Cyclopak (cyclobenzaprine/lidocaine/prilocaine/glycerin)

Dosage of lidocaine hydrochloride varies with the anesthetic procedure, the degree of anesthesia required, and individual patient response. The usual dosages should generally be reduced in children, geriatric patients, debilitated or acutely ill patients, and patients with cardiac and/or hepatic disease. The smallest dose and lowest concentration required to produce the desired effect should be used. Use of dilute solutions (i.e., 0.25-0.5%) and total dosages not to exceed 3 mg/kg are recommended for induction of IV regional anesthesia in children.

Single doses of lidocaine hydrochloride (for anesthesia other than spinal) should not exceed 4.5 mg/kg (or 300 mg) in healthy adults or 4.5 mg/kg in children younger than 10 years of age. When administered with epinephrine, lidocaine hydrochloride doses should not exceed 7 mg/kg (or 500 mg) in healthy adults or 7 mg/kg in children younger than 10 years of age. For spinal anesthesia, up to 100 mg of the drug may be given. For continuous epidural or caudal anesthesia, the maximum dose should not be repeated at intervals of less than 1.5 hours. When continuous lumbar or caudal epidural anesthesia is used for nonobstetric procedures, additional drug may be administered if necessary to attain adequate anesthesia. For paracervical block for nonobstetric and obstetric analgesia (including abortion), the maximum recommended dosage (200 mg) should not be repeated at intervals of less than 1.5 hours. For IV regional anesthesia in adults using a 0.5% solution without epinephrine, the dose administered should not exceed 4 mg/kg.

Solutions of 1-2% lidocaine hydrochloride with or without epinephrine and containing no preservatives are used for epidural or caudal anesthesia. To prevent intravascular or subarachnoid injection of a large epidural dose of lidocaine, a test dose (e.g., 2-3 mL of a 1.5% solution) of anesthetic solution should be injected at least 5 minutes prior to administering the total dose. When clinical conditions permit, use of a test dose solution that contains epinephrine (e.g., 10-15 mcg) should be considered to detect inadvertent intravascular injection. The test dose should be repeated if the patient is moved such that the epidural catheter may have been displaced. Rapid injection of a large, single dose through a catheter should be avoided; instead, the drug should be administered, when feasible, in fractional doses. In epidural anesthesia, 2-3 mL of the indicated solution is usually required for each dermatome to be anesthetized. In caudal block for production of obstetric analgesia or in epidural thoracic block, 20-30 mL of a 1% solution (200-300 mg) of the drug may be used. For surgical anesthesia with caudal block, 15-20 mL of a 1.5% solution (225-300 mg) is given. For epidural lumbar analgesia, the dose is 25-30 mL (250-300 mg) of a 1% solution, and for epidural lumbar anesthesia, the recommended dose is 15-20 mL of a 1.5% solution (225-300 mg) or 10-15 mL of a 2% solution (200-300 mg).

A solution of 5% lidocaine hydrochloride with 7.5% dextrose is used for spinal anesthesia in adults and adolescents 16 years of age or older. For obstetric low spinal or saddle-block anesthesia in a normal vaginal delivery, the dose is approximately 1 mL (50 mg). For cesarean section or deliveries which require intrauterine manipulations, 1.5 mL of the 5% solution (75 mg) may be given. For surgical anesthesia, 1.5-2 mL of the 5% solution (75-100 mg) may be administered.

The following doses of lidocaine hydrochloride have been suggested for various nerve blocks: brachial nerve block, 15-20 mL of a 1.5% solution (225-300 mg); dental nerve block, 1-5 mL of a 2% solution (20-100 mg); intercostal nerve block, 3 mL of a 1% solution (30 mg); paravertebral nerve block, 3-5 mL of a 1% solution (30-50 mg); pudendal nerve block (each side), 10 mL of a 1% solution (100 mg); and paracervical nerve block (each side) for obstetric analgesia, 10 mL of a 1% solution (100 mg). For sympathetic nerve blocks, the following doses may be used: cervical (stellate ganglion) nerve block, 5 mL of a 1% solution (50 mg), and lumbar nerve block, 5-10 mL of a 1% solution (50-100 mg). For percutaneous infiltration anesthesia, the dose of lidocaine hydrochloride is 1-60 mL of a 0.5 or 1% solution (5-300 mg). For IV regional anesthesia, 10-60 mL of a 0.5% solution (50-300 mg) may be employed.

For retrobulbar injection, 3-5 mL of a 4% sterile solution (120-200 mg) or 1.7-3 mg/kg is suggested; a portion of the dose is injected retrobulbarly and the remainder may be used to block the facial nerve.

For transtracheal injection, 2-3 mL of a 4% solution (80-120 mg) is administered rapidly. When both transtracheal injection and topical application (oropharyngeal spray) of a 4% solution are needed to achieve complete analgesia, the combined total dose of lidocaine hydrochloride administered by injection and by oropharyngeal spray should not exceed 5 mL of a 4% solution (200 mg) or 3 mg/kg.

Lidocaine hydrochloride with or without epinephrine is used for various dental procedures by infiltration injection or nerve block. In oral infiltration and/or mandibular block, initial doses of 1-5 mL of 2% lidocaine hydrochloride (20-100 mg) with epinephrine 1:100,000 are usually effective. If greater hemostasis is required, epinephrine 1:50,000 may be used. In children younger than 10 years of age, 0.9-1 mL of 2% lidocaine hydrochloride (18-20 mg) is adequate for a procedure involving 1 tooth (local infiltration), 2-3 teeth (maxillary infiltration), or teeth in an entire quadrant (mandibular block).

The manufacturer of cyclobenzaprine hydrochloride immediate-release tablets states that less frequent dosing should be considered in geriatric patients, initiating cyclobenzaprine hydrochloride with a 5-mg dose and titrating upward slowly.

Cyclobenzaprine extended-release capsules are not recommended for use in geriatric patients.

The manufacturer of cyclobenzaprine hydrochloride tablets states that less frequent dosing should be considered in patients with mild hepatic impairment, beginning with a 5-mg dose and slowly titrating upward. Use of the drug is not recommended in patients with moderate or severe hepatic impairment.

Because of limited dosing flexibility, the manufacturer of the extended-release capsules states that this dosage form is not recommended for use in patients with hepatic impairment.

Cyclobenzaprine is administered orally (as immediate-release tablets or extended-release capsules).

The extended-release capsules should be swallowed intact. Alternatively, the capsules may be opened and the contents sprinkled onto a tablespoon of applesauce and consumed immediately without chewing; foods other than applesauce have not been tested and should not be used. Following administration, patients should rinse their mouth to ensure that all the capsule contents have been swallowed. Any unused portion of the capsules should be discarded.

Lidocaine hydrochloride may be administered by infiltration or by epidural (including caudal) block, peripheral or sympathetic nerve block, and subarachnoid block. The manufacturers state that only the preservative-free, epinephrine-free 0.5% lidocaine injection should be used for IV regional anesthesia. Local anesthetics, including lidocaine hydrochloride, have been administered by continuous intra-articular infusion+ (e.g., for control of postoperative pain); however, such use has been associated with chondrolysis. Lidocaine hydrochloride solutions containing preservatives shouldnot be used for spinal or epidural (including caudal) block. Partially used bottles of solutions that do not contain preservatives should be discarded.

Aspiration for blood should be performed prior to injection of lidocaine hydrochloride to avoid inadvertent intravascular administration; however, a negative aspiration does not ensure protection against inadvertent intravascular injection.

Local anesthetics should only be administered by clinicians who are experienced in the diagnosis and management of dose-related toxicities and other acute emergencies associated with these agents. Resuscitative equipment, oxygen, drugs, and personnel required for treatment of adverse reactions should be immediately available when lidocaine is administered. Proper positioning of the patient is extremely important in spinal anesthesia. For specific procedures and techniques of administration, specialized references should be consulted.

No dosing information is available for this tab.

No dosing information is available for this tab.

Cyclobenzaprine is structurally and pharmacologically related to tricyclic antidepressants and shares the drug interaction potentials of these drugs. For additional information on potential drug interactions of tricyclic antidepressants, see Drug Interactions in the Tricyclic Antidepressants General Statement 28:16.04.28.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Tricyclic & Tetracyclic Compounds/Cisapride

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The concurrent use of cisapride with a tricyclic or tetracyclic compound may result in additive effects on the QT interval.(1,2)

CLINICAL EFFECTS: Concurrent use may result in prolongation of the QT interval, which may result in potentially life-threatening arrhythmias.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of cisapride states that cisapride should not be concomitantly administered with agents known to prolong the QT interval such as certain tricyclic antidepressants and certain tetracyclic antidepressants.(1) The manufacturer of amitriptyline states under contraindications that amitriptyline should not be given with cisapride.(2) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The manufacturer of cisapride states that QT prolongation, torsades de pointes (sometimes with syncope), cardiac arrest, and sudden death have been reported in patients who were not taking agents known to increase cisapride levels. Some of these patients were taking agents known to prolong the QT interval, such as certain tricyclic antidepressants and certain tetracyclic antidepressants. The manufacturer of cisapride states that cisapride should not be concomitantly administered with agents known to prolong the QT interval.(1) The manufacturer of amitriptyline states under contraindications that amitriptyline should not be given with cisapride due to the potential for increased QT interval and increased risk of arrhythmia.(2)

Tricyclic Compounds/Arbutamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The exact mechanism of the interaction is unknown.

CLINICAL EFFECTS: The exact clinical effects are not stated.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of arbutamine states that arbutamine should not be administered with tricyclic antidepressants.(1)

DISCUSSION: The manufacturer of arbutamine states that arbutamine should not be administered with tricyclic antidepressants.(1) There is no published documentation for this interaction.

Tricyclic Compounds/Grepafloxacin; Sparfloxacin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Unknown. Possibly additive or synergistic effects on the QTc interval.

CLINICAL EFFECTS: Increased QTc intervals which may result in life-threatening arrhythmias such as torsades de pointes.

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: Concurrent administration of grepafloxacin and agents known to produce an increase in the QTc interval and/or torsades de pointes such as tricyclic antidepressants is contraindicated unless appropriate cardiac monitoring can be assured.(1) Concurrent administration of sparfloxacin and agents known to produce an increase in the QTc interval and/or torsades de pointes is contraindicated. The manufacturer of sparfloxacin states that concurrent administration of sparfloxacin and tricyclic antidepressants should be avoided.(2) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: There is no published documentation to support this potential drug interaction. The product information for grepafloxacin states that prolongation of the QTc interval has been observed in healthy subjects receiving grepafloxacin.(1) The product information for sparfloxacin states that torsades de pointes has been reported in patients receiving sparfloxacin and disopyramide and amiodarone. Therefore, concurrent administration of sparfloxacin and agents known to produce an increase in the QTc interval and/or torsades de pointes, such as tricyclic antidepressants, is contraindicated.(2)

Tricyclic Compounds/Halofantrine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Possibly additive effects on the QTc interval.

CLINICAL EFFECTS: Concurrent use of halofantrine and tricyclic antidepressants may pre-dispose patients to development of prolonged QTc intervals.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of halofantrine states under the contraindications section of the prescribing information that unless there are compelling clinical reasons, halofantrine should not be used with tricyclic antidepressants.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: There is no published documentation to support this potential interaction. Because concurrent use may pre-dispose patients to prolongation of the QTc interval, the manufacturer of halofantrine states under the contraindications section of the prescribing information that halofantrine should not be used with tricyclic antidepressants unless compelling clinical reasons exist.(1)

Tricyclic; Tetracyclic Compounds/Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Some MAO inhibitors may enhance the effects of tricyclic and tetracyclic compounds indirectly through inhibition of microsomal enzymes.(1) Tricyclic and tetracyclic compounds may sensitize post-synaptic receptors to amines that are accumulating extraneuronally as a result of MAO inhibition.(2) Similarity between cyclobenzaprine and TCAs warrants consideration of TCA interactions for cyclobenzaprine.(6) Mirtazapine, a tetracyclic antidepressant, should also be considered for this interaction.(7)

CLINICAL EFFECTS: Concurrent use may result in a severe reaction including hyperpyrexia, convulsions, excitability, fluctuations in blood pressure, convulsions, grand mal seizures, serotonin syndrome, coma, and death.(1,3-10) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(11)

PREDISPOSING FACTORS: High doses of tricyclics or tetracyclics, or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.

PATIENT MANAGEMENT: The concurrent use of tricyclic antidepressants, cyclobenzaprine or mirtazapine and MAO inhibitors is contraindicated by the manufacturers of tricyclic antidepressants, cyclobenzaprine, mirtazapine, and tranylcypromine.(1,3-10) The manufacturers of tricyclic antidepressants, cyclobenzaprine and mirtazapine recommend at least 14 days between switching therapies.(1,3-9) The manufacturer of tranylcypromine recommends a medication-free interval of at least a week when initiating tranylcypromine in patients who have previously received a tricyclic antidepressant, then initiating tranylcypromine at a reduced dosage of 50% for one week.(10) The US manufacturer of phenelzine states that at least 14 days should elapse between the discontinuation of phenelzine and the initiation of another antidepressant. If phenelzine is used concurrently with or within 10 days of another antidepressant, the patient should be cautioned regarding the possibility of an adverse drug interaction.(8) The US manufacturer of selegiline states that at least 14 days should elapse between the discontinuation of selegiline and the initiation of a tricyclic antidepressant.(9) In emergency situations in patients maintained on tricyclics or tetracyclics, weigh the availability and safety of alternatives to methylene blue against the risk of serotonin syndrome. If methylene blue therapy is required, the patient's tricyclic, cyclobenzaprine or tetracyclic should be immediately discontinued. Patients should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first.(12) In non-emergency situations in patients maintained on tricyclics, cyclobenzaprine or tetracyclics when methylene blue therapy is planned, discontinue the patient's tricyclic or tetracyclic at least 2 weeks in advance of methylene blue therapy. The patient's tricyclic or tetracyclic therapy may be resumed 24 hours after the last dose of linezolid or methylene blue.(12) Do not initiate tricyclic, cyclobenzaprine or tetracyclic therapy in patients receiving methylene blue until 24 hours after the last dose of these agents.(12) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: It should be noted that if this interaction occurs, the consequences will be immediate and severe. Effects may continue to be seen for several days after discontinuing the MAOI. The interaction has been reported with tricyclic antidepressants and selegiline.(9) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(14,15) Metaxalone is a weak inhibitor of MAO.(34,35) The FDA AERS contains reports of serotonin syndrome with concurrent injectable methylene blue and citalopram, clomipramine, escitalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. The risk of serotonin syndrome with other psychiatric drugs is unclear.(13) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 123

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Agents That May Cause Respiratory Depression/Sodium Oxybate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3)

CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for profound sedation, respiratory depression, coma, and/or death.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3)

PATIENT MANAGEMENT: Avoid use of concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

Anticholinergics/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine has potent anticholinergic properties and inhibits serotonin receptors, including 5-HT3.(1-4) Both of these properties may cause inhibition of gastrointestinal (GI) smooth muscle contraction, resulting in decreased peristalsis.(3,4) These effects may be compounded by concurrent use of anticholinergic agents.(1-6)

CLINICAL EFFECTS: Concurrent use of clozapine with other anticholinergic agents may increase the risk of constipation (common) and serious bowel complications (uncommon), including complete bowel obstruction, fecal impaction, paralytic ileus and intestinal ischemia or infarction.(1-6)

PREDISPOSING FACTORS: The risk for serious bowel complications is higher with increasing age, higher frequency of constipation, and in patients on higher doses of clozapine or multiple anticholinergic agents.(1,5)

PATIENT MANAGEMENT: Avoid the use of other anticholinergic agents with clozapine.(1-6) If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(2) Consider a prophylactic laxative in those with a history of constipation or bowel obstruction.(2) Review patient medication list for other anticholinergic agents. When possible, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly. Counsel the patient about the importance of maintaining adequate hydration. Encourage regular exercise and eating a high-fiber diet.(2)

DISCUSSION: In a prospective cohort study of 26,720 schizophrenic patients in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus was 1.99 with clozapine and 1.48 with anticholinergics. The OR for fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics. Use of anticholinergics with 1st generation antipsychotics (FGA) increased the risk of ileus compare to FGA alone, but this analysis was not done with clozapine.(5) A retrospective cohort study of 24,970 schizophrenic patients from the Taiwanese National Health Insurance Research Database found that the hazard ratio (HR) for clozapine-induced constipation increased from 1.64 when clozapine is used alone, to 2.15 when used concomitantly with anticholinergics. However, there was no significant difference in the HR for ileus when clozapine is used with and without anticholinergics (1.95 and 2.02, respectively).(6) In the French Pharmacovigilance Database, 7 of 38 cases of antipsychotic-associated ischemic colitis or intestinal necrosis involved clozapine, and 5 of these cases involved use of concomitant anticholinergic agents. Three patients died, one of whom was on concomitant anticholinergics.(3) In a case series, 4 of 9 cases of fatal clozapine-associated GI dysfunction involved concurrent anticholinergic agents.(4)

Cyclobenzaprine/Tapentadol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tapentadol and cyclobenzaprine, a tricyclic compound, both may lower the seizure threshold, have additive effects on serotonin levels,(1) and cause additive CNS depression.(3)

CLINICAL EFFECTS: Concurrent use of tapentadol and cyclobenzaprine may result in increased risk of seizures, serotonin syndrome, suicide,(1) profound sedation, respiratory depression, coma, and/or death.(3)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. Risk of seizures may be increased in patients with epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or infections of the central nervous system.(1)

PATIENT MANAGEMENT: Tapentadol should be used with caution in patients taking tricyclic compounds, including cyclobenzaprine. Monitor patients closely for serotonin syndrome.(1) Limit prescribing opioid analgesics with CNS depressants such as cyclobenzaprine to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(3) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(3) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(3) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: Concurrent use of tapentadol with tricyclic compounds may result in additive blockage of serotonin reuptake, leading to central serotonergic hyperstimulation. Cases of serotonin syndrome have been reported with tapentadol in combination with other serotonergic drugs.(1) Use of tapentadol has been associated with increased seizure frequency in patients with seizure disorders.(1) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(6) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9)

Cyclobenzaprine/Tramadol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tramadol and cyclobenzaprine, a tricyclic compound, both may lower the seizure threshold, have additive effects on serotonin levels,(1) and cause additive CNS depression.(3)

CLINICAL EFFECTS: Concurrent use of tramadol and cyclobenzaprine may result in increased risk of seizures, serotonin syndrome, suicide,(1) profound sedation, respiratory depression, coma, and/or death.(3)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. Risk of seizures may be increased in patients with epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or infections of the central nervous system.(1)

PATIENT MANAGEMENT: Tramadol should be used with caution in patients taking tricyclic compounds, including cyclobenzaprine. Monitor patients closely for serotonin syndrome.(1) Limit prescribing opioid analgesics with CNS depressants such as cyclobenzaprine to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(3) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(3) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(3) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: The use of tramadol in patients treated with tricyclic compounds may increase the risk of seizures.(1) A review of 124 reports of seizures following tramadol therapy received by the FDA through July 31, 1996 revealed that 23% of the patients were also taking tricyclic antidepressants.(2) Therefore, the manufacturer of tramadol states that tramadol should be used with caution in patients treated with tricyclic compounds.(1) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(6) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9)

Local Anesthetics/Long-Acting Bupivacaine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of other local anesthetics or use of other local anesthetics within 96 hours following long-acting bupivacaine may result in additive neurologic and cardiovascular effects. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also increase the risk of methemoglobinemia.(1,2) Non-liposomal bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally.(1)

CLINICAL EFFECTS: Concurrent or use of local anesthetics with 96 hours of use of long-acting bupivacaine may result in neurologic and cardiovascular toxicity. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also result in methemoglobinemia.(1,2) Non-liposomal bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally.(1)

PREDISPOSING FACTORS: Use of additional agents that are associated with methemoglobinemia may further increase the risk of methemoglobinemia.(1) Patients who are at increased risk of developing methemoglobinemia include those with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.(1)

PATIENT MANAGEMENT: Avoid the use of other local anesthetics within 96 hours following the administration of long-acting bupivacaine. In patients for whom use is required, monitor for neurologic and cardiovascular effects. Also monitor for methemoglobinemia with use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine.(1,2) Non-liposomal bupivacaine may be administered in the same syringe as bupivacaine liposomal or injected immediately before bupivacaine liposomal as long as the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Lidocaine may be administered 20 minutes or more prior to bupivacaine. It is unknown if other local anesthetics may be used without compromising the release characteristic of bupivacaine liposomal.(1)

DISCUSSION: Concurrent use of other local anesthetics or use of other local anesthetics within 96 hours following long-acting bupivacaine may result in additive neurologic and cardiovascular effects. Use of articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, and tetracaine may also increase the risk of methemoglobinemia.(1,2) Non-liposome bupivacaine may impact the pharmacokinetic and/or physicochemical properties of the liposomal formulation when administered in the same syringe or used simultaneously unless the ratio of mg of non-liposomal bupivacaine to mg of bupivacaine liposomal does not exceed 1:2.(1) Local anesthetics other than bupivacaine may trigger the immediate release of bupivacaine from the liposomal formulation when administered together locally. Lidocaine may be administered 20 minutes or more prior to bupivacaine. It is unknown if other local anesthetics may be used without compromising the release characteristic of bupivacaine liposomal.(1)

Muscle Relaxants/Opioids (COUGH AND COLD)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of opioids and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Avoid prescribing opioid-including cough medications for patients taking CNS depressants such as muscle relaxants.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Selected Muscle Relaxants/Methadone (COUGH AND COLD)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of methadone and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of methadone and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Avoid prescribing methadone-including cough and cold medications for patients taking CNS depressants such as muscle relaxants.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Tricyclic Compounds/Guanethidine; Guanadrel

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Uptake of guanethidine is blocked by tricyclic antidepressants at the adrenergic neuron.

CLINICAL EFFECTS: Concurrent use of tricyclic antidepressants may result in decreased guanethidine or guanadrel effectiveness. The effects may be seen for several days after discontinuation of the tricyclic antidepressant.

PREDISPOSING FACTORS: Possibly concurrent administration of drugs that inhibit hepatic enzymes.

PATIENT MANAGEMENT: Avoid concomitant administration of these drugs. If both drugs are administered, adjust the guanethidine dose as needed based on blood pressure.

DISCUSSION: This interaction is well documented. Similarity between cyclobenzaprine and TCA's warrants consideration of TCA interactions for cyclobenzaprine.

Tricyclic; Tetracyclic Agents; Carbamazepine/Linezolid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Linezolid is a weak, reversible inhibitor of monoamine oxidase.(1) Tricyclic and tetracyclic compounds may sensitize post-synaptic receptors to amines that are accumulating extraneuronally as a result of MAO inhibition.(2) Carbamazepine is structurally related to the tricyclic antidepressants.(3) Similarity between cyclobenzaprine and tricyclics warrants consideration of tricyclic interactions for cyclobenzaprine.(4) Mirtazapine, a tetracyclic antidepressant, should also be considered for this interaction.(5)

CLINICAL EFFECTS: Concurrent use with linezolid may result in a severe reaction including hyperpyrexia, convulsions, excitability, fluctuations in blood pressure, convulsions, grand mal seizures, serotonin syndrome, coma, and death.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(6)

PREDISPOSING FACTORS: High doses of tricyclics or tetracyclics, or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.

PATIENT MANAGEMENT: The manufacturers of the tricyclic antidepressants, carbamazepine, cyclobenzaprine and mirtazapine state that coadministration with MAO inhibitors is contraindicated. Concurrent linezolid is specifically contraindicated by the manufacturers of clomipramine, desipramine, mirtazapine, nortriptyline, and trimipramine.(1,3-5,7-12) The manufacturer of linezolid does not contraindicate the use of serotonergic agents but states that they should not be coadministered unless clinically appropriate and the patient is closely monitored.(1) This recommendation is consistent with the 2011 FDA Drug Safety Communication on linezolid and serotonergic psychiatric medications.(13,14) In non-emergency situations in patients maintained on tricyclics or tetracyclics when linezolid therapy is planned, discontinue the patient's tricyclic or tetracyclic at least 2 weeks in advance of linezolid therapy. In emergency situations in patients maintained on tricyclics or tetracyclics, weigh the availability and safety of alternatives to linezolid against the risk of serotonin syndrome. If linezolid therapy is required, the patient's tricyclic or tetracyclic should be immediately discontinued. Patients should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first. The patient's tricyclic or tetracyclic therapy may be resumed 24 hours after the last dose of linezolid.(13) Clinical studies have found a low incidence of serotonin syndrome in patients on concomitant linezolid and serotonergic agents, ranging from 0.24% to 4%, depending on the quality and size of the study. While linezolid-associated serotonin syndrome is potentially serious and fatal, if treated early, it is quickly reversible with discontinuation of offending agents and supportive care. Therefore, some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(15-20) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: It should be noted that if this interaction occurs, the consequences will be immediate and severe. Effects may continue to be seen for several days after discontinuing linezolid. The FDA FAERS contains reports of serotonin syndrome with the concurrent use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. The risk of serotonin syndrome with other psychiatric drugs is unclear.(14)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Cyclobenzaprine/Meperidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cyclobenzaprine and meperidine may have additive effects on serotonin levels.(1,2)

CLINICAL EFFECTS: Concurrent administration of cyclobenzaprine with meperidine may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: Predisposing factors include elderly, renal or hepatic dysfunction, and use of multiple agents which increase central serotonin levels. Chronic use of cyclobenzaprine or meperidine would also be expected to increase the risk for serotonin toxicity.(1,2)

PATIENT MANAGEMENT: The US manufacturer of cyclobenzaprine recommends limiting use to short term duration, no more than two to three weeks. The US manufacturer of meperidine states that it should not be used for treatment of chronic pain. Use alternative therapy whenever possible, particularly in patients with renal or hepatic impairment.(1,2) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome, and seizure activity. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Case reports documenting serotonin syndrome with cyclobenzaprine and other serotonergic agents are described. The risk of serotonin syndrome with cyclobenzaprine may occur based on serotonin activity of both agents.(3,4) A case report of a 70 year old female on phenelzine (non-selective MAOI) 15 mg four times daily for several years developed serotonin syndrome after the third dose of cyclobenzaprine 10 mg three times daily. After discontinuation of both cyclobenzaprine and phenelzine, symptoms resolved within three days. Within the following month, the patient was restarted on phenelzine without any further sequelae.(5) A case report of a 53 year old male on duloxetine (SNRI) 60 mg daily developed symptoms of serotonin syndrome shortly after initiation of cyclobenzaprine 10 mg three times daily. Both cyclobenzaprine and duloxetine were stopped and cyproheptadine was given with resolution of symptoms.(5) A case report of a 27 year old female on escitalopram (SSRI) 10 mg daily presented with serotonin syndrome after an overdose of 5-6 cyclobenzaprine 10 mg tablets. The patient was treated with symptomatic care and cyproheptadine with resolution of symptoms on day two and discharged with instructions to discontinue cyclobenzaprine use.(6) Case reports describe the interaction between meperidine and serotonin-increasing agents.(7-9) Although there are no reports of serotonin syndrome specifically with the combination of cyclobenzaprine and meperidine, both drugs inhibit serotonin reuptake and caution is still warranted.

Cyclobenzaprine/Opioids (EXTENDED RELEASE)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and cyclobenzaprine may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as cyclobenzaprine, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Cyclobenzaprine/Opioids (IMMEDIATE RELEASE)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and cyclobenzaprine may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as cyclobenzaprine, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Cyclobenzaprine/Selected Ssris; Snris

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Selected serotonin or serotonin-norepinephrine reuptake inhibitors (SSRIs or SNRIs) may impair the oxidative hepatic metabolism of cyclobenzaprine. Cyclobenzaprine is metabolized by CYP1A2, CYP3A4, and to a lesser extent CYP2D6.(4) Fluvoxamine is a strong inhibitor of CYP1A2 and a weak inhibitor of CYP3A4 and CYP2D6. Sertraline and venlafaxine are weak inhibitors of CYP2D6. MECHANISM OF ACTION: Cyclobenzaprine and SSRIs or SNRIs may have additive effects on serotonin levels.(1)

CLINICAL EFFECTS: Concurrent administration of selected SSRIs or SNRIs with cyclobenzaprine may result in an increase in serum levels, toxicities, and/or clinical effects of cyclobenzaprine, including serotonin syndrome.(4) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity. CLINICAL EFFECTS: Concurrent administration of cyclobenzaprine with citalopram, duloxetine, escitalopram, levomilnacipran, milnacipran, nefazodone, or vortioxetine may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(5) PREDISPOSING FACTORS: Predisposing factors include elderly, hepatic dysfunction and use of multiple agents which increase central serotonin levels. Chronic use of cyclobenzaprine or high doses of citalopram or escitalopram would also be expected to increase the risk for serotonin toxicity.(1)

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of cyclobenzaprine at the initiation of concurrent therapy with selected SSRIs or SNRIs. Plasma concentrations of cyclobenzaprine should be monitored and the dosage adjusted accordingly. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome, and seizure activity. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. If the SSRI or SNRI is discontinued in a patient receiving cyclobenzaprine, the dosage of the cyclobenzaprine may need to be adjusted. PATIENT MANAGEMENT: The US manufacturer of cyclobenzaprine recommends limiting use to short term duration, no more than two to three weeks. Use alternative therapy whenever possible, particularly in patients with hepatic impairment.(1) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome, and seizure activity. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: There have been case reports of serotonin syndrome with trazodone and amitriptyline with lithium, and cyclobenzaprine with duloxetine.(6) The affinity of the different SSRIs, SNRIs, and tricyclics for CYP P-450 may vary. DISCUSSION: Case reports documenting serotonin syndrome with cyclobenzaprine and other serotonergic agents are described. The risk of serotonin syndrome with cyclobenzaprine and TCAs may also occur based on serotonin activity of both agents.(2,3) A case report of a 70 year old female on phenelzine (non-selective MAOI) 15 mg four times daily for several years developed serotonin syndrome after the third dose of cyclobenzaprine 10 mg three times daily. After discontinuation of both cyclobenzaprine and phenelzine, symptoms resolved within three days. Within the following month, the patient was restarted on phenelzine without any further sequelae.(4) A case report of a 53 year old male on duloxetine (SNRI) 60 mg daily developed symptoms of serotonin syndrome shortly after initiation of cyclobenzaprine 10 mg three times daily. Both cyclobenzaprine and duloxetine were stopped and cyproheptadine was given with resolution of symptoms.(4) A case report of a 27 year old female on escitalopram (SSRI) 10 mg daily presented with serotonin syndrome after an overdose of 5-6 cyclobenzaprine 10 mg tablets. The patient was treated with symptomatic care and cyproheptadine with resolution of symptoms on day two and discharged with instructions to discontinue cyclobenzaprine use.(5)

Cyclobenzaprine/Selected Tricyclic Antidepressants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cyclobenzaprine and selected tricyclic antidepressants (TCAs), including amitriptyline, clomipramine, and imipramine, may act synergistically to increase blood pressure and evoke behavioral excitation.(1)

CLINICAL EFFECTS: Concurrent administration of cyclobenzaprine with amitriptyline, clomipramine, or imipramine may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: Predisposing factors include elderly, hepatic dysfunction and use of multiple agents which increase central serotonin levels. Chronic use of cyclobenzaprine or high doses of TCAs would also be expected to increase the risk for serotonin toxicity.(1)

PATIENT MANAGEMENT: The US manufacturer of cyclobenzaprine recommends limiting use to short term duration, no more than two to three weeks. Use alternative therapy whenever possible, particularly in patients with hepatic impairment.(1) Based on serotonin receptor affinity, clomipramine would be expected to have higher risk of serotonin syndrome than imipramine followed by amitriptyline. Amitriptyline at low doses would be expected to have the lowest risk of serotonin syndrome. Cyclobenzaprine is structurally similar to tricyclic antidepressants (TCAs) and may affect serotonin receptors synergistically.(2,3) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome, and seizure activity. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Case reports documenting serotonin syndrome with cyclobenzaprine and other serotonergic agents are described. The risk of serotonin syndrome with cyclobenzaprine and TCAs may also occur based on serotonin activity of both agents.(2,3) A case report of a 70 year old female on phenelzine (non-selective MAOI) 15 mg four times daily for several years developed serotonin syndrome after the third dose of cyclobenzaprine 10 mg three times daily. After discontinuation of both cyclobenzaprine and phenelzine, symptoms resolved within three days. Within the following month, the patient was restarted on phenelzine without any further sequelae.(4) A case report of a 53 year old male on duloxetine (SNRI) 60 mg daily developed symptoms of serotonin syndrome shortly after initiation of cyclobenzaprine 10 mg three times daily. Both cyclobenzaprine and duloxetine were stopped and cyproheptadine was given with resolution of symptoms.(4) A case report of a 27 year old female on escitalopram (SSRI) 10 mg daily presented with serotonin syndrome after an overdose of 5-6 cyclobenzaprine 10 mg tablets. The patient was treated with symptomatic care and cyproheptadine with resolution of symptoms on day two and discharged with instructions to discontinue cyclobenzaprine use.(5)

Lower Strength Serotonergic Tricyclics/Fluoxetine;Paroxetine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Depending upon the interacting combination, pharmacokinetic and/or pharmacodynamic interactions are possible. Fluoxetine is a moderate inhibitor of CYP2C19 and a strong inhibitor of CYP2D6.(1) Paroxetine is a strong inhibitor of CYP2D6.(1,2) Amitriptyline, clomipramine, and imipramine are metabolized by CYP2C19 and CYP2D6.(1) Cyclobenzaprine is metabolized by CYP1A2 and CYP3A4 and so a pharmacokinetic interaction is not expected.(3) Fluoxetine, paroxetine, clomipramine and imipramine significantly increase neuronal serotonin levels. Amitriptyline increases serotonin at higher dosages.

CLINICAL EFFECTS: Concurrent administration of fluoxetine or paroxetine with tricyclics metabolized by CYP2D6 or CYP2C19 may result in an increase in serum levels, toxicities (e.g. risk for seizures, severe anticholinergic effects), and/or clinical effects of the tricyclic. Concurrent administration of fluoxetine or paroxetine with clomipramine and perhaps with imipramine, cyclobenzaprine, or high dose amitriptyline may increase the risk for serotonin syndrome.

PREDISPOSING FACTORS: Higher doses or higher systemic concentrations of fluoxetine or paroxetine may increase the magnitude of this interaction. The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4,5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4,5) Concurrent use of multiple drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(6) The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(7)

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds when concurrent therapy with fluoxetine or paroxetine is started or if the dosage of either agent is increased. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If the fluoxetine or paroxetine is discontinued in a patient receiving a tricyclic compound other than cyclobenzaprine the dosage may need to be adjusted upward as the effects of enzyme inhibition wane. The effects of fluoxetine on hepatic metabolism may last for 3-5 weeks after fluoxetine discontinuation. A cyclic compound (other than cyclobenzaprine) started after the discontinuation of fluoxetine should be started at a lower initial dosage. Patients receiving fluoxetine or paroxetine and clomipramine, imipramine, higher dose amitriptyline, or cyclobenzaprine should be monitored for serotonin syndrome. Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus. Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus. Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(20) When concurrent therapy may be associated with QT prolongation, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Case reports have shown that the addition of fluoxetine to a tricyclic compound therapy can result in an increase of 100-300% in the tricyclic compound plasma concentration as well as an increase in adverse effects, including seizures and delirium. In a 83 year-old patient, the combination of clomipramine and fluoxetine resulted in high clomipramine concentrations and cardiac side effects. The manufacturer of cyclobenzaprine reports that serotonin syndrome has been reported when combined with other serotonergic agents.(3) QTc prolongation also exists with some antidepressants. In a case report, the combination of levofloxacin, imipramine, and fluoxetine was associated with a QTc of 509msec. The authors concluded that this interaction was due to the pharmacodynamic additive effect among fluoxetine, imipramine, and levofloxacin. Cyclic agents included in this monograph are amitriptyline (<=40mg), clomipramine (<=25mg), cyclobenzaprine (structurally similar to amitriptyline), and imipramine (<=10mg).

Muscle Relaxants/Buprenorphine For Mat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of buprenorphine and muscle relaxants may result in additive CNS depression.(1,2)

CLINICAL EFFECTS: Concurrent use of buprenorphine and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1,2)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing opioid reversal agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(6) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(7) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(8) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(9) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(10) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(11) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2)

Muscle Relaxants/Gabapentinoids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of gabapentinoids and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of gabapentinoids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing muscle relaxants and gabapentinoids to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a gabapentinoid with a muscle relaxant, prescribe a lower initial dose of the gabapentinoid than indicated in the absence of a muscle relaxant and titrate based upon clinical response. If a muscle relaxant is indicated in a patient already taking a gabapentinoid, prescribe a lower dose of the muscle relaxant and titrate based upon clinical response.(1) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1)

DISCUSSION: Clinical trials have shown no pharmacokinetic interaction between pregabalin and muscle relaxants.(2) Among 49 case reports submitted to FDA over a 5 year period (2012-2017), 12 people died from respiratory depression with gabapentinoids. Two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals were reviewed. A trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. Three observational studies showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after surgery. Several animal studies also showed that pregabalin plus opioids can depress respiratory function. Muscle relaxants are expected to have a similar effect when used with gabapentinoids.(1)

Selected Muscle Relaxants/Levomethadyl

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of levomethadyl and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of levomethadyl and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics ho are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Selected Muscle Relaxants/Methadone (IMMEDIATE RELEASE)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of methadone and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of methadone and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing methadone with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Selected Muscle Relaxants/Selected Opioids For Mat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of diacetylmorphine or methadone and muscle relaxants may result in additive CNS depression.(1-3) Levomethadone is an enantiomer of methadone.(4)

CLINICAL EFFECTS: Concurrent use of diacetylmorphine or methadone and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1-3)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Medication assisted treatment (MAT) with diacetylmorphine or methadone is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's diacetylmorphine or methadone treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(5) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(6)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(7) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(8) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(9) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(10) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(11) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(12) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(13) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2)

Serotonergic Agents/Centanafadine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Centanafadine is a norepinephrine, dopamine, and serotonin reuptake inhibitor.(1) Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of centanafadine with other serotonergic agents may increase the risk of serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,2)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: If concurrent use of centanafadine with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue centanafadine and/or the other serotonergic agents immediately and initiate supportive measures.(1)

DISCUSSION: Centanafadine inhibits reuptake of norepinephrine, dopamine, and serotonin.(1)

Tricyclic Compounds/Cimetidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cimetidine inhibits the hepatic metabolism of tricyclic antidepressants.

CLINICAL EFFECTS: The pharmacological and toxic effects of tricyclic antidepressants may be increased.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(9)

PATIENT MANAGEMENT: Observe the patient for an increased or decreased response to tricyclic antidepressant therapy if cimetidine is started or stopped. Adjust the dose of the tricyclic agent accordingly. This interaction can probably be avoided by administration of an H-2 receptor antagonist other than cimetidine (e.g., famotidine, nizatidine, ranitidine).

DISCUSSION: Both controlled studies and case reports have demonstrated that concurrent administration of tricyclic antidepressants and cimetidine can result in an increase in plasma tricyclic antidepressant concentrations. Adverse effects have been reported. Similarity between cyclobenzaprine and TCA's warrants consideration of TCA interactions for cyclobenzaprine.

Tricyclic Compounds/Fosamprenavir; Tipranavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Fosamprenavir and tipranavir may inhibit the metabolism of tricyclic compounds.(1,2)

CLINICAL EFFECTS: Concurrent use of fosamprenavir(1) or tipranavir(2) with tricyclic compounds may result in elevated levels of the tricyclic agents and serious and/or life-threatening effects.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The manufacturer of fosamprenavir(1) recommends caution with concurrent use of these agents with tricyclic compounds, along with concentration monitoring of the tricyclics. The manufacturer of tipranavir recommends dosage reduction and concentration monitoring of desipramine when coadministered with tipranavir/ritonavir.(2)

DISCUSSION: Amprenavir has been shown to be a potent inhibitor of CYP3A4.(1,3) Fosamprenavir is a prodrug of amprenavir.(1) Therefore, the manufacturer of amprenavir(3) and fosamprenavir(1) recommends caution with concurrent use of these agents with tricyclic compounds, along with concentration monitoring of the tricyclic compounds. No interaction studies have been performed on the combination of tipranavir-ritonavir and desipramine. Desipramine is a sensitive substrate of CYP2D6 while tipranavir-ritonavir is a moderate CYP2D6 inhibitor.(5,6) In one clinical study, six subjects were given 50 mg desipramine on three occasions: alone, after a 60 mg dose of fluoxetine (strong CYP2D6 inhibitor), and after eight daily 60 mg doses of fluoxetine. Fluoxetine significantly reduced oral clearance of desipramine by up to 10-fold and prolonged the half-life of desipramine by up to 4-fold.(7)

Tricyclic Compounds/Inhaled Direct-Acting Sympathomimetics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown. However, it is speculated that direct-acting sympathomimetic amines have an enhanced effect due to tricyclic blockage of norepinephrine reuptake.

CLINICAL EFFECTS: Increased effect of direct acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of inhaled sympathomimetics and tricyclic compounds or the use of these agents within 14 days of each other should be approached with extreme caution.

DISCUSSION: Epinephrine and other direct-acting sympathomimetic amines exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and tachycardia) in individuals concurrently receiving or previously treated with tricyclic antidepressants. Protriptyline, amitriptyline, and desipramine have also been reported to interact with direct-acting sympathomimetics. Similarity between cyclobenzaprine and the tricyclic antidepressants consideration of tricyclic antidepressant interactions for cyclobenzaprine.

Tricyclic Compounds/Inhaled Indirect-Acting Sympathomimetics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown. However, it is speculated that indirect-acting sympathomimetics would have decreased activity due to tricyclic blockage of their uptake into the adrenergic neuron.

CLINICAL EFFECTS: Decreased effect of indirect acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of inhaled sympathomimetics and tricyclic compounds or the use of these agents within 14 days of each other should be approached with extreme caution.

DISCUSSION: Epinephrine and other direct-acting sympathomimetic amines exert enhanced cardiovascular effects (e.g., arrhythmias, hypertension, and tachycardia) in individuals concurrently receiving or previously treated with tricyclic antidepressants. Similarity between cyclobenzaprine and the tricyclic antidepressants warrants consideration of tricyclic antidepressant interactions for cyclobenzaprine.

Tricyclic Compounds/Inhaled Mixed-Acting Sympathomimetics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown. However, it is speculated that indirect-acting sympathomimetics would have decreased activity due to tricyclic blockage of their uptake into the adrenergic neuron.

CLINICAL EFFECTS: Decreased effect of indirect acting sympathomimetics.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of inhaled sympathomimetics and tricyclic compounds or the use of these agents within 14 days of each other should be approached with extreme caution.

DISCUSSION: Mixed acting sympathomimetic amines have also been reported to interact with tricyclic antidepressants. These include norepinephrine, phenylephrine, dopamine, and methoxamine. Similarity between cyclobenzaprine and the tricyclic antidepressants consideration of tricyclic antidepressant interactions for cyclobenzaprine.

Tricyclic Compounds/Terbinafine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Terbinafine may inhibit the metabolism of tricyclic compounds by CYP2D6.(1-5)

CLINICAL EFFECTS: Concurrent use of terbinafine may result in elevated levels of and toxicity from the tricyclic agent.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(6)

PATIENT MANAGEMENT: Monitor tricyclic levels in patients receiving concurrent therapy with terbinafine. The dose of the tricyclic agent may need to be adjusted if terbinafine is initiated or discontinued. The effect of terbinafine on tricyclics may last for up to four weeks after terbinafine discontinuation.

DISCUSSION: In a study in 12 healthy subjects, a single dose of desipramine (50 mg) was given alone, after 21 days of terbinafine (250 mg daily), and 2 and 4 weeks after discontinuation of terbinafine. Administration after 21 days of terbinafine therapy increased the area-under-curve (AUC) and maximum concentration (Cmax) of desipramine by 5-fold and 2-fold, respectively. The AUC and Cmax of desipramine were still elevated when desipramine was administered 4 weeks after the completion of terbinafine therapy.(1,2) There are case reports of toxicity during concurrent terbinafine and desipramine,(3) imipramine,(4) and nortriptyline.(5,7-8) In the UK manufacturer states that terbinafine decreased the clearance of desipramine by 82%.(9)

Tricyclic Compounds; Mirtazapine/Clonidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Clonidine decreases blood pressure via alpha-2 agonism.(1) Tricyclic compounds(2) and mirtazapine(3) antagonize alpha-2, which may result in a loss of effect of clonidine.

CLINICAL EFFECTS: The concurrent use of clonidine and tricyclic compounds(1,3,4-16) and mirtazapine(3,17) may result in decreased effectiveness of clonidine and hypertensive crisis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent use of clonidine with tricyclic compounds or mirtazapine. Consider using an alternative agent in patients maintained on clonidine. If concurrent administration is warranted, blood pressure should be carefully monitored, particularly in the first two weeks of therapy, when this interaction is most likely to occur. The dosage of clonidine may need to be adjusted or the tricyclic compound or mirtazapine may need to be discontinued.

DISCUSSION: This interaction has been reported in patients receiving amitriptyline,(6) clomipramine,(7,8) desipramine,(2,9-11) imipramine(12-16), and protriptyline.(11) In one patient, a hypertensive crisis resulted. Other patients experienced a decrease in blood pressure control. A controlled trial demonstrated a decrease in anti-hypertensive effect when desipramine was added to a clonidine regimen. This decrease in hypertensive-control may be overcome by increasing the dose of clonidine and monitoring blood pressure closely. Cyclobenzaprine is structurally related to the tricyclic antidepressants and, especially at higher dosages, has similar effects.(18) Therefore, it is prudent to consider cyclobenzaprine in this interaction. Hypertensive crisis has been reported during concurrent clonidine and mirtazapine therapy.(3,17) Mianserin(19,20) and maprotiline,(21) tetracyclic antidepressants, have been shown not to affect the antihypertensive effects of clonidine.

Tricyclic Compounds; Mirtazapine/Moxonidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moxonidine decreases blood pressure via imidazoline-1 and alpha-2 receptor agonism.(1) Tricyclic compounds(2) and mirtazapine(3) antagonize alpha-2, which may result in a loss of effect of moxonidine.

CLINICAL EFFECTS: The concurrent use of moxonidine and tricyclic compounds and mirtazapine may result in decreased effectiveness of moxonidine and decreased blood pressure control.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of moxonidine with tricyclic compounds or mirtazapine is not recommended.(1) Consider using an alternative agent in patients maintained on moxonidine. If concurrent administration is necessary, blood pressure should be carefully monitored. The dosage of moxonidine may need to be adjusted or the tricyclic compound or mirtazapine may need to be discontinued.

DISCUSSION: Moxonidine is an imidazoline-1 and alpha-2 receptor agonist.(1) Since tricyclic antidepressants and mirtazapine may reduce the effectiveness of centrally acting antihypertensive agents, the concurrent use of moxonidine is not recommended. No studies have evaluated the current use of moxonidine with tricyclic antidepressants or mirtazapine. Loss of blood pressure control and hypertensive crisis have been reported with clonidine,(4-22) and a similar interaction may occur with moxonidine. The sedative effect of tricyclic antidepressants can be potentiated by moxonidine.

There is no enhanced messaging for this drug.

• 30 day risk period post-myocardial infarction
• Cardiac arrhythmia
• Chronic heart failure
• Heart block
• Hyperthyroidism
• Large open wound
• Methemoglobinemia
• Serotonin syndrome

• Atrial fibrillation
• Bradycardia
• Butyrylcholinesterase deficiency
• Disease of liver
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• Heart block
• Hemolytic anemia from pyruvate kinase and g6PD deficiencies
• Myasthenia gravis
• Sepsis
• Shock
• Structural disorder of heart

• Disease of liver
• Glaucoma
• Hypotension
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Open angle glaucoma
• Respiratory depression
• Seizure disorder
• Urinary retention

There is no enhanced messaging for this drug.

Less Frequent

• Dermatitis due to topical drug

Rare or Very Rare

• Abnormal electroencephalogram
• Abnormal hepatic function tests
• Acute cognitive impairment
• Acute myocardial infarction
• Acute respiratory failure
• Anaphylaxis
• Anaphylaxis
• Angioedema
• Angioedema
• Ataxia
• Bradycardia
• Bronchospastic pulmonary disease
• Bronchospastic pulmonary disease
• Cardiac arrhythmia
• Cardiac arrhythmia
• Cerebrovascular accident
• Cholestasis
• CNS toxicity
• CNS toxicity
• Cyanosis
• Depression
• DRESS syndrome
• Drug-induced psychosis
• Dyspnea
• Extrapyramidal disease
• Eyelid edema
• Hallucinations
• Headache disorder
• Heart block
• Hepatitis
• Hypertension
• Hypotension
• Jaundice
• Methemoglobinemia
• Neuroleptic malignant syndrome
• Paranoid disorder
• Pruritus of skin
• Respiratory depression
• Seizure disorder
• Seizure disorder
• Serotonin syndrome
• SIADH syndrome
• Syncope
• Tachycardia
• Unconsciousness
• Urinary retention
• Urticaria

More Frequent

• Dizziness
• Drowsy
• Dyspepsia
• Fatigue
• Nausea
• Xerostomia

Less Frequent

• Blanching of skin
• Blurred vision
• Dysgeusia
• Edema
• Erythema
• Headache disorder
• Pruritus of skin
• Skin rash
• Stinging of skin
• Urticaria

Rare or Very Rare

• Accidental fall
• Acne vulgaris
• Acute abdominal pain
• Acute cognitive impairment
• Agitation
• Allergic dermatitis
• Anorexia
• Anticholinergic toxicity
• Apprehension
• Bell's palsy
• Blurred vision
• Chest pain
• Constipation
• Diarrhea
• Disturbance of attention
• Dizziness
• Drowsy
• Dysarthria
• Dysuria
• Edema
• Euphoria
• Flatulence
• Galactorrhea not associated with childbirth
• Gastrointestinal irritation
• Gynecomastia
• Hyperhidrosis
• Hypotension
• Increased urinary frequency
• Insomnia
• Libido changes
• Loss of taste
• Malaise
• Muscle fasciculation
• Muscle fasciculation
• Muscle weakness
• Nervousness
• Nervousness
• Palpitations
• Paresthesia
• Parotitis
• Sensation of cold
• Sensation of warmth
• Skin rash
• Tinnitus
• Tinnitus
• Tremor
• Tremor
• Vasodilation of blood vessels
• Vertigo
• Vomiting
• Vomiting

No enhanced messaging available.

No enhanced messaging available.

Reproduction studies in animals using cyclobenzaprine doses up to 20 times the human dose have not revealed evidence of harm to the fetus. There are no adequate and controlled studies to date using cyclobenzaprine in pregnant women, and the drug should be used during pregnancy only when clearly needed.

It is not known whether cyclobenzaprine is distributed into milk; however, the drug is distributed into milk in rats. Because some related tricyclic antidepressants are distributed into milk, cyclobenzaprine should be used with caution in nursing women.

No enhanced messaging available.