanidine with drugs that carry a possible risk for QT prolongation or TdP and are also CYP1A2 inhibitors, such as fluphenazine. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Flurazepam: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Fluticasone; Salmeterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Fluticasone; Vilanterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Fluvoxamine: (Severe) The combination of tizanidine and fluvoxamine is contraindicated. An in vivo pharmacokinetic study revealed that fluvoxamine may drastically increase the serum concentrations of tizanidine, leading to a severe and prolonged decrease in blood pressure as well as additive CNS effects. The mean maximal effect on blood pressure was a 35 mmHg decrease in systolic blood pressure, a 20 mmHg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate. Drowsiness was significantly increased and performance on a psychomotor task was significantly impaired. Systolic blood pressures dropped to 80 mmHg or less and somnolence and dizziness were prevalent for 3 to 6 hours after tizanidine intake. The mechanism appears to be due to inhibition of tizanidine hepatic metabolism (via CYP1A2) by fluvoxamine. Serum concentrations (AUC) of tizanidine (given as a single 4 mg dose) were increased a mean of 33-fold (range 14 to 103 fold) after 4 days of fluvoxamine 100 mg/day PO or placebo. Tizanidine Cmax was increased approximately 12-fold (range 5 to 32), elimination half-life was increased almost 3-fold. Serum increases of tizanidine occurred in all 10 subjects receiving active drug. In addition, both drugs have been associated with QT prolongation and there is an increased risk of QT prolongation and torsade de pointes (TdP) during coadministration.
    Formoterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Formoterol; Mometasone: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as tizanidine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Tizanidine administration may also result in QT prolongation. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Minor) One case of increased phenytoin serum concentrations and associated drowsiness has been reported with the addition of tizanidine therapy. The mechanism and significance of this potential interaction with phenytoin or fosphenytoin is unknown.
    Gemifloxacin: (Major) Gemifloxacin should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5-10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and tizanidine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Tizanidine administration may also result in QT prolongation.
    Glycopyrrolate; Formoterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Granisetron: (Major) Granisetron should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, may result in clinical consequences.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with tizanidine. Both halogenated anesthetics and tizanidine administration may result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Haloperidol: (Major) Haloperidol should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. According to the manufacturer of haloperidol, caution is advisable when prescribing the drug concurrently with medications known to prolong the QT interval.
    Homatropine; Hydrocodone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Hydrocodone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Hydromorphone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydromorphone is initiated in a patient taking a skeletal muscle relaxant, use an initial dose of hydromorphone at 1/3 to 1/2 the usual dosage and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and tizanidine. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Tizanidine administration may result in QT prolongation.
    Hydroxyprogesterone: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP1A2 isoenzymes. The metabolism of drugs metabolized by CYP1A2, such as tizanidine may be increased during treatment with hydroxyprogesterone.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include tizanidine. Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can also cause additive CNS depression.
    Ibuprofen; Oxycodone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone or oxycodone; naloxone is initiated in a patient taking a skeletal muscle relaxant, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage and titrate to clinical response; reduced initial doses of oxycodone; naltrexone, aspirin, ASA; oxycodone, and ibuprofen; oxycodone are also recommended. If a decision is made to start treatment with acetaminophen; oxycodone extended-release tabIets, start with 1 tablet PO every 12 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Ibutilide: (Major) Ibutilide should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idarubicin: (Moderate) Tizanidine administration may result in QT prolongation. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Iloperidone: (Major) Coadministration of iloperidone and tizanidine should be avoided. Tizanidine administration may result in QT prolongation. Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Iloprost: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Imipramine: (Minor) Tizanidine should be used cautiously and with close monitoring with tricyclic antidepressants. Tizanidine administration may result in QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Indacaterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Indacaterol; Glycopyrrolate: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Indapamide: (Moderate) The effects of indapamide may be additive when administered with other antihypertensive agents or diuretics. This may be desirable, but occasionally orthostatic hypotension may occur. Dosages should be adjusted based on clinical response.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with tizanidine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Tizanidine administration may also result in QT prolongation.
    Itraconazole: (Major) Itraconazole should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Kava Kava, Piper methysticum: (Moderate) The use of tizanidine with the phytomedicinal kava kava, Piper methysticum could potentiate the sedative effects of either agent.
    Ketoconazole: (Major) Ketoconazole should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Both drugs have been associated with prolongation of the QT interval. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Labetalol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Lapatinib: (Major) Lapatinib should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Lapatinib can prolong the QT interval. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Lenvatinib: (Major) Tizanidine should be used cautiously and with close monitoring with lenvatinib. Tizanidine administration may result in QT prolongation. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Leuprolide: (Moderate) Tizanidine should be used cautiously and with close monitoring with leuprolide. Tizanidine administration may result in QT prolongation. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Leuprolide; Norethindrone: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur. (Moderate) Tizanidine should be used cautiously and with close monitoring with leuprolide. Tizanidine administration may result in QT prolongation. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Levalbuterol: (Minor) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Levobetaxolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Levobunolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Levofloxacin: (Major) Coadministration of levofloxacin and tizanidine should be avoided. Tizanidine administration may result in QT prolongation. Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Rare cases of torsade de pointes (TdP) have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin.
    Levonorgestrel: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Levorphanol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If levorphanol is initiated in a patient taking a skeletal muscle relaxant, reduce the initial dose of levorphanol by approximately 50% or more. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Lithium: (Moderate) Lithium should be used cautiously and with close monitoring with tizanidine. Both lithium and tizanidine may result in QT prolongation.
    Long-acting beta-agonists: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Loop diuretics: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Loperamide: (Moderate) Loperamide should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation and high doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Coadministration may further increase the risk of QT prolongation and TdP.
    Loperamide; Simethicone: (Moderate) Loperamide should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation and high doses of loperamide have been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Coadministration may further increase the risk of QT prolongation and TdP.
    Lopinavir; Ritonavir: (Major) Lopinavir; ritonavir should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. The use of lopinavir; ritonavir could result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes. (Major) Ritonavir should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. The use of ritonavir could result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Lorazepam: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Loxapine: (Moderate) Concurrent use of tizanidine and antipsychotics like loxapine can cause additive CNS depression.
    Lurasidone: (Moderate) Concurrent use of tizanidine and CNS depressants can cause additive CNS depression. These agents include but are not limited to: antipsychotics.
    Maprotiline: (Major) Maprotiline should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Meclizine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Mefloquine: (Major) Mefloquine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Mepenzolate: (Moderate) CNS depression can be increased when mepenzolate is combined with other CNS depressants such as skeletal muscle relaxants.
    Meperidine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Meperidine; Promethazine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Tizanidine should be used cautiously and with close monitoring with promethazine. Tizanidine administration may result in QT prolongation. Promethazine carries a possible risk of QT prolongation.
    Mephobarbital: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Mestranol; Norethindrone: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Metaproterenol: (Minor) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Methadone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If methadone is initiated in a patient taking a skeletal muscle relaxant, reduced dosages are recommended; in opioid-naive adults, use an initial methadone dose of 2.5 mg PO every 12 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, tizanidine administration may result in QT prolongation. Coadminister methadone with drugs known to prolong the QT interval with extreme caution and a careful assessment of treatment risks vs. benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Methohexital: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Methscopolamine: (Moderate) CNS depression can be increased when methscopolamine is combined with other CNS depressants such as skeletal muscle relaxants.
    Metoprolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Metronidazole: (Moderate) Tizanidine should be used cautiously and with close monitoring with metronidazole. Tizanidine administration may result in QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Mexiletine: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors, such as mexiletine, as concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Midazolam: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Midostaurin: (Major) The concomitant use of midostaurin and tizanidine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Postmarketing cases of QT prolongation associated with the use of tizanidine have been reported.
    Mifepristone, RU-486: (Moderate) Tizanidine should be used cautiously and with close monitoring with mifepristone. Tizanidine administration may result in QT prolongation. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used.
    Mirtazapine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and tizanidine. Coadminister with caution. Tizanidine administration may result in QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Molindone: (Moderate) Concurrent use of tizanidine and antipsychotics like molindone can cause additive CNS depression.
    Morphine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Morphine; Naltrexone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a skeletal muscle relaxant, reduced initial dosages are recommended. For extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Moxifloxacin: (Major) Moxifloxacin should be avoided in combination with tizanidine. Tizanidine administration may result in QT prolongation. Prolongation of the QT interval has been reported with administration of moxifloxacin. Post-marketing surveillance has identified very rare cases of ventricular arrhythmias including torsade de pointes (TdP), usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded. According to the manufacturer, moxifloxacin should be avoided in patients taking drugs that can result in prolongation of the QT interval.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants, like tizanidine, can potentiate the effects of nabilone on CNS and respiratory depression.
    Nadolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Nalbuphine: (Moderate) Concurrent use of tizanidine and CNS depressants like nalbuphine can cause additive CNS depression.
    Nebivolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Nebivolol; Valsartan: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Nilotinib: (Major) Tizanidine administration may result in QT prolongation. Coadministration of nilotinib and a drug that prolongs the QT interval is not advised; nilotinib prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation.
    Norethindrone: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Norfloxacin: (Major) Tizanidine is primarily metabolized by CYP1A2. The presystemic availability of tizanidine has been shown to be substantially increased by coadministration with CYP1A2 inhibitors. Average increases in tizanidine AUC of 10-fold and 33-fold have been reported following administration of strong CYP1A2 inhibitors. These increases in tizanidiine concentrations have been associated with significant hypotensive and sedative effects. The use of potent CYP1A2 inhibitors with tizanidine is contraindicated. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors, as concurrent use could lead to substantial increases in tizanidine blood concentrations. In addition, tizanidine administration may result in QT prolongation and should be coadministered cautiously and with close monitoring with drugs that carry a possible risk for QT prolongation and TdP. Drugs that are associated with QT prolongation that are also CYP1A2 inhibitors include amiodarone, citalopram, fluphenazine, norfloxacin, and vemurafenib. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Norgestrel: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Nortriptyline: (Minor) Tizanidine should be used cautiously and with close monitoring with tricyclic antidepressants. Tizanidine administration may result in QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as tizanidine. Therapeutic monitoring is recommended with coadministration as there is the potential for enhanced hypotensive and sedative effects.
    Ofloxacin: (Major) Tizanidine should be used cautiously and with close monitoring with ofloxacin. Tizanidine administration may result in QT prolongation. Some quinolones, including ofloxacin, have been associated with QT prolongation and infrequent cases of arrhythmia. Post-marketing surveillance for ofloxacin has identified very rare cases of torsades de pointes (TdP).
    Olanzapine: (Moderate) Tizanidine should be used cautiously and with close monitoring with olanzapine. Tizanidine administration may result in QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP).
    Olodaterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. The use of ritonavir could result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Ondansetron: (Major) If ondansetron and tizanidine must be coadministered, ECG monitoring is recommended. Tizanidine administration may result in QT prolongation. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001).
    Oral Contraceptives: (Major) If possible, avoid the concurrent use of tizanidine with oral contraceptives (OC), as concurrent use could lead to substantial increases in tizanidine blood concentrations. A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take combined hormonal OCs concurrently with tizanidine. Combined OCs increased tizanidine AUC by 4-fold and the mean Cmax by 3-fold in a parallel-group study in healthy women. Increased hypotensive effects were also noted in women taking tizanidine and OCs. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Osimertinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of tizanidine with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Tizanidine administration may also result in QT prolongation.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of tizanidine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience. Tizanidine administration may also result in QT prolongation.
    Oxazepam: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Oxycodone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone or oxycodone; naloxone is initiated in a patient taking a skeletal muscle relaxant, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage and titrate to clinical response; reduced initial doses of oxycodone; naltrexone, aspirin, ASA; oxycodone, and ibuprofen; oxycodone are also recommended. If a decision is made to start treatment with acetaminophen; oxycodone extended-release tabIets, start with 1 tablet PO every 12 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Oxymorphone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxymorphone is initiated in a patient taking a skeletal muscle relaxant, use an initial dose of oxymorphone at 1/3 to 1/2 the usual dosage and titrate to clinical response. If the extended-release oxymorphone tablets are used concurrently with a skeletal muscle relaxant, use an initial dosage of 5 mg PO every 12 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Paliperidone: (Major) Avoid coadministration of paliperidone and tizanidine. Tizanidine administration may result in QT prolongation. Paliperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. However, if coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential.
    Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include tizanidine.
    Pasireotide: (Major) Pasireotide should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Cautious use of pasireotide and drugs that prolong the QT interval is needed, as coadministration may have additive effects on the prolongation of the QT interval.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval, such as tizanidine, is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation.
    Peginterferon Alfa-2b: (Major) Tizanidine is primarily metabolized by CYP1A2. The presystemic availability of tizanidine has been shown to be substantially increased by coadministration with CYP1A2 inhibitors, such as peginterferon alfa-2b. Average increases in tizanidine AUC of 10-fold and 33-fold have been reported following administration of strong CYP1A2 inhibitors. These increases in tizanidine concentrations have been associated with significant hypotensive and sedative effects. The use of potent CYP1A2 inhibitors with tizanidine is contraindicated. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors, as concurrent use could lead to substantial increases in tizanidine blood concentrations. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Penbutolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Pentamidine: (Major) Pentamidine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Systemic pentamidine has been associated with QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Pentazocine: (Moderate) Concurrent use of tizanidine and CNS depressants like pentazocine can cause additive CNS depression.
    Pentazocine; Naloxone: (Moderate) Concurrent use of tizanidine and CNS depressants like pentazocine can cause additive CNS depression.
    Pentobarbital: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Perphenazine: (Moderate) Tizanidine should be used cautiously with perphenazine. Tizanidine administration may result in QT prolongation. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Coadministration may increase the risk of QT prolongation.
    Perphenazine; Amitriptyline: (Moderate) Tizanidine should be used cautiously with perphenazine. Tizanidine administration may result in QT prolongation. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Coadministration may increase the risk of QT prolongation. (Minor) Tizanidine should be used cautiously and with close monitoring with tricyclic antidepressants. Tizanidine administration may result in QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Phenobarbital: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Phenoxybenzamine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Phentolamine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Phenylephrine; Promethazine: (Moderate) Tizanidine should be used cautiously and with close monitoring with promethazine. Tizanidine administration may result in QT prolongation. Promethazine carries a possible risk of QT prolongation.
    Phenytoin: (Minor) One case of increased phenytoin serum concentrations and associated drowsiness has been reported with the addition of tizanidine therapy. The mechanism and significance of this potential interaction with phenytoin is unknown.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as tizanidine. Coadministration may increase the risk for QT prolongation.
    Pimozide: (Severe) Because of the potential for torsades de pointes (TdP), coadministration of tizanidine and pimozide is contraindicated. Tizanidine administration may result in QT prolongation. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Pindolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Pirbuterol: (Minor) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Posaconazole: (Major) Posaconazole should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Potassium-sparing diuretics: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Prazosin: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include tizanidine.
    Primidone: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Procainamide: (Major) Procainamide should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Prochlorperazine: (Moderate) Tizanidine should be used cautiously and with close monitoring with prochlorperazine. Tizanidine administration may result in QT prolongation. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation.
    Promethazine: (Moderate) Tizanidine should be used cautiously and with close monitoring with promethazine. Tizanidine administration may result in QT prolongation. Promethazine carries a possible risk of QT prolongation.
    Propafenone: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors, such as propafenone, as concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur. In addition, coadministration may increase the risk for QT prolongation. Tizanidine administration may result in QT prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Propranolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Protriptyline: (Minor) Tizanidine should be used cautiously and with close monitoring with tricyclic antidepressants. Tizanidine administration may result in QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Quazepam: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Quetiapine: (Major) Avoid coadministration of tizanidine and quetiapine. Tizanidine administration may result in QT prolongation. Quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Quinidine: (Major) Quinidine and dextromethorphan; quinidine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Quinine: (Major) Avoid concurrent use of quinine with other drugs that may cause QT prolongation and TdP including tizanidine. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Ramelteon: (Moderate) Concurrent use of tizanidine and CNS depressants like ramelteon can cause additive CNS depression.
    Ranolazine: (Major) Ranolazine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Regadenoson: (Moderate) Tizanidine should be used cautiously and with close monitoring with regadenoson. Tizanidine administration may result in QT prolongation. Regadenoson has been associated with QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Remifentanil: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Reserpine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Ribociclib: (Major) Avoid coadministration of ribociclib with tizanidine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Tizanidine may also cause QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with tizanidine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Tizanidine may also cause QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Rilpivirine: (Major) Tizanidine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Risperidone: (Major) Risperidone should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes; however, data are currently lacking to establish causality in association with torsades de pointes (TdP). Reports of QT prolongation and torsades de pointes during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting. Since risperidone may prolong the QT interval, it should be used cautiously with other agents also known to have this effect, taking into account the patient's underlying disease state(s) and additional potential risk factors. If coadministration is chosen, and the patient has known risk factors for cardiac disease or arrhythmia, then the patient should be closely monitored clinically.
    Ritonavir: (Major) Ritonavir should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. The use of ritonavir could result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Romidepsin: (Major) Both tizanidine and romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Salmeterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Saquinavir: (Major) Avoid coadministration of tizanidine and saquinavir. Tizanidine administration may result in QT prolongation. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Secobarbital: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Sertraline: (Major) Sertraline should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Short-acting beta-agonists: (Minor) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Simeprevir: (Moderate) Tizanidine is primarily metabolized by CYP1A2. Tizanidine clearance may be reduced by coadministration of mild inhibitors of CYP1A2, such as simeprevir. Increased tizanidine concentrations may lead to oversedation, significant hypotension, potential liver problems, and other events.
    Solifenacin: (Moderate) Tizanidine should be used cautiously and with close monitoring. Tizanidine administration may result in QT prolongation. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsades de pointes (TdP) has been reported with post-marketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation.
    Sorafenib: (Major) Tizanidine administration may result in QT prolongation. Sorafenib has been associated with QT prolongation. If sorafenib and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Sotalol: (Major) Sotalol should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    Spironolactone: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Sufentanil: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Tizanidine should be used cautiously and with close monitoring with sulfamethoxazole; trimethoprim. Tizanidine administration may result in QT prolongation. QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Sunitinib: (Major) Sunitinib should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Sunitinib can prolong the QT interval. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Tacrine: (Major) Tacrine is a substrate and inhibitor of CYP1A2, the primary isoenzyme responsible for the metabolism of tizanidine. Therefore, addition of tacrine to a stable tizanidine regimen may lead to tizanidine-related adverse effects such as oversedation, significant hypotension, or potential liver problems. Close monitoring for adverse effects is recommended during concomitant therapy
    Tacrolimus: (Major) Tacrolimus should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Tacrolimus causes QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Tamoxifen: (Moderate) Caution is advised with the concomitant use of tamoxifen and tizanidine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Tizanidine administration may also result in QT prolongation.
    Tapentadol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If tapentadol is initiated in a patient taking a skeletal muscle relaxant, a reduced initial dosage of tapentadol is recommended. If the extended-release tapentadol tablets are used concurrently with a skeletal muscle relaxant, use an initial tapentadol dose of 50 mg PO every 12 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Telavancin: (Major) Telavancin should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Telavancin has also been associated with QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Telithromycin: (Major) Telithromycin should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Telithromycin is associated with QT prolongation and torsades de pointes. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Temazepam: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Terazosin: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Terbutaline: (Minor) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Teriflunomide: (Moderate) Use caution when administering teriflunomide and tizanidine concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as tizanidine, may decrease tizanidine exposure and lead to a reduction in efficacy.
    Tetrabenazine: (Major) Avoid coadministration of tizanidine and tetrabenazine. Tizanidine administration may result in QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc.
    Thalidomide: (Moderate) Thalidomide frequently causes drowsiness and somnolence and may enhance the sedative activity of tizanidine.
    Thiabendazole: (Severe) Tizanidine is contraindicated for use with potent CYP1A2 inhibitors. Thiabendazole is a potent inhibitor of CYP1A2 hepatic enzymes. Thiabendazole may increase the plasma concentrations of tizanidine. Changes in the pharmacokinetics of tizanidine when administered with fluvoxamine, another strong CYP1A2 inhibitor, resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment.
    Thiazide diuretics: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Thiopental: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Thioridazine: (Severe) Because of the potential for torsades de pointes (TdP), use of tizanidine with thioridazine is contraindicated. Tizanidine administration may result in QT prolongation. Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP).
    Thiothixene: (Moderate) Concurrent use of tizanidine and antipsychotics like thiothixene can cause additive CNS depression.
    Ticlopidine: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors, such as ticlopidine, as concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Timolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Tiotropium; Olodaterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Tolcapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as tizanidine, due to the possibility of additive sedation.
    Tolterodine: (Moderate) Tizanidine should be used cautiously and with close monitoring with tolterodine. Tizanidine administration may result in QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. This should be taken into consideration when prescribing tolterodine to patients taking other drugs that are associated with QT prolongation.
    Toremifene: (Major) Toremifene should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Tramadol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Trandolapril; Verapamil: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors. Verapamil is a weak CYP1A2 inhibitor. Concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Trazodone: (Major) Avoid coadministration of tizanidine and trazodone. Tizanidine administration may result in QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Treprostinil: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Triamterene: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Triazolam: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Tricyclic antidepressants: (Minor) Tizanidine should be used cautiously and with close monitoring with tricyclic antidepressants. Tizanidine administration may result in QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Trifluoperazine: (Moderate) Tizanidine should be used cautiously with trifluoperazine. Tizanidine administration may result in QT prolongation. Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation.
    Trimipramine: (Minor) Tizanidine should be used cautiously and with close monitoring with tricyclic antidepressants. Tizanidine administration may result in QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Triprolidine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Umeclidinium; Vilanterol: (Moderate) Beta-agonists should be used cautiously with tizanidine. Tizanidine administration may result in QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Valerian, Valeriana officinalis: (Moderate) Concurrent use of tizanidine with the phytomedicinal valerian, Valeriana officinalis can cause additive CNS depression.
    Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval, such as tizanidine, due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib. If coadministration is necessary, perform more frequent monitoring of the QT interval. Monitor an ECG before and during use. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose.
    Vardenafil: (Major) Vardenafil should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Vardenafil is associated with QT prolongation. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug.
    Vasodilators: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Vemurafenib: (Major) Avoid the use of vemurafenib with tizanidine; the tizanidine Cmax and AUC values were significantly increased when these agents were coadministered in a drug interaction study. If concomitant use of these drugs is required, initiate tizanidine at the 2-mg dose and increase in 2- to 4-mg increments daily based on the patient response. Monitor patients closely for tizanidine toxicity; if adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy. Vemurafenib is a moderate CYP1A2 inhibitor and tizanidine is a CYP1A2 substrate with a narrow therapeutic index. In a drug interaction study (n = 16), the tizanidine Cmax increased 2.2-fold and the tizanidine AUC value increased 4.7-fold when a single 2-mg PO dose of tizanidine was given following 21 days of vemurafenib 960 mg PO twice daily in cancer patients.
    Venlafaxine: (Moderate) Tizanidine should be used cautiously and with close monitoring with venlafaxine. Tizanidine administration may result in QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsades de pointes (TdP) has reported with post-marketing use. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Verapamil: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors. Verapamil is a weak CYP1A2 inhibitor. Concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Voriconazole: (Major) Voriconazole should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Vorinostat: (Moderate) Tizanidine should be used cautiously and with close monitoring with vorinostat. Tizanidine administration may result in QT prolongation. Vorinostat therapy is associated with a risk of QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Zileuton: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors, such as zileuton, as concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Ziprasidone: (Severe) Given the potential for QT prolongation, ziprasidone is contraindicated for use with tizanidine. Tizanidine administration may result in QT prolongation. Ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine.

    PREGNANCY AND LACTATION

    Pregnancy

    It is not known whether tizanidine is excreted into human breast milk, although as a lipid soluble drug, it might be expected to pass into breast milk. The effect of this exposure is not known and because of the possibility for serious adverse events in a nursing infant (e.g., sedation, hypotension, hepatic injury, and hallucinations/psychotic-like symptoms) the use of tizanidine during breast-feeding is not recommended. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Tizanidine is a central-acting alpha2-adrenergic agonist which acts at presynaptic receptors. It is structurally and pharmacologically related to clonidine, but has only 2—10% of clonidine's antihypertensive potency. The antispasmodic activity of tizanidine results from agonism at central pre-synaptic alpha2-receptors. The response to agonism at these receptors is a decrease in the release of excitatory amino acids which in turn leads to inhibition of spinal motor neurons. In animal models, tizanidine has no direct effect on skeletal muscle fibers or the neuromuscular junction, and no major effect on monosynaptic spinal reflexes. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons.

    PHARMACOKINETICS

    Tizanidine is administered orally as capsules or tablets. It is approximately 30% bound to plasma proteins. Approximately 95% of an oral dose is metabolized, primarily by the hepatic cytochrome isoenzyme CYP1A2 and presumably to inactive metabolites with half-lives ranging from 20 to 40 hours. The half-life of tizanidine is approximately 2 hours. Following single and multiple oral dosing, about 60% and 20% of the dose is recovered in the urine and feces, respectively.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2
    Tizanidine is primarily metabolized by the hepatic cytochrome isoenzyme CYP1A2.

    Oral Route

    Tizanidine is well-absorbed, with an absolute oral bioavailability of 40% due to extensive first pass metabolism in the liver; the tablets and capsules are bioequivalent under fasted conditions, but not under fed conditions. Following oral administration of the tablet or capsule in the fasted state, peak plasma concentrations of tizanidine occur in about 1 hour. Food increases the Cmax of the tablets by about 30% and delays the time to peak concentration by approximately 25 minutes. When the capsules are given with food, the Cmax is decreased by 20% and the Tmax is increased by 2—3 hours. As a result, the Cmax of the capsules is about two-thirds the Cmax for the tablet when given with food. Food also increases the extent of absorption of both the tablets and capsules; the increase is approximately 30% for the tablets and about 10% for the capsules. Sprinkling the contents of the capsule on applesauce results in a 15—20% increase in Cmax and AUC of tizanidine and a 15-minute decrease in the time to peak concentration. Once absorbed, tizanidine is widely distributed throughout the body. The intrapatient effects of tizanidine on muscle tone are correlated with plasma concentrations; adverse effects are dose-related.