PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • 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 between 68 to 77 degrees F, excursions permitted 59 to 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.

    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.

    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 / 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.
    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.
    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) Avoid concomitant use of tizanidine and amiodarone as increased serum concentrations of tizanidine may occur. If use together is necessary, initiate tizanidine with the 2 mg dose and increase daily in 2 to 4 mg increments based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
    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.
    Amobarbital: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Anagrelide: (Moderate) Avoid concomitant use of tizanidine and anagrelide as increased serum concentrations of tizanidine may occur. If use together is necessary, initiate tizanidine with the 2 mg dose and increase daily in 2 to 4 mg increments based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate; anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction.
    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.
    Aripiprazole: (Moderate) Use tizanidine and aripiprazole together with caution due to additive CNS depression. Monitor patients for symptoms of excess sedation.
    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.
    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.
    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.
    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.
    Buprenorphine: (Major) Concomitant use of buprenorphine and tizanidine can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve concomitant use of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor patients closely for signs of respiratory depression and sedation.
    Buprenorphine; Naloxone: (Major) Concomitant use of buprenorphine and tizanidine can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve concomitant use of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor patients closely for signs of respiratory depression and sedation.
    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.
    Cannabidiol: (Moderate) Consider a dose adjustment of tizanidine as clinically appropriate when administered with cannabidiol. Increased or decreased tizanidine exposure is possible. Additive somnolence and sedation may occur. Tizanidine is a sensitive CYP1A2 substrate. In vitro data predicts inhibition or induction of CYP1A2 by cannabidiol potentially resulting in clinically significant interactions.
    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.
    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.
    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.
    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) Concomitant use of tizanidine and ciprofloxacin is contraindicated due to the risk of tizanidine toxicity, including clinically significant hypotension, bradycardia, and sedation. Tizanidine is a CYP1A2 substrate and ciprofloxacin is a strong CYP1A2 inhibitor. After a single 4 mg tizanidine dose, Cmax and AUC increased by 7-fold and 10-fold, respectively, when administered with ciprofloxacin during pharmacokinetic trials.
    Clemastine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    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.
    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.
    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.
    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.
    Cyclizine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Cyproheptadine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Deutetrabenazine: (Moderate) Use tizanidine and deutetrabenazine together with caution due to additive CNS depression. Monitor patients for symptoms of excess sedation.
    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.
    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.
    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.
    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: (Moderate) Concomitant use of dronabinol with other CNS depressants, like tizanidine, can potentiate the effects of dronabinol on respiratory depression.
    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.
    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.
    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.
    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. Hypotension may occur. Alcohol increases the overall amount of drug in the bloodstream after a dose of tizanidine. 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; Ferrous bisglycinate: (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.
    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.
    Fluphenazine: (Moderate) Use tizanidine and fluphenazine together with caution due to additive CNS depression. Monitor patients for symptoms of excess sedation.
    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.
    Fluvoxamine: (Severe) Concomitant use of tizanidine and fluvoxamine is contraindicated due to the risk of tizanidine toxicity, including clinically significant hypotension, bradycardia, and sedation. Tizanidine is a CYP1A2 substrate and fluvoxamine is a strong CYP1A2 inhibitor. After a single 4 mg tizanidine dose, Cmax, AUC, and half-life increased by 12-fold, 33--fold, and 3-fold, respectively, when administered with fluvoxamine during pharmacokinetic trials.
    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.
    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.
    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.
    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) Use tizanidine and hydroxyzine together with caution due to additive CNS depression. Consider tizanidine dosage reduction and monitor patients for symptoms of excess sedation.
    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.
    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.
    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.
    Kava Kava, Piper methysticum: (Moderate) The use of tizanidine with the phytomedicinal kava kava, Piper methysticum could potentiate the sedative effects of either agent.
    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.
    Leflunomide: (Moderate) Closely monitor for reduced efficacy of tizanidine if coadministered with leflunomide. An adjustment of the tizanidine dose may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. 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.
    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.
    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.
    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.
    Lofexidine: (Moderate) Use tizanidine and lofexidine together with caution due to additive CNS depression. Monitor patients for symptoms of excess sedation and hypotension.
    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.
    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.
    Meclizine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    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.
    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.
    Methadone: (Major) Concomitant use of methadone and tizanidine can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve concomitant use of these drugs for use in 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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    Primidone: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    Propafenone: (Major) Avoid concomitant use of tizanidine and propafenone as increased serum concentrations of tizanidine may occur. If use together is necessary, initiate tizanidine with the 2 mg dose and increase daily in 2 to 4 mg increments based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate and propafenone is a CYP1A2 inhibitor.
    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.
    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.
    Ramelteon: (Moderate) Concurrent use of tizanidine and CNS depressants like ramelteon can cause additive CNS depression.
    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.
    Rucaparib: (Major) Avoid coadministration of tizanidine with rucaparib if possible due the risk of increased plasma concentrations of tizanidine. If concomitant use is unavoidable, monitor for an increase in tizanidine-related adverse reactions (e.g., hypotension, bradycardia, excessive drowsiness). Tizanidine is a sensitive CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor.
    Secobarbital: (Moderate) Concurrent use of tizanidine and CNS depressants like barbiturates can cause additive CNS depression.
    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.
    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.
    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
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    Triprolidine: (Moderate) Concurrent use of tizanidine and CNS depressants like sedating h1-blockers can cause additive CNS depression.
    Valerian, Valeriana officinalis: (Moderate) Concurrent use of tizanidine with the phytomedicinal valerian, Valeriana officinalis can cause additive CNS depression.
    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.
    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.
    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.

    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.