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  • CLASSES

    Muscle Relaxants, Peripherally Acting

    BOXED WARNING

    Females, hepatic disease, hepatitis, hepatotoxicity, multiple sclerosis

    Oral dantrolene is contraindicated in patients with active hepatic disease, such as cirrhosis or hepatitis, because the drug can increase the risk of developing hepatotoxicity. Overt hepatitis is most frequently reported between the third and twelfth month of therapy; however, it has occurred at varying intervals after start of therapy. The risk of dantrolene-induced hepatotoxicity (sometimes fatal) appears to be greater in females, patients over 35 years old, patients with multiple sclerosis, and patients taking other drugs concomitantly (especially estrogens); serum bilirubin appears to be predictive of mortality (mean of 17 mg/dl in the fatal cases vs. 6.5 mg/dl in nonfatal cases). Also, the incidence of hepatotoxicity with oral doses of 400 mg/day or less is much lower than the incidence with doses of 800 mg/day or more. The risk of serious hepatic injury is markedly increased even with sporadic short courses of higher doses. Spontaneous reports have suggested that geriatric patients taking oral dantrolene may have more fatal outcomes from hepatic events; however, many of these reports had several confounding factors such as concurrent illnesses or concomitant potentially hepatotoxic medications. Use oral dantrolene only in conjunction with appropriate monitoring of hepatic function including frequent determination of SGOT or SGPT. Dantrolene therapy should be stopped if no observable benefit is derived after a total of 45 days of treatment. Doses should be given at the lowest possible effective dose for each patient.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral and IV skeletal muscle relaxant used for prevention or treatment of malignant hyperthermia
    Oral formulation may be used for chronic spasticity resulting from upper motor neuron disorders
    Chronic oral use associated with hepatotoxicity

    COMMON BRAND NAMES

    Dantrium, Revonto, RYANODEX

    HOW SUPPLIED

    Dantrium/Dantrolene/Dantrolene Sodium Oral Cap: 25mg, 50mg, 100mg
    Dantrium/Revonto Intravenous Inj Pwd F/Sol: 20mg
    RYANODEX Intravenous Inj Pwd F/Susp: 250mg

    DOSAGE & INDICATIONS

    For treatment of chronic spasticity resulting from upper motor neuron disorders (e.g., spinal cord injury, stroke, cerebral palsy, or multiple sclerosis).
    NOTE: Dantrolene is not indicated for the treatment of skeletal muscle spasm resulting from rheumatic disorders.
    NOTE: Stop dantrolene if no observable benefit is derived after a total of 45 days of treatment. Brief withdrawal of dantrolene for 2—4 days may help to detect subtle but meaningful spasticity improvement with dantrolene.
    Oral dosage
    Adults

    Initially, 25 mg PO once daily. In elderly patients, initiate cautiously. If needed, increase dose every 7 days. A gradual dose titration of 25 mg PO once daily for 7 days, 25 mg PO three times daily for 7 days, 50 mg PO three times daily for 7 days, and 100 mg PO three times daily is recommended. Doses higher than 400 mg/day (100 mg PO four times daily) should not be used. Administer the lowest possible dose that decreases spasticity severity and helps the patient's functionality.

    Children 5 years of age and older

    Initially, 0.5 mg/kg PO once daily. If needed, increase dose every 7 days. A gradual dose titration of 0.5 mg/kg PO once daily for 7 days, 0.5 mg/kg PO three times daily for 7 days, 1 mg/kg PO three times daily for 7 days, and 2 mg/kg PO three times daily is recommended. Maximum dosage is 100 mg PO four times daily.

    For malignant hyperthermia.
    For treatment of an acute malignant hyperthermia crisis.
    Intravenous dosage (Revonto injectable solution OR Ryanodex injectable suspension)
    Adults, Adolescents, and Children

    Initially, minimum 1 mg/kg rapid IV injection, with 2.5 mg/kg IV recommended as the starting dose by MHAUS; start immediately when the crisis is recognized and repeat doses until symptoms subside. If the physiologic and metabolic abnormalities reappear, repeat the regimen starting with 1 mg/kg IV. A maximum cumulative dose of 10 mg/kg is recommended; however, up to 30 mg/kg may be needed. Give for 1 to 3 days after the crisis occurs. If oral administration is not feasible, start post crisis dosing with 1 mg/kg IV, individualizing the dose as the clinical situation dictates to prevent recurrence of malignant hyperthermia manifestations. MHAUS suggests 1 mg/kg IV every 4 to 6 hours or 0.25 mg/kg/hour IV infusion for 24 hours or more.

    Oral dosage
    Adults, Adolescents, and Children

    For post crisis follow-up, give 4 to 8 mg/kg/day PO in 4 divided doses for 1 to 3 days.

    For prevention of malignant hyperthermia in susceptible patients undergoing surgery.
    Intravenous dosage (Revonto injectable solution)

    NOTE: Monitor vital signs of patients who receive intravenous dantrolene. Malignant hyperthermia attenuation instead of prevention may occur; monitor patients for early clinical and metabolic signs of malignant hyperthermia.

    Adults, Adolescents, and Children

    2.5 mg/kg IV infused over 1 hour starting 1.25 hours before anesthesia with additional individualized doses during surgery as needed.

    Intravenous dosage (Ryanodex injectable suspension)

    NOTE: Monitor vital signs of patients who receive intravenous dantrolene. Malignant hyperthermia attenuation instead of prevention may occur; monitor patients for early clinical and metabolic signs of malignant hyperthermia.

    Adults, Adolescents, and Children

    2.5 mg/kg IV given over a period of at least 1 minute starting 1.25 hours before anesthesia with additional individualized doses during surgery as needed.

    Oral dosage
    Adults, Adolescents, and Children

    4 to 8 mg/kg/day PO in 3 to 4 divided doses starting 1 to 2 days before surgery. Give last dose 3 to 4 hours prior to surgery.

    For the treatment of neuroleptic malignant syndrome†.
    NOTE: Response to dantrolene in this condition has not always been successful.
    Oral dosage
    Adults

    100 to 300 mg/day PO, given in divided doses.

    Geriatric

    See adult dosage. Insufficient data are available to evaluate the dose-response in elderly patients; initiate dosage cautiously. Monitor clinical response.

    Intravenous dosage
    Adults

    1.25 to 1.5 mg/kg IV.

    Geriatric

    See adult dosage. Insufficient data are available to evaluate the dose-response in elderly patients; initiate dosage cautiously. Monitor clinical response.

    For succinylcholine-induced muscle fasciculations and post-op myalgia†.
    Oral dosage
    Adults > 45 kg

    150 mg PO, given 2 hours preoperatively.

    Adults < 45 kg

    100 mg PO, given 2 hours preoperatively.

    Geriatric

    See adult dosage. Insufficient data are available to evaluate the dose-response in elderly patients; initiate dosage cautiously. Monitor clinical response.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    The maximum dosage is dependent on route of administration and indication for therapy.

    Elderly

    The maximum dosage is dependent on route of administration and indication for therapy.

    Adolescents

    The maximum dosage is dependent on route of administration and indication for therapy.

    Children

    The maximum dosage is dependent on route of administration and indication for therapy.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Oral dantrolene is contraindicated in patients with active hepatic disease, such as cirrhosis or hepatitis, due to the risk of hepatotoxicity.

    Renal Impairment

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

    ADMINISTRATION

    Oral Administration
    Extemporaneous Compounding-Oral

    Extemporaneous 5 mg/mL dantrolene oral suspension†:
    Empty the contents of five 100 mg capsules into a solution consisting of 150 mg of citric acid and 10 mL of water.
    Add syrup BP to a total volume of 100 mL. NOTE: Syrup BP contains sucrose 667 g and purified water to 1000 g (66.7% w/w).
    The suspension is chemically stable for at least 150 days when stored at 25 degrees C in high density polyethylene bottles. Because of the absence of microbiological testing, a shelf-life of 30 days is advised if 0.15% w/v methyl hydroxybenzoate is added to the syrup BP.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Injectable solution (Revonto)
    Reconstitution:
    Reconstitute 20 mg by adding 60 mL of sterile water for injection (without a bacteriostatic agent). Do not use any other solutions.
    Shake the vial until the solution is clear. To speed reconstitution, consider warming the sterile water for injection; at 40 degrees C, a clear solution was present at 30 seconds whereas at 15—20 degrees C, a clear solution took more than 180 seconds. Protect the vial contents from direct light.
    Transfer the needed vial contents to a larger volume sterile intravenous plastic bag. Do not transfer reconstituted dantrolene to large glass bottles for prophylactic infusion. Precipitate formation has been observed with the use of some glass bottles as reservoirs.
    Store reconstituted solutions at 20—25 degrees C (68—77 degrees F). Use the solution within 6 hours of reconstitution.
    Intravenous injection:
    Rapid, continuous intravenous injection of dantrolene solution is recommended for the treatment of malignant hyperthermia.
    Infusion of dantrolene solution over 1 hour is recommended when used prophylactically.
     
    Injectable suspension (Ryanodex)
    Reconstitution:
    Reconstitute 250 mg by adding 5 mL of sterile water for injection (without a bacteriostatic agent). Do not use any other solutions.
    Shake well to ensure an orange-colored uniform suspension.
    Do not dilute or transfer to another container prior to administration.
    Store reconstituted suspensions at 20—25 degrees C (68—77 degrees F). Use within 6 hours of reconstitution.
    Intravenous injection:
    Administer dantrolene suspension as an intravenous push for treatment of malignant hyperthermia.
    Administer dantrolene suspension intravenously over at least 1 minute when using for prevention of malignant hyperthermia.
    Inject into the intravenous catheter while an IV infusion of 0.9% Sodium Chloride injection or 5% Dextrose injection is freely running. Alternatively, administer into an indwelling catheter without a freely running infusion. Assure patency before injection. Flush the line to ensure no dantrolene remains in the catheter.

    STORAGE

    Dantrium:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Revonto :
    - Protect from light
    - Reconstituted product may be stored at controlled room temperature (68 to 77 degrees F) for use within 6 hours
    - Store unreconstituted product at 68 to 77 degrees F
    RYANODEX:
    - Avoid prolonged exposure to light
    - Protect from light
    - Reconstituted product may be stored at controlled room temperature (68 to 77 degrees F)
    - Store unreconstituted product at 68 to 77 degrees F; excursions permitted to 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Oral dantrolene is contraindicated for use in patients who use spasticity to sustain upright posture and balance in locomotion or to obtain or maintain increased function.
     
    Consider the mannitol content in dantrolene vials if mannitol is used to prevent or treat late renal complications of malignant hyperthermia.

    Myopathy, neuromuscular disease

    Dantrolene should be used with caution in patients with pre-existing myopathy or with neuromuscular disease as muscle weakness is likely to occur with treatment. Decrease in grip strength and leg muscle weakness has been observed. Patients should not ambulate without assistance until normal strength and balance returns.

    Females, hepatic disease, hepatitis, hepatotoxicity, multiple sclerosis

    Oral dantrolene is contraindicated in patients with active hepatic disease, such as cirrhosis or hepatitis, because the drug can increase the risk of developing hepatotoxicity. Overt hepatitis is most frequently reported between the third and twelfth month of therapy; however, it has occurred at varying intervals after start of therapy. The risk of dantrolene-induced hepatotoxicity (sometimes fatal) appears to be greater in females, patients over 35 years old, patients with multiple sclerosis, and patients taking other drugs concomitantly (especially estrogens); serum bilirubin appears to be predictive of mortality (mean of 17 mg/dl in the fatal cases vs. 6.5 mg/dl in nonfatal cases). Also, the incidence of hepatotoxicity with oral doses of 400 mg/day or less is much lower than the incidence with doses of 800 mg/day or more. The risk of serious hepatic injury is markedly increased even with sporadic short courses of higher doses. Spontaneous reports have suggested that geriatric patients taking oral dantrolene may have more fatal outcomes from hepatic events; however, many of these reports had several confounding factors such as concurrent illnesses or concomitant potentially hepatotoxic medications. Use oral dantrolene only in conjunction with appropriate monitoring of hepatic function including frequent determination of SGOT or SGPT. Dantrolene therapy should be stopped if no observable benefit is derived after a total of 45 days of treatment. Doses should be given at the lowest possible effective dose for each patient.

    Cardiac disease

    Use dantrolene with caution in patients with cardiac disease with severe cardiac function impairment. Long-term oral dantrolene has been associated with pleural effusion with pericarditis.

    Chronic obstructive pulmonary disease (COPD), pulmonary disease

    Use dantrolene with caution in patients with pulmonary disease, particularly chronic obstructive pulmonary disease (COPD). Dantrolene may cause respiratory depression associated with muscle weakness. Monitor vital signs and adequacy of ventilation in patients receiving intravenous dantrolene. Respiratory muscle weakness leading to decreased inspiratory capacity or dyspnea may occur.

    Sunlight (UV) exposure

    Dantrolene may evoke a photosensitivity reaction; patients should be cautioned about sunlight (UV) exposure.

    Pregnancy

    Dantrolene is classified as FDA pregnancy risk category C. No adequate and well-controlled studies in pregnant women have been conducted. Dantrolene was embryocidal in the rabbit and was associated with decreased pup survival in the rat when given at doses seven times the human oral dose. Dantrolene readily crossed the placenta when 100 mg PO daily was given for 2—10 days to term pregnant women awaiting labor and delivery. Maternal and fetal whole blood concentrations were approximately equal at delivery. Neonatal concentrations fell about 50% per day for 2 days before sharply declining. No neonatal respiratory depression or neuromuscular side effects were detected. However, more study is needed before definitive conclusions can be made. Therefore, dantrolene should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, particularly during the first or second trimester where data are lacking.

    Breast-feeding

    According to the manufacturer, breast-feeding should be discontinued during dantrolene treatment because of the potential for serious adverse reactions in the nursing infant. Dantrolene has been detected in human milk at concentrations less than 2 mcg/ml during repeat intravenous administration over 3 days. A postpartum female received intravenous dantrolene 160 mg after delivery, 560 mg on postpartum day 1, 320 mg on day 2, and 80 mg on day 3. Breast milk concentrations were 1.2 mcg/ml on day 2 and 0.05 mcg/ml on day 3. The estimated half-life of dantrolene in breast milk was approximately 9 hours. Based upon these data, the amount of infant exposure to dantrolene through breast-feeding would be negligible 2 days after the last maternal dose. If used short term, the data suggest that alternate feeding methods may be pursued during active dantrolene treatment, and breast-feeding may be resumed 1—2 days after treatment is stopped. However, if chronic treatment (e.g., spasticity) is needed, an alternate drug (e.g., baclofen) may be considered, as the American Academy of Pediatrics usually considers baclofen compatible with lactation, although the nursing infant should be monitored for sedation or poor feeding.

    Driving or operating machinery

    Muscle weakness, dizziness, or lightheadedness may occur up to 48 hours after intravenous dantrolene receipt. Patients should not engage in driving or operating machinery during this time. Similar symptoms may also occur with oral dantrolene use. Caution patients against driving or participating in hazardous activities.

    Extravasation

    Avoid extravasation of injectable dantrolene; the pH is high, and tissue necrosis is possible.

    Geriatric

    The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of medications in residents (e.g., geriatric adults) 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. Dantrolene has anticholinergic properties which may be especially problematic in the elderly. 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, although close monitoring is warranted. Abrupt discontinuation of some muscle relaxants may cause or predispose individuals to seizures or hallucinations.

    ADVERSE REACTIONS

    Severe

    AV block / Early / 0-3.0
    GI bleeding / Delayed / Incidence not known
    cirrhosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    pleural effusion / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    tissue necrosis / Early / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    visual impairment / Early / Incidence not known

    Moderate

    dysphagia / Delayed / 0-13.0
    dysphonia / Delayed / 0-13.0
    sinus tachycardia / Rapid / 0-3.0
    blurred vision / Early / 3.0-3.0
    gastritis / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    dystonic reaction / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    confusion / Early / Incidence not known
    erythema / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    crystalluria / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    urinary retention / Early / Incidence not known
    urinary incontinence / Early / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known

    Mild

    flushing / Rapid / 3.0-27.0
    drowsiness / Early / 0-17.0
    headache / Early / 0-13.0
    nausea / Early / 0-10.0
    malaise / Early / 0-10.0
    vomiting / Early / 0-6.0
    dizziness / Early / 0-3.0
    injection site reaction / Rapid / 0-3.0
    asthenia / Delayed / 3.0-3.0
    diarrhea / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    dysgeusia / Early / Incidence not known
    insomnia / Early / Incidence not known
    diaphoresis / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    nocturia / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    lacrimation / Early / Incidence not known
    diplopia / Early / Incidence not known
    weakness / Early / Incidence not known
    myalgia / Early / Incidence not known
    back pain / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    fever / Early / Incidence not known
    fatigue / 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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Alfentanil: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aliskiren; Amlodipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    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 dantrolene with tricyclic antidepressants can result in additive CNS depression.
    Amitriptyline; Chlordiazepoxide: (Moderate) Concomitant use of dantrolene 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.
    Amlodipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Amlodipine; Atorvastatin: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Amlodipine; Benazepril: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Amlodipine; Olmesartan: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Amlodipine; Telmisartan: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Amlodipine; Valsartan: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    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) Simultaneous use of dantrolene and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase CNS depression (e.g., drowsiness). 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 dantrolene can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with dantrolene 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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants. (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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Brompheniramine; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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. 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. 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 dantrolene, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
    Calcium-channel blockers: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Carbetapentane; Chlorpheniramine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants. (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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants. (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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants. (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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants. (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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants. (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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Carbinoxamine; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Carbinoxamine; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Chloral Hydrate: (Moderate) Simultaneous use of dantrolene and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase CNS depression (e.g., drowsiness). 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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Chlorpheniramine; Dextromethorphan: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Chlorpheniramine; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Clevidipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Clomipramine: (Moderate) Concomitant use of dantrolene 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) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    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 dantrolene.
    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 dantrolene.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Cyproheptadine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Desipramine: (Moderate) Concomitant use of dantrolene 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 dantrolene, may have additive effects and worsen drowsiness or sedation.
    Dexchlorpheniramine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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 dantrolene.
    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.
    Diltiazem: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Dimenhydrinate: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Diphenhydramine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Diphenhydramine; Ibuprofen: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Diphenhydramine; Naproxen: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Diphenhydramine; Phenylephrine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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 dantrolene with tricyclic antidepressants can result in additive CNS depression.
    Doxylamine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Doxylamine; Pyridoxine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as droperidol, can increase CNS depression.
    Enalapril; Felodipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    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.
    Estrogens: (Moderate) Concomitant use of dantrolene and estrogens may increase the risk of developing hepatotoxicity. While a definite drug interaction with dantrolene and estrogen therapy has not yet been established, caution should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has occurred more often, for example, in women over 35 years of age receiving concomitant estrogen therapy.
    Eszopiclone: (Moderate) Simultaneous use of dantrolene and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase CNS depression (e.g., drowsiness). 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: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Etomidate: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Felodipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    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) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    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.
    Haloperidol: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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 dantrolene with tricyclic antidepressants can result in additive CNS depression.
    Isoflurane: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Isradipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    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.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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 dantrolene.
    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) Simultaneous use of dantrolene and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase CNS depression (e.g., drowsiness). 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.
    Methotrexate: (Moderate) Concomitant administration of methotrexate and dantrolene may result in elevated methotrexate concentrations. Elevated methotrexate concentrations were noted in a girl who received oral dantrolene a day before intravenous methotrexate 12 g/m2 (18 grams). The methotrexate concentration was 418 micromol/L twenty-four hours after the dose. The threshold value of 0.2 micromol/L was reached 324 hours after the start of the methotrexate infusion despite administration of carboxypeptidase-G2, an enzyme that hydrolyzes methotrexate to nontoxic metabolites, at hours 54 and 78. Three weeks later, a methotrexate dose of 10 grams was well-tolerated with a standard decrease in plasma concentrations. The clearance of methotrexate may have been impaired by dantrolene or the metabolite 5-hydroxydantrolene. Also, altered protein binding may have occurred; both dantrolene and methotrexate bind to albumin.
    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.
    Nicardipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Nifedipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Nimodipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Nisoldipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Nortriptyline: (Moderate) Concomitant use of dantrolene with tricyclic antidepressants can result in additive CNS depression.
    Olanzapine: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    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.
    Perindopril; Amlodipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    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 dantrolene 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 dantrolene.
    Pimozide: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    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 dantrolene.
    Propofol: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Protriptyline: (Moderate) Concomitant use of dantrolene 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) Simultaneous use of dantrolene and other CNS depressants such as antipsychotics can increase CNS depression (e.g., drowsiness).
    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.
    Risperidone: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    Rocuronium: (Moderate) Concomitant use of skeletal muscle relaxants with other CNS depressants can result in additive CNS depression. Also, dantrolene may potentiate neuromuscular block.
    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) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Sevoflurane: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    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.
    Trandolapril; Verapamil: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    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 dantrolene 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 dantrolene with tricyclic antidepressants can result in additive CNS depression.
    Triprolidine: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    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.
    Verapamil: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Zaleplon: (Moderate) Simultaneous use of dantrolene and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase CNS depression (e.g., drowsiness). 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 dantrolene.
    Zolpidem: (Moderate) Simultaneous use of dantrolene and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase CNS depression (e.g., drowsiness). 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

    Dantrolene is classified as FDA pregnancy risk category C. No adequate and well-controlled studies in pregnant women have been conducted. Dantrolene was embryocidal in the rabbit and was associated with decreased pup survival in the rat when given at doses seven times the human oral dose. Dantrolene readily crossed the placenta when 100 mg PO daily was given for 2—10 days to term pregnant women awaiting labor and delivery. Maternal and fetal whole blood concentrations were approximately equal at delivery. Neonatal concentrations fell about 50% per day for 2 days before sharply declining. No neonatal respiratory depression or neuromuscular side effects were detected. However, more study is needed before definitive conclusions can be made. Therefore, dantrolene should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, particularly during the first or second trimester where data are lacking.

    According to the manufacturer, breast-feeding should be discontinued during dantrolene treatment because of the potential for serious adverse reactions in the nursing infant. Dantrolene has been detected in human milk at concentrations less than 2 mcg/ml during repeat intravenous administration over 3 days. A postpartum female received intravenous dantrolene 160 mg after delivery, 560 mg on postpartum day 1, 320 mg on day 2, and 80 mg on day 3. Breast milk concentrations were 1.2 mcg/ml on day 2 and 0.05 mcg/ml on day 3. The estimated half-life of dantrolene in breast milk was approximately 9 hours. Based upon these data, the amount of infant exposure to dantrolene through breast-feeding would be negligible 2 days after the last maternal dose. If used short term, the data suggest that alternate feeding methods may be pursued during active dantrolene treatment, and breast-feeding may be resumed 1—2 days after treatment is stopped. However, if chronic treatment (e.g., spasticity) is needed, an alternate drug (e.g., baclofen) may be considered, as the American Academy of Pediatrics usually considers baclofen compatible with lactation, although the nursing infant should be monitored for sedation or poor feeding.

    MECHANISM OF ACTION

    Dantrolene's mechanism of action differs from that of other oral skeletal muscle relaxants. Dantrolene is believed to decrease muscle contraction by directly interfering with calcium ion release from the sarcoplasmic reticulum within skeletal muscle cells. This "uncouples" the excitation-contraction process, making dantrolene useful in treating malignant hyperthermia. Dantrolene does not interfere with calcium entry at the cell surface as do verapamil and other calcium-channel inhibitors. Dantrolene has little or no effect on cardiac or smooth muscle at doses used for skeletal muscle relaxation. The extent of its CNS effect is not known.
     
    Clinically, dantrolene is used to treat malignant hyperthermia and upper motor neuron disorders. In upper motor neuron disorders, dantrolene attenuates muscle response to direct stimulation, monosynaptic, and polysynaptic reflexes. The drug produces generalized, mild weakness of skeletal muscles and overall improvement in muscle tone.

    PHARMACOKINETICS

    Dantrolene is administered orally and intravenously. Skeletal muscle relaxation duration and intensity are related to blood concentrations. Significant amounts of dantrolene are bound to albumin, and this binding is readily reversible.
     
    Dantrolene is hepatically metabolized: the major metabolites are 5-hydroxydantrolene and an acetylamino metabolite of dantrolene. Another metabolite with an unknown structure appears related to the acetylamino metabolite. Dantrolene may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid. Dantrolene is probably metabolized by hepatic microsomal enzymes, so enhancement of its metabolism by other drugs is possible. However, neither phenobarbital nor diazepam appears to affect dantrolene metabolism. Dantrolene and its metabolites are eliminated renally.

    Oral Route

    After oral administration, absorption is incomplete but consistent; dose-related blood concentrations are obtained. Therapeutic effects in patients being treated for upper motor neuron disorders may not be apparent for a week or longer. After an oral 100 mg dose, the mean half-life of dantrolene is 8.7 hours in healthy adults.

    Intravenous Route

    After completion of an intravenous infusion of dantrolene for malignant hyperthermia prophylaxis, whole blood concentrations of dantrolene remain at a near steady state concentration for 3 or more hours. The mean half-life of dantrolene after intravenous administration ranges from 4—11 hours.