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  • CLASSES

    Muscle Relaxants, Centrally Acting, Plain

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, centrally acting, skeletal muscle relaxant with sedative properties; does not directly relax skeletal muscle
    Use had largely fallen out of favor; used as an adjunct to rest, physical therapy, analgesics and other measures for acute musculoskeletal pain in adults
    Best to avoid hepatotoxic agents concurrently; chlorzoxazone has been associated with hepatotoxicity

    COMMON BRAND NAMES

    Lorzone, Parafon Forte DSC, Relax-DS

    HOW SUPPLIED

    Chlorzoxazone/Lorzone/Parafon Forte DSC/Relax-DS Oral Tab: 250mg, 375mg, 500mg, 750mg

    DOSAGE & INDICATIONS

    For adjunctive therapy to rest, physical therapy, and other measures for musculoskeletal pain associated with acute musculoskeletal conditions.
    Oral dosage
    Adults

    Initially, 250 to 500 mg PO given 3 to 4 times per day. The usual initial dose for painful musculoskeletal conditions is 500 mg PO 3 to 4 times daily. Geriatric or debilitated patients may need a lower initial dose. If adequate response is not obtained at initial dose, may increase. Max: 750 mg PO 3 or 4 times daily. As improvement occurs, reduce to lowest effective dose.

    MAXIMUM DOSAGE

    Adults

    3,000 mg/day PO.

    Geriatric

    3,000 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    In general, avoid use in patients with hepatic impairment. Although causal factors are not known, chlorzoxazone has been associated with idiosyncratic, unpredictable, severe (and fatal) rare hepatotoxicity; risk factors for these events are not known. During treatment, if signs or symptoms of potential hepatic injury are reported, chlorzoxazone should be immediately discontinued.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    If stomach upset occurs, chlorzoxazone may be taken with food or milk.
    The tablets may be crushed and mixed with food, milk, or fruit juice.
    Parafon Forte DSC (500 mg) is a scored caplet and may be cut in half if a 250 mg dosage form is needed.

    STORAGE

    Generic:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Lorzone:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Parafon Forte DSC:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Relax-DS :
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Remular S :
    - Avoid exposure to heat
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Chlorzoxazone is contraindicated in any patient with a known or suspected intolerance or hypersensitivity to the drug or any of the product ingredients. If a sensitivity reaction such as urticaria, pruritus, or skin erythema occurs, discontinue chlorzoxazone. Angioedema or anaphylactic reactions are extremely rare.

    Coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion

    Coadministration with other CNS depressants with chlorzoxazone requires caution due to the additive effects. Ethanol ingestion with chlorzoxazone increases the risk for sedation and impairment, and while data are lacking, may increase the risk for hepatotoxicity. Warn patients that the CNS depressant effects of chlorzoxazone may impair driving or operating machinery or the ability to perform other hazardous activities.

    Hepatic disease, hepatitis, jaundice

    Chlorzoxazone should be used cautiously, if at all, in patients with hepatic disease. Serious (including fatal) hepatotoxicity has been rarely reported in patients receiving chlorzoxazone. The mechanism is unknown but appears to be idiosyncratic and unpredictable. Factors predisposing patients to hepatotoxicity are unknown. Most cases reported have been mild and resolved after discontinuation of the medication, but a few were associated with very high elevations of serum transaminases, severe hepatitis, or permanent liver damage; some cases have been fatal. The clinician should strongly consider monitoring liver function tests (LFTs) during chlorzoxazone treatment. Patients should promptly discontinue the drug and report any early signs of hepatic disease to their prescriber, including fever, rash, anorexia, nausea/vomiting, fatigue, right upper quadrant pain, dark urine or jaundice. If signs and symptoms of liver toxicity occur, chlorzoxazone should be discontinued immediately. Additionally, if elevated LFTs (e.g., AST, ALT, alkaline phosphatase and bilirubin) are reported, chlorzoxazone should be immediately discontinued.

    Renal failure, renal impairment

    The inactive metabolite (6-hydroxychlorzoxazone) of chlorzoxazone is rapidly excreted in the urine; therefore, use with caution in patients with severe renal impairment and renal failure, as significant renal impairment may influence the excretion of this metabolite. However, no dosage adjustments have been recommended during clinical use.

    Geriatric

    In general, use chlorzoxaone with caution in the geriatric patient; it may be advisable in some patients to start with lower initial dosages. According to the Beers Criteria, skeletal muscle relaxants including chlorzoxazone are considered potentially inappropriate medications (PIMs) for use in geriatric patients and should be avoided because most muscle relaxants are poorly tolerated by older adults. Some muscle relaxants can cause anticholinergic effects, sedation, and are associated with an increased risk of fractures. In addition, there is questionable effectiveness of the dosages tolerated by older adults. 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 3 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 with selected agents, although close monitoring is warranted. Abrupt discontinuation of some muscle relaxants may cause or predispose individuals to seizures or hallucinations.

    Pregnancy

    Chlorzoxazone has not been evaluated for safe use during pregnancy; therefore, its effects on the fetus are unknown. The reproductive effects of chlorzoxazone in animals have not been studied. Until further information becomes available, chlorzoxazone should be used during pregnancy only when the benefits to the mother strongly outweigh any potential risks to the fetus. The molecular weight of the drug suggests that placental transfer is likely. In one surveillance study, 42 newborns had been exposed to chlorzoxazone during the first trimester. One major birth defect was observed and two were expected. Earlier data from the same study reported on 264 first trimester exposures with 17 defects observed and 17 expected. The effects of chlorzoxazone during labor and delivery are unknown.

    Breast-feeding

    There are no breast-feeding recommendations available from the manufacturer. The effects of chlorzoxazone on a nursing infant are unknown. It is not known if chlorzoxazone is distributed into breast milk; however, the molecular weight of the drug is low enough that excretion into breast milk is likely. Because no information is available on the use of chlorzoxazone during breast-feeding, an alternate treatment may be preferred (or an alternate form of feeding), especially while nursing a newborn or premature infant. If chlorzoxazone administration cannot be avoided during breast-feeding, the nursing infant should be monitored for commonly encountered adverse effects of chlorzoxazone, such as sedation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    Safety and efficacy of chlorzoxazone have not been established in pediatric patients, and this drug is not recommended for use in adolescents, children, or infants. Only 1 study has been performed in pediatric patients, and it is of insufficient quality to determine safety and efficacy in musculoskeletal conditions in children.

    ADVERSE REACTIONS

    Severe

    torticollis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    GI bleeding / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known

    Mild

    drowsiness / Early / 1.0-10.0
    dizziness / Early / 1.0-10.0
    malaise / Early / 1.0-10.0
    urticaria / Rapid / 0-1.0
    rash / Early / 0-1.0
    urine discoloration / Early / 10.0
    headache / Early / Incidence not known
    ecchymosis / Delayed / Incidence not known
    petechiae / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    diarrhea / Early / Incidence not known
    nausea / Early / Incidence not known
    dyspepsia / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    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) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    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.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Additive CNS depression is possible if skeletal muscle relaxants are used concomitantly with other CNS depressants. Dosage adjustments of one or both medications may be necessary.
    Acetaminophen; Diphenhydramine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants.
    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 one-third to one-half 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 tablets, 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.
    Acetaminophen; Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with skeletal muscle relaxants may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    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.
    Acrivastine; Pseudoephedrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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.
    Alprazolam: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Amitriptyline: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression.
    Amitriptyline; Chlordiazepoxide: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression. (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Amobarbital: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Amoxapine: (Moderate) Skeletal muscle relaxants should be combined cautiously with cyclic antidepressants like maprotiline because they could cause additive CNS depressant effects. Depending on the specific agent (e.g., cyclobenzaprine, and orphenadrine), additive anticholinergic effects may also be seen. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Patients should be monitored for excessive adverse effects from either agent.
    Anxiolytics; Sedatives; and Hypnotics: (Moderate) Concurrent use of chlorzoxazone and CNS depressants such as certain sedatives or hypnotics can cause additive CNS depression. A reduction in the dose of these medications may be considered to minimize additive sedative effects, if they occur. With hypnotic medications, the risk of next-day psychomotor impairment is increased during co-administration of other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    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) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    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 one-third to one-half 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 tablets, 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.
    Atracurium: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with chlorzoxazone can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with chlorzoxazone can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    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) Use skeletal muscle relaxants 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.
    Barbiturates: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    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.
    Benzodiazepines: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Botulinum Toxins: (Moderate) Excessive neuromuscular weakness may be exacerbated by coadministration of a botulinum toxin with skeletal muscle relaxants. Advise patients to seek medical assistance if they develop any unusual symptoms (including difficulty with swallowing, speaking, or breathing or walking), or if any existing symptom worsens during use of a botulinum toxin.
    Brompheniramine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including skeletal muscle relaxants.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants. (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants. (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Brompheniramine; Pseudoephedrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Buprenorphine: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants, such as chlorzoxazone. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include skeletal muscle relaxants, such as chlorzoxazone. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buspirone: (Moderate) Concomitant use of skeletal muscle relaxants with buspirone can result in additive CNS depression. Dosage adjustments of either or both medications may be necessary.
    Butabarbital: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as chlorzoxazone, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
    Carbetapentane; Chlorpheniramine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including skeletal muscle relaxants.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including skeletal muscle relaxants.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including 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 including 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 including 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 including skeletal muscle relaxants.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including 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 including skeletal muscle relaxants.
    Carbetapentane; Pyrilamine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including skeletal muscle relaxants.
    Carbidopa; Levodopa; Entacapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation.
    Carbinoxamine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants. (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants. (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Carbinoxamine; Phenylephrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Carbinoxamine; Pseudoephedrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Chloral Hydrate: (Moderate) Concurrent use of chlorzoxazone 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.
    Chlorcyclizine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Chlordiazepoxide: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Chlordiazepoxide; Clidinium: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Chlorpheniramine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Chlorpheniramine; Dextromethorphan: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants. (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants. (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants. (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants. (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Chlorpheniramine; Phenylephrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Chlorpromazine: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Cisatracurium: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    Clemastine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Clomipramine: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression.
    Clonazepam: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Clorazepate: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Clozapine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants, such as clozapine. Dosage adjustments of one or both medications may be necessary.
    Codeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Codeine; Guaifenesin: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including chlorzoxazone.
    Codeine; Promethazine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including chlorzoxazone.
    COMT inhibitors: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation.
    Cyclizine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Cyproheptadine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Desipramine: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression.
    Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as chlorzoxazone, may have additive effects and worsen drowsiness or sedation.
    Dexchlorpheniramine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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. Dosage adjustments of either or both medications may be necessary.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Dextromethorphan; Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including chlorzoxazone.
    Diazepam: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    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) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Diphenhydramine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants. (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Diphenhydramine; Ibuprofen: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Diphenhydramine; Naproxen: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Diphenhydramine; Phenylephrine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Disulfiram: (Minor) Chlorzoxazone is a known substrate for the cytochrome P450 isozyme CYP2E1. Disulfiram inhibits CYP2E1 and has been shown to interfere with the clearance of chlorzoxazone.
    Doxacurium: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    Doxepin: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression.
    Doxylamine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Doxylamine; Pyridoxine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Dronabinol, THC: (Moderate) Concomitant use of skeletal muscle relaxants with dronabinol can result in additive CNS depression and dizziness, which can impair the ability to undertake tasks requiring mental alertness. Utilize appropriate caution if these drugs are given together.
    Droperidol: (Moderate) Additive CNS depression is possible if skeletal muscle relaxants are used concomitantly with other CNS depressants. Dosage adjustments of one or both medications may be necessary.
    Enflurane: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Entacapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, due to the possibility of additive sedation.
    Estazolam: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Eszopiclone: (Moderate) Concurrent use of chlorzoxazone 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.
    Ethanol: (Moderate) It is recommended that patients avoid or limit the ingestion of alcoholic beverages. Ingestion of alcohol (ethanol) with chlorzoxazone increases the risk for sedation and impairment, and while data are lacking, chronic alcohol use with this drug may increase the risk for hepatotoxicity. Both alcohol and chlorzoxazone are substrates for CYP2E1. Warn patients that the CNS depressant effects of chlorzoxazone may impair driving or operating machinery or the ability to perform other hazardous activities.
    Etomidate: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Ezetimibe; Simvastatin: (Moderate) One case report has noted a possible drug interaction between simvastatin and chlorzoxazone. Rhabdomyolysis, slight renal insufficiency and cholestatic hepatitis occurred in a 73-year old woman 14 days after chlorzoxazone was added to an established simvastatin regimen. Withdrawal of chlorzoxazone combined with volume substitution and forced diuresis lead to an almost complete resolution of symptoms. As chlorzoxazone is a substrate for the CYP2E1 isozyme, and simvastatin is a substrate for the CYP3A4 isozyme, it appears unlikely that the interaction was due to metabolic interference. The authors speculate that the interaction may have occurred via chlorzoxazone-induced cholestasis which then lead to increased blood concentrations of simvastatin resulting in rhabdomyolysis and renal impairment.
    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.
    Fluoxetine; Olanzapine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants, such as olanzapine. Dosage adjustments of one or both medications may be necessary.
    Fluphenazine: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Flurazepam: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Fospropofol: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    General anesthetics: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    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 opioid 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 is 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 tablets 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 opioid 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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants.
    Halothane: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including 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 opioid 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 is 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 tablets 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 opioid cough medications in patients taking skeletal muscle relaxants.
    Hydrocodone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid 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 is 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 tablets 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 opioid 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 opioid 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 is 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 tablets 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 opioid 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 opioid 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 is 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 tablets 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 opioid 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 opioid 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 is 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 tablets 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 opioid 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 opioid 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 is 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 tablets 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 opioid 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 opioid 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 is 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 tablets 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 opioid 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.
    Hydroxyzine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    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 one-third to one-half 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 tablets, 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.
    Imipramine: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression.
    Isoflurane: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Isoniazid, INH: (Moderate) Isoniazid is an known inducer and substrate of the CYP2E1 isozyme and chlorzoxazone is a substrate for CYP2E1. Theoretically, isoniazid when combined with chlorzoxazone could lead to increased or decreased metabolism and altered therapeutic levels of chlorzoxazone. If these drugs are used concomitantly, observe and question the patient in regard to adequate pain relief or the occurrence of side effects from chlorzoxazone, such as excessive CNS depression, GI distress or possible hepatotoxicity.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Isoniazid is an known inducer and substrate of the CYP2E1 isozyme and chlorzoxazone is a substrate for CYP2E1. Theoretically, isoniazid when combined with chlorzoxazone could lead to increased or decreased metabolism and altered therapeutic levels of chlorzoxazone. If these drugs are used concomitantly, observe and question the patient in regard to adequate pain relief or the occurrence of side effects from chlorzoxazone, such as excessive CNS depression, GI distress or possible hepatotoxicity.
    Isoniazid, INH; Rifampin: (Moderate) Isoniazid is an known inducer and substrate of the CYP2E1 isozyme and chlorzoxazone is a substrate for CYP2E1. Theoretically, isoniazid when combined with chlorzoxazone could lead to increased or decreased metabolism and altered therapeutic levels of chlorzoxazone. If these drugs are used concomitantly, observe and question the patient in regard to adequate pain relief or the occurrence of side effects from chlorzoxazone, such as excessive CNS depression, GI distress or possible hepatotoxicity.
    Kava Kava, Piper methysticum: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants, such as kava kava can result in additive CNS depression. Persons taking other CNS-active medications such as, skeletal muscle relaxants, should discuss the use of herbal supplements with their health care professional prior to consuming kava kava. Patients should not abruptly stop taking their prescribed medications.
    Ketamine: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    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) Monitor for additive sedation during coadministration of lofexidine and chlorzoxazone. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
    Lorazepam: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Loxapine: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    Maprotiline: (Moderate) Skeletal muscle relaxants should be combined cautiously with cyclic antidepressants like maprotiline because they could cause additive CNS depressant effects. Depending on the specific agent (e.g., cyclobenzaprine, and orphenadrine), additive anticholinergic effects may also be seen. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Patients should be monitored for excessive adverse effects from either agent.
    Meclizine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Mepenzolate: (Moderate) CNS depression can be increased when mepenzolate is combined with other CNS depressants such as skeletal muscle relaxants.
    Meperidine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Meperidine; Promethazine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including chlorzoxazone.
    Mephobarbital: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Meprobamate: (Moderate) Concurrent use of chlorzoxazone 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.
    Mesoridazine: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Methadone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If methadone is initiated in a patient taking a skeletal muscle relaxant, reduced dosages are recommended; in opioid-naive adults, use an initial methadone dose of 2.5 mg PO every 12 hours. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Methohexital: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Methscopolamine: (Moderate) CNS depression can be increased when methscopolamine is combined with other CNS depressants such as skeletal muscle relaxants.
    Midazolam: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Mirtazapine: (Moderate) Skeletal muscle relaxants may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances. In addition, anecdotal evidence from case reports suggests that cyclobenzaprine may possess serotonin augmenting effects that may be clinically relevant during administration of the drug with serotonin-enhancing medications. In theory, there is a remote possibility that serotonin syndrome may occur from concurrent administration of cyclobenzaprine and mirtazapine since mirtazapine increases central serotonin activity. In addition, cyclobenzaprine is closely related to the tricyclic antidepressants, which are known to decrease serotonin reuptake. Caution is advisable during concurrent use with mirtazapine until more information about cyclobenzaprine's effects on serotonin becomes available.
    Mivacurium: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    Molindone: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as molindone, can increase CNS depression. In addition, antipsychotics are associated with anticholinergic effects; therefore, additive effects may be seen during concurrent use of molindone and other drugs having anticholinergic activity. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    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 skeletal muscle relaxants can potentiate the effects of nabilone on respiratory depression, sedation and dizziness, which can impair the ability to undertake tasks requiring mental alertness.
    Nalbuphine: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as skeletal muscle relaxants, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Neuromuscular blockers: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    Niacin; Simvastatin: (Moderate) One case report has noted a possible drug interaction between simvastatin and chlorzoxazone. Rhabdomyolysis, slight renal insufficiency and cholestatic hepatitis occurred in a 73-year old woman 14 days after chlorzoxazone was added to an established simvastatin regimen. Withdrawal of chlorzoxazone combined with volume substitution and forced diuresis lead to an almost complete resolution of symptoms. As chlorzoxazone is a substrate for the CYP2E1 isozyme, and simvastatin is a substrate for the CYP3A4 isozyme, it appears unlikely that the interaction was due to metabolic interference. The authors speculate that the interaction may have occurred via chlorzoxazone-induced cholestasis which then lead to increased blood concentrations of simvastatin resulting in rhabdomyolysis and renal impairment.
    Nortriptyline: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression.
    Olanzapine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants, such as olanzapine. Dosage adjustments of one or both medications may be necessary.
    Oxazepam: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in 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 one-third to one-half 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 tablets, 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 one-third to one-half 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.
    Pancuronium: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with skeletal muscle relaxants may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    Pentazocine; Naloxone: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with skeletal muscle relaxants may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    Pentobarbital: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Perphenazine: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Perphenazine; Amitriptyline: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression. (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Phenobarbital: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Phenothiazines: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Phenylephrine; Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including chlorzoxazone.
    Primidone: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Prochlorperazine: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Promethazine: (Moderate) Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur when it is combined with other CNS depressants including chlorzoxazone.
    Propofol: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Protriptyline: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression.
    Quazepam: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Quetiapine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including quetiapine. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Rapacuronium: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    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.
    Rocuronium: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    Rufinamide: (Moderate) In theory, plasma concentrations of chlorzoxazone or other CYP2E1 substrates may be increased due to the weak 2E1 inhibitory effects of rufinamide.
    Secobarbital: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Sedating H1-blockers: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Sevoflurane: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Simvastatin: (Moderate) One case report has noted a possible drug interaction between simvastatin and chlorzoxazone. Rhabdomyolysis, slight renal insufficiency and cholestatic hepatitis occurred in a 73-year old woman 14 days after chlorzoxazone was added to an established simvastatin regimen. Withdrawal of chlorzoxazone combined with volume substitution and forced diuresis lead to an almost complete resolution of symptoms. As chlorzoxazone is a substrate for the CYP2E1 isozyme, and simvastatin is a substrate for the CYP3A4 isozyme, it appears unlikely that the interaction was due to metabolic interference. The authors speculate that the interaction may have occurred via chlorzoxazone-induced cholestasis which then lead to increased blood concentrations of simvastatin resulting in rhabdomyolysis and renal impairment.
    Simvastatin; Sitagliptin: (Moderate) One case report has noted a possible drug interaction between simvastatin and chlorzoxazone. Rhabdomyolysis, slight renal insufficiency and cholestatic hepatitis occurred in a 73-year old woman 14 days after chlorzoxazone was added to an established simvastatin regimen. Withdrawal of chlorzoxazone combined with volume substitution and forced diuresis lead to an almost complete resolution of symptoms. As chlorzoxazone is a substrate for the CYP2E1 isozyme, and simvastatin is a substrate for the CYP3A4 isozyme, it appears unlikely that the interaction was due to metabolic interference. The authors speculate that the interaction may have occurred via chlorzoxazone-induced cholestasis which then lead to increased blood concentrations of simvastatin resulting in rhabdomyolysis and renal impairment.
    Sodium Oxybate: (Major) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with skeletal muscle relaxants.
    Succinylcholine: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    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.
    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) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Thalidomide: (Major) Avoid the concomitant use of thalidomide with other central nervous system depressants such as skeletal muscle relaxants due to the potential for additive sedative effects.
    Thiethylperazine: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Thiopental: (Moderate) Additive CNS depression may occur if barbiturates are used concomitantly with skeletal muscle relaxants. Caution should be exercised during concomitant use of skeletal muscle relaxants and barbiturates; dosage reduction of one or both agents may be necessary.
    Thioridazine: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Thiothixene: (Moderate) Thiothixene can potentiate the CNS-depressant action of other drugs, such skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Tolcapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including skeletal muscle relaxants, 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.
    Trazodone: (Moderate) CNS depressants, such as skeletal muscle relaxants, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Triazolam: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
    Tricyclic antidepressants: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression.
    Trifluoperazine: (Moderate) Phenothiazines can potentiate the CNS-depressant action of other drugs such as skeletal muscle relaxants. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Trimipramine: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression.
    Triprolidine: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Tubocurarine: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    Vecuronium: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    Zaleplon: (Moderate) Concurrent use of chlorzoxazone 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.
    Ziprasidone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including chlorzoxazone.
    Zolpidem: (Moderate) Concurrent use of chlorzoxazone 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.

    PREGNANCY AND LACTATION

    Pregnancy

    Chlorzoxazone has not been evaluated for safe use during pregnancy; therefore, its effects on the fetus are unknown. The reproductive effects of chlorzoxazone in animals have not been studied. Until further information becomes available, chlorzoxazone should be used during pregnancy only when the benefits to the mother strongly outweigh any potential risks to the fetus. The molecular weight of the drug suggests that placental transfer is likely. In one surveillance study, 42 newborns had been exposed to chlorzoxazone during the first trimester. One major birth defect was observed and two were expected. Earlier data from the same study reported on 264 first trimester exposures with 17 defects observed and 17 expected. The effects of chlorzoxazone during labor and delivery are unknown.

    There are no breast-feeding recommendations available from the manufacturer. The effects of chlorzoxazone on a nursing infant are unknown. It is not known if chlorzoxazone is distributed into breast milk; however, the molecular weight of the drug is low enough that excretion into breast milk is likely. Because no information is available on the use of chlorzoxazone during breast-feeding, an alternate treatment may be preferred (or an alternate form of feeding), especially while nursing a newborn or premature infant. If chlorzoxazone administration cannot be avoided during breast-feeding, the nursing infant should be monitored for commonly encountered adverse effects of chlorzoxazone, such as sedation. 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

    The exact mode of action of chlorzoxazone has not been identified, but appears to be related to its sedative properties. Chlorzoxazone has no direct relaxant effect on skeletal muscle. Data available from animal experiments and human study indicate that chlorzoxazone acts primarily at the level of the spinal cord and subcortical areas of the brain where it inhibits multisynaptic reflex arcs involved in producing and maintaining skeletal muscle spasm of varied etiology. The clinical result is a reduction of the skeletal muscle spasm with relief of pain and increased mobility of the involved muscles. Pain relief is postulated to be due to alterations in the perception of pain. Chlorzoxazone is not associated with significant anticholinergic effects. The mechanism responsible for the rare hepatic toxicity seen with chlorzoxazone is unknown. The reaction is idiosyncratic and unpredictable. Factors that may predispose patients to hepatic toxicity with chlorzoxazone have not been identified.

    PHARMACOKINETICS

    Chlorzoxazone is administered orally. The drug is well distributed, with the highest concentrations found in plasma and fat, and lower concentrations found in the liver, muscle, brain and kidneys. The volume of distribution is roughly 14 L. It is not known if the drug is distributed into human milk or crosses the placenta. Metabolism occurs in the liver by CYP2E1, producing an inactive metabolite, 6-hydroxychlorzoxazone, which is then rapidly excreted as the glucuronide in the urine. Less than 1% of a dose is excreted unchanged in urine within 24 hours; 74% of the metabolite is excreted within 10 hours. The half-life of chlorzoxazone is roughly 60 minutes in adults with normal hepatic function.
     
    Affected cytochrome P450 (CYP450) enzymes and drug transporters: CYP2E1, CYP3A4
    Chlorzoxazone is metabolized by CYP2E1 to its inactive metabolite. Chlorzoxazone is often used in clinical studies that research the effect of various conditions or drugs on CYP2E1-mediated hepatic metabolism; it is considered an index substrate for this enzyme. In addition, chlorzoxazone may be a weak inhibitor of CYP3A4.

    Oral Route

    Absorption of chlorzoxazone from the GI tract is rapid and complete. Blood levels can be detected within the first 30 minutes after administration. Blood levels of chlorzoxazone can be detected in humans during the first 30 minutes and peak levels occur approximately 1 to 2 hours after oral administration.