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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/Dantrolene/Dantrolene Sodium/Revonto Intravenous Inj Pwd F/Sol: 20mg
    RYANODEX Intravenous Inj Pwd F/Susp: 250mg

    DOSAGE & INDICATIONS

    For the treatment of chronic spasticity due to 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 due to rheumatic disorders.
    Oral dosage
    Adults

    25 mg PO once daily for 7 days, then 25 mg PO 3 times daily for 7 days, then 50 mg PO 3 times daily for 7 days, then 100 mg PO 3 times daily. May increase dose up to 100 mg PO 4 times daily if needed. Use the lowest dose compatible with optimal response. Max: 400 mg/day. Discontinue dantrolene if benefits are not evident within 45 days.

    Children and Adolescents 5 to 17 years

    0.5 mg/kg/dose PO once daily for 7 days, then 0.5 mg/kg/dose PO 3 times daily for 7 days, then 1 mg/kg/dose PO 3 times daily for 7 days, then 2 mg/kg/dose PO 3 times daily. May increase dose up to 100 mg PO 4 times daily if needed. Use the lowest dose compatible with optimal response. Max: 400 mg/day. Discontinue dantrolene if benefits are not evident within 45 days.

    For the treatment of malignant hyperthermia.
    Intravenous dosage (Dantrium, Revonto)
    Adults

    2.5 mg/kg/dose IV once, initially; repeat 2.5 mg/kg/dose IV as needed until symptoms subside, then 1 mg/kg/dose IV every 4 to 6 hours or 0.25 mg/kg/hour continuous IV infusion for 24 hours or longer if clinically indicated. Max: 10 mg/kg (up to 30 mg/kg). Discontinue dantrolene or extend the dosing interval to every 8 to 12 hours if metabolic stability for 24 hours, core temperature less than 38 degrees C, creatine kinase decreasing, no evidence of myoglobinuria, and muscle rigidity abated.

    Infants, Children, and Adolescents

    2.5 mg/kg/dose IV once, initially; repeat 2.5 mg/kg/dose IV as needed until symptoms subside, then 1 mg/kg/dose IV every 4 to 6 hours or 0.25 mg/kg/hour continuous IV infusion for 24 hours or longer if clinically indicated. Max: 10 mg/kg (up to 30 mg/kg). Discontinue dantrolene or extend the dosing interval to every 8 to 12 hours if metabolic stability for 24 hours, core temperature less than 38 degrees C, creatine kinase decreasing, no evidence of myoglobinuria, and muscle rigidity abated.

    Intravenous dosage (Ryanodex)
    Adults

    2.5 mg/kg/dose IV once, initially; repeat 2.5 mg/kg/dose IV as needed until symptoms subside, then 1 mg/kg/dose IV every 4 to 6 hours for 24 hours or longer if clinically indicated. Max: 10 mg/kg (up to 30 mg/kg).  Discontinue dantrolene or extend the dosing interval to every 8 to 12 hours if metabolic stability for 24 hours, core temperature less than 38 degrees C, creatine kinase decreasing, no evidence of myoglobinuria, and muscle rigidity abated.

    Infants, Children, and Adolescents

    2.5 mg/kg/dose IV once, initially; repeat 2.5 mg/kg/dose IV as needed until symptoms subside, then 1 mg/kg/dose IV every 4 to 6 hours for 24 hours or longer if clinically indicated. Max: 10 mg/kg (up to 30 mg/kg).  Discontinue dantrolene or extend the dosing interval to every 8 to 12 hours if metabolic stability for 24 hours, core temperature less than 38 degrees C, creatine kinase decreasing, no evidence of myoglobinuria, and muscle rigidity abated.

    Oral dosage
    Adults

    4 to 8 mg/kg/day PO in 4 divided doses for 1 to 3 days after malignant hyperthermia crisis. Adjust dose to minimize skeletal muscle weakness, sedation, or excessive gastrointestinal irritation.

    Infants, Children, and Adolescents

    4 to 8 mg/kg/day PO in 4 divided doses for 1 to 3 days after malignant hyperthermia crisis. Adjust dose to minimize skeletal muscle weakness, sedation, or excessive gastrointestinal irritation.

    For malignant hyperthermia prophylaxis in susceptible patients undergoing surgery.
    Intravenous dosage
    Adults

    2.5 mg/kg/dose IV once starting about 1.25 hours before anticipated anesthesia. If surgery is prolonged, administer additional individualized doses during anesthesia and surgery. 

    Infants, Children, and Adolescents

    2.5 mg/kg/dose IV once starting about 1.25 hours before anticipated anesthesia. If surgery is prolonged, administer additional individualized doses during anesthesia and surgery. 

    Oral dosage
    Adults

    4 to 8 mg/kg/day PO in 3 to 4 divided doses starting 1 to 2 days before surgery, with the last dose given 3 to 4 hours before surgery. Adjust dose to minimize skeletal muscle weakness, sedation, or excessive gastrointestinal irritation.

    Infants, Children, and Adolescents

    4 to 8 mg/kg/day PO in 3 to 4 divided doses starting 1 to 2 days before surgery, with the last dose given 3 to 4 hours before surgery. Adjust dose to minimize skeletal muscle weakness, sedation, or excessive gastrointestinal irritation.

    For the treatment of neuroleptic malignant syndrome†.
    Intravenous dosage
    Adults

    1 to 2.5 mg/kg/dose IV once, initially. May continue 1 to 2.5 mg/kg/dose IV every 6 hours or 0.25 mg/kg/hour continuous IV infusion for 48 to 72 hours.

    Oral dosage
    Adults

    75 to 600 mg/day PO in divided doses.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

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

    Geriatric

    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.

    Infants

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

    Neonates

    Safety and efficacy have not been established.

    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 1,000 g (66.7% w/w).
    Storage: 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 (Dantrium, 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 to 20 degrees C, a clear solution was present at more than 180 seconds.
    Transfer 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.
    Storage (Dantrium): Store reconstituted solutions at 15 to 30 degrees C (59 to 86 degrees F). Use the solution within 6 hours of reconstitution. Avoid prolonged exposure to light.
    Storage (Revonto): Store reconstituted solutions at 20 to 25 degrees C (68 to 77 degrees F). Use the solution within 6 hours of reconstitution. Avoid prolonged exposure to light.
    Intravenous injection
    Malignant hyperthermia treatment: Administer by continuous, rapid IV push.
    Malignant hyperthermia prophylaxis: Administer IV over approximately 1 hour.
     
    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 the vial to ensure an orange-colored uniform suspension.
    Do not dilute or transfer the reconstituted product to another container for infusion.
    Storage: Store reconstituted suspensions at 20 to 25 degrees C (68 to 77 degrees F). Use within 6 hours of reconstitution.
    Intravenous injection
    Malignant hyperthermia treatment: Administer by IV push.
    Malignant hyperthermia prophylaxis: Administer IV over at least 1 minute.
    Inject the reconstituted solution into an 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:
    - Avoid excessive humidity
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Revonto :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - 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

    Available data from published case reports with dantrolene injection use during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Dantrolene readily crosses the placenta; however, no serious adverse events have been reported in the neonate following maternal administration of dantrolene prior to delivery. There are risks to both the pregnant woman and fetus associated with untreated malignant hyperthermia, including death. Life-sustaining therapy should not be withheld due to pregnancy. Dantrolene readily crossed the placenta when 100 mg PO daily was given for 2 to 10 days to term pregnant women awaiting labor and obstetric 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. During animal studies, 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, when given for non-life-saving indications, 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

    Breast-feeding should be discontinued during treatment with oral dantrolene because of the potential for serious adverse reactions such as respiratory depression or muscle weakness in the nursing infant. During intravenous treatment for malignant hypothermia, breast-feeding is not recommended during treatment with dantrolene, and for 3 days after the last dose. Dantrolene is reported to be present in human milk following intravenous administration over 3 days. There are no data on the effects on the breastfed infant or the effects on milk production. Dantrolene has been detected in human milk at concentrations of less than 2 mcg/mL during repeat intravenous administration over 3 days. A postpartum female received intravenous dantrolene 160 mg after delivery, 560 mg IV on postpartum day 1, then 320 mg IV on day 2, and 80 mg IV 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 to 2 days after treatment is stopped. However, if chronic treatment (e.g., spasticity) is needed, an alternate drug (e.g., baclofen) may be considered, 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
    hepatic failure / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    cirrhosis / 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
    elevated hepatic enzymes / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / 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; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    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: (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: (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 : (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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial oxycodone dosage by one-third to one-half when using the extended-release tablets.
    Acetaminophen; Pamabrom; 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.
    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.
    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 alfentanil with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. 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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    Amitriptyline: (Moderate) Concomitant use of dantrolene with tricyclic antidepressants can result in additive CNS depression.
    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; Celecoxib: (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; 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; Valsartan; 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.
    Amobarbital: (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    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) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial oxycodone dosage by one-third to one-half when using the extended-release tablets.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with dantrolene can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    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) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    Belladonna; Opium: (Major) Concomitant use of opium with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of benzhydrocodone with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. 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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    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; 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.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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; 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.
    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.
    Brompheniramine; Pseudoephedrine; 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.
    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) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    Butalbital; Acetaminophen: (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    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, Magnesium, Potassium, Sodium Oxybates: (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.
    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.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and dantrolene. CNS depressants can potentiate the effects of cannabidiol.
    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. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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.
    Celecoxib; Tramadol: (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and dantrolene. Concurrent use may result in additive CNS depression.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with skeletal muscle relaxants should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with skeletal muscle relaxants should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Chlophedianol; Dexbrompheniramine: (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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    Chlordiazepoxide; Amitriptyline: (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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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; 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.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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; Ibuprofen; 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.
    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.
    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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    Clozapine: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    Codeine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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.
    Codeine; Promethazine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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.
    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. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    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.
    Dexbrompheniramine: (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.
    Dexbrompheniramine; 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.
    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.
    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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene. (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.
    Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with dantrolene can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    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: (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. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Esketamine: (Major) Closely monitor patients receiving esketamine and skeletal muscle relaxants for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
    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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    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) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
    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.
    Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and dantrolene. Concurrent use may result in additive CNS depression.
    Fentanyl: (Major) Concomitant use of fentanyl with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    Fospropofol: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Gabapentin: (Major) Concomitant use of dantrolene with gabapentin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
    General anesthetics: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Hydrocodone: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
    Hydromorphone: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations.
    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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial oxycodone dosage by one-third to one-half when using the extended-release tablets.
    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.
    Ketamine: (Moderate) General anesthetics potentiate the effects of other CNS depressants, including skeletal muscle relaxants.
    Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and dantrolene. Concurrent use may result in additive CNS depression.
    Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and dantrolene. Dosage adjustments of lemborexant and dantrolene may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
    Levamlodipine: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with skeletal muscle relaxants should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Levorphanol: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial levorphanol dosage by 50% or more.
    Lofexidine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and dantrolene. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
    Lorazepam: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    Loxapine: (Moderate) Loxapine is a central nervous system (CNS) depressant. The concurrent use of loxapine with other CNS depressants (e.g., muscle relaxants such as dantrolene) can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with loxapine.
    Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and skeletal muscle relaxants. Concurrent use may result in additive 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 opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations.
    Meperidine; Promethazine: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. (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.
    Mephobarbital: (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    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 methadone with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Methohexital: (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    Mirtazapine: (Moderate) Skeletal muscle relaxants like dantrolene 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.
    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 morphine with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at 1/3 to 1/2 the recommended starting dosage. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Morphine; Naltrexone: (Major) Concomitant use of morphine with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at 1/3 to 1/2 the recommended starting dosage. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Nabilone: (Major) Avoid use together if possible. Use of nabilone with skeletal muscle relaxants can potentiate the CNS depressant effects of nabilone on sedation, dizziness and other side effects, which can impair the ability to undertake tasks requiring mental alertness.
    Nalbuphine: (Major) Concomitant use of nalbuphine with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of nalbuphine with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations.
    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.
    Olanzapine; Fluoxetine: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    Olanzapine; Samidorphan: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    Oliceridine: (Major) Concomitant use of oliceridine with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene 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.
    Olmesartan; 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.
    Opicapone: (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. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    Oxycodone: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial oxycodone dosage by one-third to one-half when using the extended-release tablets.
    Oxymorphone: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial oxymorphone dosage by one-third to one-half.
    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) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    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.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with dantrolene. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Phenobarbital: (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    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.
    Pimozide: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    Porfimer: (Major) Avoid coadministration of porfimer with dantrolene due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like dantrolene may increase the risk of a photosensitivity reaction.
    Pregabalin: (Major) Concomitant use of dantrolene with pregabalin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
    Primidone: (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    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) 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; Dextromethorphan: (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; Phenylephrine: (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.
    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.
    Pseudoephedrine; 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.
    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.
    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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    Quetiapine: (Moderate) Simultaneous use of dantrolene and other CNS depressants such as antipsychotics can increase CNS depression (e.g., drowsiness).
    Remifentanil: (Major) Concomitant use of remifentanil with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Remimazolam: (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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and dantrolene. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Risperidone: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
    Secobarbital: (Moderate) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    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.
    Sufentanil: (Major) Concomitant use of sufentanil with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Tapentadol: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations.
    Telmisartan; 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.
    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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    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) Concomitant use of skeletal muscle relaxants with barbiturates can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take barbiturates with another CNS depressant for symptoms of excess sedation.
    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. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Tramadol: (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Tramadol; Acetaminophen: (Major) Concomitant use of tramadol with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. 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. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
    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.
    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.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with dantrolene is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like dantrolene may increase the risk of a photosensitivity reaction.
    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

    Available data from published case reports with dantrolene injection use during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Dantrolene readily crosses the placenta; however, no serious adverse events have been reported in the neonate following maternal administration of dantrolene prior to delivery. There are risks to both the pregnant woman and fetus associated with untreated malignant hyperthermia, including death. Life-sustaining therapy should not be withheld due to pregnancy. Dantrolene readily crossed the placenta when 100 mg PO daily was given for 2 to 10 days to term pregnant women awaiting labor and obstetric 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. During animal studies, 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, when given for non-life-saving indications, 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 should be discontinued during treatment with oral dantrolene because of the potential for serious adverse reactions such as respiratory depression or muscle weakness in the nursing infant. During intravenous treatment for malignant hypothermia, breast-feeding is not recommended during treatment with dantrolene, and for 3 days after the last dose. Dantrolene is reported to be present in human milk following intravenous administration over 3 days. There are no data on the effects on the breastfed infant or the effects on milk production. Dantrolene has been detected in human milk at concentrations of less than 2 mcg/mL during repeat intravenous administration over 3 days. A postpartum female received intravenous dantrolene 160 mg after delivery, 560 mg IV on postpartum day 1, then 320 mg IV on day 2, and 80 mg IV 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 to 2 days after treatment is stopped. However, if chronic treatment (e.g., spasticity) is needed, an alternate drug (e.g., baclofen) may be considered, although the nursing infant should be monitored for sedation or poor feeding.

    MECHANISM OF ACTION

    In isolated nerve-muscle preparation, dantrolene has been shown to produce relaxation by affecting the contractile response of the muscle at a site beyond the myoneural junction, directly on the muscle itself. In skeletal muscle, dantrolene dissociates the excitation-contraction coupling, probably by interfering with the release of calcium from the sarcoplasmic reticulum. This effect appears to be more pronounced in fast muscle fibers as compared to slow ones, but generally affects both. In the anesthetic-induced malignant hyperthermia syndrome, evidence points to an intrinsic abnormality of skeletal muscle tissue. In affected humans, it has been postulated that triggering agents (e.g., general anesthetics and depolarizing neuromuscular blocking agents) produce a change within the cell which results in an elevated myoplasmic calcium. This elevated myoplasmic calcium activates acute cellular catabolic processes that cascade to the malignant hyperthermia crisis. The addition of dantrolene to the triggered malignant hyperthermic muscle cell may reestablish a normal level of ionized calcium in the myoplasm. Inhibition of calcium release from the sarcoplasmic reticulum by dantrolene reestablishes the myoplasmic calcium equilibrium, increasing the percentage of bound calcium. In this way, physiologic, metabolic, and biochemical changes associated with the malignant hyperthermia crisis may be reversed or attenuated. 

    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.