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  • CLASSES

    Tricyclic and other cyclic Antidepressants

    BOXED WARNING

    Children, suicidal ideation

    Safety and effectiveness have been established for use of clomipramine in adolescents and children 10 to 17 years old for the treatment of obsessive compulsive disorder (OCD). Greater than 150 adolescent patients have received clomipramine in open-label trials of OCD for periods of several months to several years. There is limited data on the use of clomipramine in children for other indications. Clomipramine is not FDA-approved for the treatment of depression in pediatric patients. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment of SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or at the time of dose increase or decrease; such observation would generally include at least weekly face-to-face contact with patients during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as indicated beyond 12 weeks; additional contact by telephone may be appropriate between visits. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary psychiatric disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with clomipramine. In patients who exhibit changes in symptoms, worsening of depression or emergent suicidality, a decision should be made to change or discontinue treatment. If discontinuing, medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. A major depressive episode may be the initial presentation of bipolar disorder. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. While side effects observed in children with OCD are similar to those observed in adults, data are derived from relatively short term studies and from extrapolation of experience in adult patients. No studies have evaluated the effect of clomipramine on the growth, development, and maturation of children long-term. Although there is no evidence to suggest that clomipramine adversely affects these parameters, the absence of such findings is not adequate to rule out a potential for such effects during chronic use. Clomipramine should be used with caution in children and adolescents with a known family history of heart disease, or in those who are taking other medications concomitantly that might cause drug interactions. QTc interval prolongation, tachycardias, and other side effects have been reported in children who have taken TCAs; there are rare reports of deaths due to cardiovascular side effects. Routine cardiovascular monitoring has been suggested for children receiving tricyclic antidepressants due to the potential of these agents to produce adverse cardiac effects.

    DEA CLASS

    Rx

    DESCRIPTION

    Tricyclic antidepressant with significant serotonin reuptake inhibitor activity; anticholinergic and orthostatic effects
    Used primarily for obsessive-compulsive disorder (OCD) in adults and pediatric patients 10 years and older
    Boxed warning for use in pediatric patients and young adults due to risk for suicidality

    COMMON BRAND NAMES

    Anafranil

    HOW SUPPLIED

    Anafranil/Clomipramine/Clomipramine Hydrochloride Oral Cap: 25mg, 50mg, 75mg

    DOSAGE & INDICATIONS

    For treatment of obsessive-compulsive disorder (OCD).
    Oral dosage
    Adults

    Initially, 25 mg PO once daily, may gradually increase in the first 2 weeks to 100 mg/day PO, given in divided doses. During initial titration, daily dose should be given in divided doses with meals to reduce gastrointestinal side effects. Max: 250 mg/day. After titration, the total daily dose may be given every night at bedtime to minimize daytime sedation.

    Children and Adolescents 10 years and older

    Initially, 25 mg PO once daily, gradually increasing up to a total of 100 mg/day PO given in divided doses; or 3 mg/kg/day given in divided doses, whichever is the smaller, over the first 2 weeks. These initial doses should be divided and taken with meals to reduce gastrointestinal side effects. After the initial titration, the dosage may be increased further gradually over the next several weeks up to a daily maximum of 3 mg/kg/day or 200 mg/day, whichever is smaller. After titration, the total daily dose may be given every night at bedtime to minimize daytime sedation. In clinical trials in pediatric patients for OCD, the average effective dose range was 100 to 200 mg/day.

    For the treatment of behavioral symptoms associated with autistic disorder†.
    Oral dosage
    Adults

    Initially, 25 mg PO once daily. Increase if needed to 75 to 100 mg/day PO. Further titrate gradually if necessary. Max: 250 mg/day PO.

    Children and Adolescents

    Initially, 25 mg PO once daily. May increase gradually to 200 mg/day PO or to 3 mg/kg/day PO, whichever is less.

    For the treatment of premature ejaculation†.
    Oral dosage
    Adult males

    25 to 50 mg/day PO has been shown to increase ejaculatory latency and other measures of premature ejaculation (PE) and is suggested per treatment guidelines; beneficial effects as well as adverse event rates appear to be dose-related. In one study, men with baseline mean ejaculatory latency of 81 seconds were randomized to receive 25 mg/day of clomipramine, 50 mg/day of clomipramine, or placebo. Clomipramine therapy was associated with marked improvement: 25 mg/day of clomipramine increased ejaculatory latency to 202 seconds and 50 mg/day of clomipramine to 419 seconds.
    Alternatively, 25 mg PO given 4 to 24 hours pre-intercourse has demonstrated efficacy and is suggested per treatment guidelines. It is unclear if daily or situational dosing is more effective in the management of PE. Likewise, the optimal interval for situational dosing before intercourse is not well defined. The choice of regimen is ultimately defined by clinical judgement and patient preference in light of the frequency of sexual activity.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    250 mg/day PO.

    Elderly

    250 mg/day PO.

    Adolescents

    3 mg/kg/day PO or 200 mg/day PO, whichever is smaller.

    Children

    >= 10 years: 3 mg/kg/day PO or 200 mg/day PO, whichever is smaller.
    < 10 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; but dosage adjustments may be necessary. In dosing clomipramine in patients with liver disease, use caution by using the lower initial doses and titrating slowly to patient clinical response and tolerance.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed for patients with mild or moderate impairment. The manufacturer recommends that clomipramine be used with caution in patients with severe renal impairment or renal failure as the effects of renal impairment on the disposition of clomipramine or its metabolites have not been determined.

    ADMINISTRATION

    Oral Administration

    During initiation and titration of dosage, administer with meals to reduce gastrointestinal adverse effects. Once a satisfactory daily dosage has been established the total dosage may be given at bedtime to minimize daytime sedation.

    STORAGE

    Anafranil:
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Carbamazepine hypersensitivity, serious rash, tricyclic antidepressant hypersensitivity

    Clomipramine is contraindicated in patients with a hypersensitivity to clomipramine or with a tricyclic antidepressant hypersensitivity. Alternative therapy should be considered in patients with tricyclic antidepressant hypersensitivity. Rare cases of drug rash with eosinophilia and systemic symptoms (DRESS) have been reported with the use of clomipramine. In the event of serious rash or severe acute reactions such as DRESS, discontinue clomipramine therapy immediately and institute appropriate treatment. Tricyclic antidepressants may also display cross-sensitivity in patients with a carbamazepine hypersensitivity. The potential for cross-reactivity between tricyclics and other structurally similar compounds such as cyclobenzaprine or tetracyclic antidepressants (e.g., maprotiline, amoxapine) has not been established.

    MAOI therapy

    The use of monoamine oxidase inhibitor therapy (MAOI therapy intended to treat psychiatric disorders) with clomipramine or within 14 days of stopping treatment with clomipramine is contraindicated because of an increased risk of serotonin syndrome. The use of clomipramine within 14 days of discontinuing MAOI therapy is also contraindicated. Starting clomipramine in a patient who is being treated with linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.

    Acute myocardial infarction, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, long QT syndrome, myocardial infarction, orthostatic hypotension, QT prolongation, tachycardia

    Clomipramine is contraindicated in patients who are in the acute recovery phase following acute myocardial infarction; use of clomipramine could cause sudden death. Clomipramine may cause orthostatic hypotension, particularly in the initial dosing titration. Modest orthostatic decreases in blood pressure and modest tachycardia were each seen in approximately 20% of patients taking clomipramine in clinical trials; but patients were frequently asymptomatic. Use tricyclic antidepressants (TCAs) with caution and with close monitoring in patients with any cardiac disease (e.g., heart failure, history of myocardial infarction, congenital heart disease). TCAs, including clomipramine, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time. Myocardial infarction and stroke have been reported with drugs of this class. Although the risk of cardiovascular adverse events is higher after acute overdose, patients with cardiovascular disease should be closely monitored via ECGs and clinical exams. TCAs should not be given to patients with QT prolongation. Clomipramine is a drug with a possible risk for prolonging the QT interval. Use clomipramine with caution in patients with conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. There have been reports of sudden death in pediatric patients treated with TCAs that were not associated with overdoses. Although cardiac monitoring is recommended, it is unclear whether monitoring can prevent a sudden death event. The American Heart Association recommends conducting a detailed patient and family history and physical examination prior to initiating ADHD pharmacologic treatment, and obtaining a baseline ECG is a reasonable addition to the initial evaluation. Once the medication is started, a repeat ECG may be helpful if the original ECG was obtained before the child was 12 years old, if cardiac symptoms develop, or there is a change in family history. If a child or adolescent has any significant findings on physical examination, ECG, or family history, a pediatric cardiologist should be consulted before the medication is initiated.

    Children, suicidal ideation

    Safety and effectiveness have been established for use of clomipramine in adolescents and children 10 to 17 years old for the treatment of obsessive compulsive disorder (OCD). Greater than 150 adolescent patients have received clomipramine in open-label trials of OCD for periods of several months to several years. There is limited data on the use of clomipramine in children for other indications. Clomipramine is not FDA-approved for the treatment of depression in pediatric patients. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment of SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or at the time of dose increase or decrease; such observation would generally include at least weekly face-to-face contact with patients during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as indicated beyond 12 weeks; additional contact by telephone may be appropriate between visits. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary psychiatric disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with clomipramine. In patients who exhibit changes in symptoms, worsening of depression or emergent suicidality, a decision should be made to change or discontinue treatment. If discontinuing, medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. A major depressive episode may be the initial presentation of bipolar disorder. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. While side effects observed in children with OCD are similar to those observed in adults, data are derived from relatively short term studies and from extrapolation of experience in adult patients. No studies have evaluated the effect of clomipramine on the growth, development, and maturation of children long-term. Although there is no evidence to suggest that clomipramine adversely affects these parameters, the absence of such findings is not adequate to rule out a potential for such effects during chronic use. Clomipramine should be used with caution in children and adolescents with a known family history of heart disease, or in those who are taking other medications concomitantly that might cause drug interactions. QTc interval prolongation, tachycardias, and other side effects have been reported in children who have taken TCAs; there are rare reports of deaths due to cardiovascular side effects. Routine cardiovascular monitoring has been suggested for children receiving tricyclic antidepressants due to the potential of these agents to produce adverse cardiac effects.

    Bipolar disorder, mania, schizophrenia

    All effective antidepressants can transform depression into mania or hypomania in predisposed individuals. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. If a patient develops manic symptoms, clomipramine should be withheld and appropriate therapy initiated to treat the manic symptoms. Additionally, depression may be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes. Clomipramine may precipitate an acute psychotic episode in patients with unrecognized schizophrenia. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of unusual changes in behavior or suicidality. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. It should be noted that clomipramine is not approved for use in treating bipolar depression.

    Alcoholism, coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion

    Clomipramine can induce significant sedation, particularly during the initiation of treatment. Clomipramine may enhance the response to alcohol, the effects of barbiturates, and increase sedation or central nervous system (CNS) effects during coadministration with other CNS depressants. Patients should use caution with ethanol ingestion. In patients who may use alcohol excessively (e.g., alcoholism), the potentiation of CNS effects may increase the danger inherent in any suicide attempt or overdosage. Patients should use caution when driving or operating machinery until they are aware of the effects of the medication.

    Electroconvulsive therapy (ECT), seizure disorder, seizures

    Clomipramine should be used with caution in patients with a preexisting seizure disorder because tricyclic antidepressants (TCAs) can lower the seizure threshold. If seizures occur during TCA therapy, the TCA should be discontinued. Concurrent administration of clomipramine and electroconvulsive therapy (ECT) may increase the hazards associated with such therapy. Such treatment should be limited to patients for whom it is essential.

    Hepatic disease, poor metabolizers

    Tricyclic antidepressants (TCAs) such as clomipramine should be used with caution in patients with hepatic disease and periodic monitoring of hepatic enzyme levels is recommended in such patients. The effects of hepatic impairment on the disposition of clomipramine have not been determined. Poor metabolizers of CYP2D6 have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses; use with caution in patients who are CYP2D6 PMs. During premarketing testing, clomipramine was occasionally associated with elevations of liver enzymes (SGOT and SGPT) of potential clinical importance (i.e., values greater than 3 times the upper limit of normal). In the vast majority of instances, these enzyme increases were not associated with other clinical findings suggestive of hepatic injury; moreover, none were jaundiced. Rare reports of more severe liver injury, some fatal, have been recorded in foreign postmarketing experience.

    Surgery

    Prior to elective surgery with general anesthetics, therapy with clomipramine should be discontinued for as long as is clinically feasible, and the anesthetist should be advised.

    Anticholinergic medications, ileus, prostatic hypertrophy, urinary retention

    The anticholinergic effects of tricyclic antidepressants (TCAs) limit the use of the drugs in certain patients. The anticholinergic effects of clomipramine may be additive with other anticholinergic medications. These actions can decrease GI motility, causing constipation and in some cases, paralytic ileus. Patients who have risk factors for urinary retention, such as those with benign prostatic hypertrophy, should also be treated with caution. Anticholinergic effects appear most frequently and cause the greatest morbidity in elderly patients.

    Closed-angle glaucoma, increased intraocular pressure

    Caution is recommended when prescribing clomipramine to patients with controlled closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

    Contact lenses

    The anticholinergic effects of clomipramine may increase lens discomfort for wearers of contact lenses. Mydriasis, disturbance of accommodation, and dry eyes may contribute to blurred vision and lens intolerance. The use of lubricating drops may be necessary.

    Agranulocytosis, leukopenia

    Although no instances of severe hematologic toxicity were seen in the premarketing experience with clomipramine, there have been postmarketing reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in association with clomipramine use. As is the case with other tricyclic antidepressants, leukocyte and differential blood counts should be obtained in patients who develop fever and sore throat during treatment.

    Hyperthyroidism, hypothyroidism, thyroid disease

    Tricyclic antidepressants (TCAs) like clomipramine should be used with caution in patients who have thyroid disease. Close supervision is required when clomipramine is given to patients with hyperthyroidism or those patients with hypothyroidism who are receiving thyroid medication.

    Diabetes mellitus, pheochromocytoma

    Tricyclic antidepressants (TCAs) affect blood glucose concentrations because of their effect on the endocrine system; both elevation and lowering of blood sugar levels have been reported. Therefore, clomipramine should be used with caution in patients with diabetes mellitus. TCAs should also be used with caution in patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma) in whom these drugs may provoke hypertensive crises.

    Radiographic contrast administration

    Similar to other tricyclic antidepressants (TCAs), clomipramine lowers the seizure threshold. Because of a potential increased risk of seizures, TCAs should not be used during intrathecal radiographic contrast administration. Tricyclic antidepressant therapy should be discontinued 48 hours before and not restarted for at least 24 hours after myelography.

    Sunlight (UV) exposure

    Patients may be more prone to sunburn during therapy with clomipramine. Patients should avoid excessive exposure to sunlight since there have been reports of photosensitization during the use of tricyclic antidepressants (TCAs). Suitable precautions should be taken to limit effects prior to sunlight (UV) exposure, such as wearing long-sleeved clothing and a hat, and using sunscreens.

    Renal failure, renal impairment

    The manufacturer recommends that clomipramine be used with caution in patients with severe renal impairment or renal failure; the effects of renal impairment on the disposition of clomipramine have not been determined.

    Abrupt discontinuation

    Following prolonged therapy, abrupt discontinuation of a tricyclic antidepressant (TCA) should be avoided because it could precipitate a drug discontinuation syndrome. Symptoms of cholinergic rebound such as nausea, vomiting, or diarrhea may occur. Other typical symptoms of antidepressant discontinuation syndrome include flu-like symptoms, insomnia, imbalance, sensory disturbances, and hyperarousal. A variety of withdrawal symptoms have been reported in association with abrupt discontinuation of clomipramine, including dizziness, nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia, and irritability. In addition, such patients may experience a worsening of psychiatric status. While the withdrawal effects have not been systematically evaluated in controlled trials, they are well known with TCAs, and it is recommended that the dosage be tapered gradually and the patient monitored carefully during discontinuation.

    Geriatric

    As with all tricyclic antidepressants (TCAs), use of clomipramine should be cautious in geriatric patients. Starting at the low end of the dosage range is recommended, with slow dosage titration and careful observation. Geriatric patients are particularly sensitive to the peripheral and central anticholinergic side effects and may be at increased risk for falls. According to the Beers Criteria, tricyclic antidepressants (TCAs) such as clomipramine are considered potentially inappropriate medications (PIMs) for use in geriatric patients and should be avoided in this population due to the potential for orthostatic hypotension, anticholinergic effects or toxicity (e.g., constipation, urinary difficulties, blurred vision, delirium), and sedation. In addition, the Beers expert panel recommends avoiding clomipramine in geriatric patients with the following disease states or symptoms due to the potential for exacerbation of the condition or increased risk of adverse effects: syncope (increased risk of orthostatic hypotension or bradycardia), dementia/cognitive impairment (drug-induced CNS effects), delirium/high risk of delirium (possible new-onset or worsening delirium), or lower urinary tract symptoms/benign prostatic hyperplasia in men (possible urinary retention or hesitancy). Further, the Beers expert panel recommends avoiding TCAs in elderly patients with a history of falls or fractures, unless safer alternatives are not available, since TCAs can produce ataxia, impaired psychomotor function, syncope, and additional falls. If clomipramine must be used in an elderly patient with a history of falls or fractures, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. Lastly, TCAs can cause or exacerbate hyponatremia and SIADH and the elderly are at increased risk of developing these conditions. Sodium levels should be closely monitored when starting or changing dosages of TCAs in older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities. According to OBRA, the duration of therapy should be in accordance with pertinent literature for the condition being treated, including clinical practice guidelines. TCAs are rarely the medications of choice in the elderly because of strong anticholinergic and sedating properties. However, TCAs may be appropriate in residents being treated for neurogenic pain when the benefits outweigh the risks and safer medications or interventions are either not indicated or have been considered, attempted, and failed. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. Prior to discontinuation, many antidepressants may need a taper to avoid a withdrawal syndrome. Concurrent use of 2 or more antidepressants may increase the risk of side effects; in such cases there should be documentation of expected benefits that outweigh the associated risks and monitoring for any increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.

    Neonates, pregnancy

    There are no adequate or well-controlled studies regarding the use of clomipramine in pregnant women; clomipramine should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Tricyclic antidepressants (TCAs) cross the placenta. Although animal studies have not shown evidence of teratogenicity with clomipramine, the drug may be associated with an increased risk of teratogenicity in humans when used maternally during early pregnancy, primarily related to cardiovascular defects. Neonatal complications after in utero exposure to TCAs including withdrawal symptoms, hypoglycemia, respiratory diagnoses, developmental delays, and jaundice have been reported. Neonatal withdrawal symptoms have included lethargy, cyanosis, tachypnea with respiratory acidosis, jitteriness, tremors, hypertonia, hypotonia, feeding difficulties, and seizures. Neonates exhibiting signs or symptoms of drug toxicity or withdrawal should be carefully monitored. The impact of in utero exposure to antidepressants or antipsychotics compared to no psychotropic exposure was assessed in infants 6 months of age using the Infant Neurological International Battery (INFANIB), a neuromotor exam that tests posture, tone, reflexes, and motor skills, and using a visual habituation paradigm of a neutral female face. The infants exposed to antipsychotics (n = 22) showed significantly lower INFANIB scores than those exposed to an antidepressant (n = 202) or no psychotropic drug (n = 85). There were no significant differences regarding habituation between the medication exposure groups. In a prospective trial evaluating the effects of in utero exposure to tricyclic or tetracyclic antidepressants in infants 15 to 71 months of age compared to similar non-exposed controls, exposure to antidepressants did not adversely affect IQ, language, behavior, or temperament. The effects of clomipramine on labor and obstetric delivery are unknown. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at http://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants.

    Breast-feeding

    Clomipramine is excreted into breast milk, and the manufacturer recommends that a decision be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother. In a small study comparing 10 breast-fed infants exposed to a tricyclic antidepressant through nursing to a similar group of 15 bottle-fed infants, the milk:maternal plasma ratios were 0.4 to 1.2 and 0.4 to 3, respectively. Overall, the daily doses of tricyclics ingested by the breast-fed infants were about 1% of the maternal dose per kg. Detectable amounts of drug were found in the plasma of one of the two infants exposed to clomipramine; however, no developmental delays or other adverse effects were noted in either of the infants. Due to individual variability in response to medications for obsessive-compulsive disorder (OCD), it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. However, because a pooled analysis found that maternal use of sertraline and paroxetine usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred agents when initiating OCD therapy in a breast-feeding mother. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Tobacco smoking

    Tobacco smoking has been shown to increase the clearance of TCAs such as clomipramine, by inducing hepatic microsomal enzymes. Plasma concentrations of clomipramine were significantly lower in smokers than in nonsmokers. The effect of tobacco on hepatic microsomal enzymes is not related to the nicotine component, so sudden smoking cessation may result in a reduced clearance of TCAs and increased TCA effects, despite the initiation of nicotine replacement products.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 7.0-18.0
    bronchospasm / Rapid / 2.0-7.0
    seizures / Delayed / 0-2.1
    suicidal ideation / Delayed / 0.1-1.0
    bradycardia / Rapid / 0.1-1.0
    cardiac arrest / Early / 0.1-1.0
    coma / Early / 0.1-1.0
    hearing loss / Delayed / 0.1-1.0
    peptic ulcer / Delayed / 0.1-1.0
    epididymitis / Delayed / 0.1-1.0
    oliguria / Early / 0.1-1.0
    serotonin syndrome / Delayed / 0-1.0
    ventricular tachycardia / Early / 0-0.1
    atrial flutter / Early / 0-0.1
    AV block / Early / 0-0.1
    myocardial infarction / Delayed / 0-0.1
    heart failure / Delayed / 0-0.1
    torticollis / Delayed / 0-0.1
    night blindness / Delayed / 0-0.1
    keratitis / Delayed / 0-0.1
    GI obstruction / Delayed / 0-0.1
    ileus / Delayed / 0-0.1
    cyanosis / Early / 0-0.1
    laryngospasm / Rapid / 0-0.1
    stroke / Early / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 22.0-47.0
    ejaculation dysfunction / Delayed / 6.0-42.0
    impotence (erectile dysfunction) / Delayed / 0-20.0
    myoclonia / Delayed / 2.0-13.0
    blurred vision / Early / 1.0-10.0
    withdrawal / Early / 1.0-10.0
    memory impairment / Delayed / 7.0-9.0
    chest pain (unspecified) / Early / 4.0-7.0
    urinary retention / Early / 2.0-7.0
    orthostatic hypotension / Delayed / 4.0-6.0
    depression / Delayed / 0-5.0
    hot flashes / Early / 2.0-5.0
    palpitations / Early / 4.0-4.0
    sinus tachycardia / Rapid / 2.0-4.0
    hypertonia / Delayed / 2.0-4.0
    galactorrhea / Delayed / 0-4.0
    confusion / Early / 2.0-3.0
    migraine / Early / 0-3.0
    dysarthria / Delayed / 0-3.0
    elevated hepatic enzymes / Delayed / 1.0-3.0
    paresis / Delayed / 0-2.0
    blepharospasm / Early / 0-2.0
    stomatitis / Delayed / 0-2.0
    dysphagia / Delayed / 0-2.0
    vaginitis / Delayed / 0-2.0
    cystitis / Delayed / 0-2.0
    dyspnea / Early / 0-2.0
    myasthenia / Delayed / 1.0-2.0
    mania / Early / 0.1-1.0
    euphoria / Early / 0.1-1.0
    hallucinations / Early / 0.1-1.0
    hostility / Early / 0.1-1.0
    psychosis / Early / 0.1-1.0
    delirium / Early / 0.1-1.0
    teeth grinding (bruxism) / Delayed / 0.1-1.0
    ataxia / Delayed / 0.1-1.0
    dysphonia / Delayed / 0.1-1.0
    encephalopathy / Delayed / 0.1-1.0
    dyskinesia / Delayed / 0.1-1.0
    hyperacusis / Delayed / 0.1-1.0
    conjunctivitis / Delayed / 0-1.0
    photophobia / Early / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    colitis / Delayed / 0.1-1.0
    hemorrhoids / Delayed / 0.1-1.0
    glossitis / Early / 0.1-1.0
    esophagitis / Delayed / 0-1.0
    psoriasis / Delayed / 0.1-1.0
    atopic dermatitis / Delayed / 0.1-1.0
    vaginal bleeding / Delayed / 0.1-1.0
    hematuria / Delayed / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    lymphadenopathy / Delayed / 0.1-1.0
    hypothyroidism / Delayed / 0.1-1.0
    hyperglycemia / Delayed / 0.1-1.0
    gout / Delayed / 0.1-1.0
    diabetes mellitus / Delayed / 0.1-1.0
    hypokalemia / Delayed / 0.1-1.0
    hypercholesterolemia / Delayed / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    hyperuricemia / Delayed / 0.1-1.0
    hepatitis / Delayed / 0.1-1.0
    impulse control symptoms / Delayed / 0-0.1
    bundle-branch block / Early / 0-0.1
    hyperreflexia / Delayed / 0-0.1
    hyperesthesia / Delayed / 0-0.1
    aphasia / Delayed / 0-0.1
    nystagmus / Delayed / 0-0.1
    dystonic reaction / Delayed / 0-0.1
    choreoathetosis / Delayed / 0-0.1
    exophthalmos / Delayed / 0-0.1
    blepharitis / Early / 0-0.1
    skin ulcer / Delayed / 0-0.1
    cervical dysplasia / Delayed / 0-0.1
    pyuria / Delayed / 0-0.1
    proteinuria / Delayed / 0-0.1
    endometrial hyperplasia / Delayed / 0-0.1
    hemoptysis / Delayed / 0-0.1
    hypoventilation / Rapid / 0-0.1
    myopathy / Delayed / 0-0.1
    hematoma / Early / 0-0.1
    goiter / Delayed / 0-0.1
    glycosuria / Early / 0-0.1
    akathisia / Delayed / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    ST-T wave changes / Rapid / Incidence not known
    PR prolongation / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known
    pseudoparkinsonism / Delayed / Incidence not known
    EEG changes / Delayed / Incidence not known
    cycloplegia / Early / Incidence not known
    erythema / Early / Incidence not known
    testicular swelling / Early / Incidence not known
    anemia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    hyperthermia / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known

    Mild

    xerostomia / Early / 63.0-84.0
    drowsiness / Early / 46.0-54.0
    dizziness / Early / 41.0-54.0
    tremor / Early / 33.0-54.0
    headache / Early / 28.0-52.0
    fatigue / Early / 35.0-39.0
    nausea / Early / 9.0-33.0
    hyperhidrosis / Delayed / 9.0-29.0
    insomnia / Early / 11.0-25.0
    dyspepsia / Early / 13.0-22.0
    anorexia / Delayed / 12.0-22.0
    libido decrease / Delayed / 0-21.0
    weight gain / Delayed / 2.0-18.0
    pharyngitis / Delayed / 0-14.0
    diarrhea / Early / 7.0-13.0
    abdominal pain / Early / 11.0-13.0
    myalgia / Early / 0-13.0
    rhinitis / Early / 7.0-12.0
    appetite stimulation / Delayed / 0-11.0
    anxiety / Delayed / 2.0-9.0
    paresthesias / Delayed / 2.0-9.0
    dysgeusia / Early / 4.0-8.0
    flushing / Rapid / 7.0-8.0
    rash / Early / 4.0-8.0
    vomiting / Early / 7.0-7.0
    tinnitus / Delayed / 4.0-6.0
    flatulence / Early / 0-6.0
    pruritus / Rapid / 2.0-6.0
    increased urinary frequency / Early / 0-6.0
    sinusitis / Delayed / 2.0-6.0
    weight loss / Delayed / 5.0-5.0
    fever / Early / 0-4.0
    agitation / Early / 0-3.0
    yawning / Early / 0-3.0
    purpura / Delayed / 0-3.0
    irritability / Delayed / 2.0-2.0
    syncope / Early / 0-2.0
    mydriasis / Early / 0-2.0
    halitosis / Early / 0-2.0
    breast enlargement / Delayed / 0-2.0
    leukorrhea / Delayed / 0-2.0
    laryngitis / Delayed / 0-2.0
    chills / Rapid / 0-2.0
    asthenia / Delayed / 0-2.0
    paranoia / Early / 0.1-1.0
    hyperkinesis / Delayed / 0.1-1.0
    somnambulism / Early / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    parosmia / Delayed / 0.1-1.0
    ocular pain / Early / 0.1-1.0
    diplopia / Early / 0.1-1.0
    otalgia / Early / 0.1-1.0
    gingivitis / Delayed / 0.1-1.0
    hypersalivation / Early / 0.1-1.0
    gastroesophageal reflux / Delayed / 0.1-1.0
    dental caries / Delayed / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    urticaria / Rapid / 0-1.0
    maculopapular rash / Early / 0.1-1.0
    pallor / Early / 0.1-1.0
    skin discoloration / Delayed / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    perineal pain / Early / 0.1-1.0
    nocturia / Early / 0.1-1.0
    amenorrhea / Delayed / 0-1.0
    polyuria / Early / 0.1-1.0
    mastalgia / Delayed / 0-1.0
    hyperventilation / Early / 0.1-1.0
    hypoesthesia / Delayed / 0-0.1
    hiccups / Early / 0-0.1
    stool discoloration / Delayed / 0-0.1
    cheilitis / Delayed / 0-0.1
    folliculitis / Delayed / 0-0.1
    hypertrichosis / Delayed / 0-0.1
    seborrhea / Delayed / 0-0.1
    gynecomastia / Delayed / 0-0.1
    vertigo / Early / 1.0
    orgasm dysfunction / Delayed / Incidence not known
    malaise / Early / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Abarelix carries an established risk for QT prolongation. In a single, active-controlled, clinical study comparing abarelix to LHRH agonist plus nonsteroidal antiandrogen, periodic ECGs were performed. Both therapies prolonged the mean QTc interval by >10 msec from baseline. Patients with a baseline QTc value greater than 450 milliseconds may not be appropriate candidates for abarelix receipt. Prescribers need to weigh the potential benefits and risks of abarelix use in patients with prolonged QT syndrome or in patients taking other drugs that may prolong the QT interval, including tricyclic antidepressants (TCAs). Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). ECG monitoring is recommended if the drugs must be used together.
    Abiraterone: (Moderate) Monitor for an increase in clomipramine-related adverse reactions if coadministration with abiraterone is necessary; a dose reduction of clomipramine may be necessary. Clomipramine is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor. Patients who are stable on a given dose of clomipramine may become abruptly toxic when given abiraterone is concomitant therapy.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed.
    Acetaminophen; Butalbital: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Acetaminophen; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Dextromethorphan; Doxylamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Avoid use of tricyclic antidepressants with isometheptene, a sympathomimetic amine, whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable. (Major) The CNS depressant effects of dichloralphenazone can be potentiated by tricyclic antidepressants.
    Acetaminophen; Diphenhydramine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Guaifenesin; Phenylephrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Acetaminophen; Pentazocine: (Moderate) Pain medications such as pentazocine should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Propoxyphene: (Moderate) As propoxyphene inhibits CYP2D6, increased effects of tricyclic antidepressants that are CYP2D6 substrates, such as amitriptyline, clomipramine, desipramine, doxepin, imipramine, and nortriptyline, may be seen with concomitant use. Because of additive CNS depression and decreased TCA metabolism, propoxyphene in combination with tricyclic antidepressants is a major cause of drug-related death.
    Acetaminophen; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Acetaminophen; Tramadol: (Major) Concomitant use of tramadol with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of seizures and serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of tramadol with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression, serotonin syndrome, and seizures. Monitor for signs of urinary retention and reduced gastric motility.
    Acetazolamide: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Acetylcholine Chloride: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
    Acrivastine; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Albendazole: (Moderate) Albendazole induces cytochrome P450 1A and although not studied, may induce the metabolism of tricyclic antidepressants. Albendazole may increase the clearance of the tricyclic antidepressants. Conversely, the discontinuation of albendazole therapy may result in a reduced clearance of tricyclic antidepressants, leading to an increase in serum concentrations. The patient's clinical status should be monitored carefully when albendazole is prescribed and on discontinuation of albendazole therapy.
    Alfentanil: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Alfuzosin: (Minor) Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. The manufacturer warns that the QT effect of alfuzosin should be considered prior to administering the drug to patients taking other medications known to prolong the QT interval. Tricyclic antidepressants should be used cautiously and with close monitoring with alfuzosin. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Alosetron: (Moderate) Alosetron, if combined with drugs that possess anticholinergic properties like tricyclic antidepressants, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    Alprazolam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Amantadine: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
    Ambenonium Chloride: (Moderate) The therapeutic benefits of ambenonium may be diminished when co-administered with the antimuscarinics. Drugs known to exhibit anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity include tricyclic antidepressants.
    Amifampridine: (Major) Carefully consider the need for concomitant treatment with tricyclic antidepressants and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Tricyclic antidepressants may increase the risk of seizures.
    Amiodarone: (Major) If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Carefully asses treatmentt risks versus benefits. Amiodarone is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Drugs with a possible risk for QT prolongationthat should be used cautiously with amiodarone include tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations) or in patients with other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of such combined therapies.
    Amitriptyline; Chlordiazepoxide: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Amobarbital: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
    Amoxapine: (Severe) The use of amoxapine with chemically-related cyclic antidepressants like tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects, CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive dry mouth, constipation, drowsiness, bladder difficulties, or changes in heart rate or rhythm might be possible.
    Amoxicillin; Clarithromycin; Lansoprazole: (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) Coadministration may result in increased clomipramine exposure. Omeprazole is a CYP2C19 inhibitor and clomipramine is a CYP2C19 substrate. (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amphetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as amphetamines and tricyclic antidepressants (TCAs). Both TCAs and amphetamines inhibit the reuptake of serotonin and amphetamines also increase central serotonin release. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The MAOI and sympathomimetic activity of amphetamines may also be of concern. Theoretically, the cardiovascular effects of TCAs or amphetamines may be potentiated through the stimulation of norepinephrine release. Although combination therapy with amphetamines and TCAs is used clinically, further study is needed to fully evaluate the severity and frequency of adverse effects that may occur. If serotonin syndrome is suspected, all serotonergic agents should be discontinued and appropriate medical management should be initiated. If the patient experiences changes in heart rate or rhythm, an ECG may be indicated. A dose reduction of one or both agents may be needed if side effects occur.
    Amphetamine; Dextroamphetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as amphetamines and tricyclic antidepressants (TCAs). Both TCAs and amphetamines inhibit the reuptake of serotonin and amphetamines also increase central serotonin release. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The MAOI and sympathomimetic activity of amphetamines may also be of concern. Theoretically, the cardiovascular effects of TCAs or amphetamines may be potentiated through the stimulation of norepinephrine release. Although combination therapy with amphetamines and TCAs is used clinically, further study is needed to fully evaluate the severity and frequency of adverse effects that may occur. If serotonin syndrome is suspected, all serotonergic agents should be discontinued and appropriate medical management should be initiated. If the patient experiences changes in heart rate or rhythm, an ECG may be indicated. A dose reduction of one or both agents may be needed if side effects occur.
    Amphetamines: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as amphetamines and tricyclic antidepressants (TCAs). Both TCAs and amphetamines inhibit the reuptake of serotonin and amphetamines also increase central serotonin release. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The MAOI and sympathomimetic activity of amphetamines may also be of concern. Theoretically, the cardiovascular effects of TCAs or amphetamines may be potentiated through the stimulation of norepinephrine release. Although combination therapy with amphetamines and TCAs is used clinically, further study is needed to fully evaluate the severity and frequency of adverse effects that may occur. If serotonin syndrome is suspected, all serotonergic agents should be discontinued and appropriate medical management should be initiated. If the patient experiences changes in heart rate or rhythm, an ECG may be indicated. A dose reduction of one or both agents may be needed if side effects occur.
    Anagrelide: (Moderate) Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP and should be used cautiously with anagrelide.
    Anticholinergics: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Apomorphine: (Moderate) Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines; however, large increases (> 60 msecs from pre-dose) have occurred. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended. Apomorphine should be used with caution in patients receiving tricyclic antidepressants, which have been associated with QT prolongation, primarily in overdosage or when excessive plasma concentrations are encountered. In addition, apomorphine causes considerable somnolence, and concomitant administration of apomorphine and CNS agents like the tricyclic antidepressants could result in additive CNS effects.
    Apraclonidine: (Moderate) Tricyclic antidepressants have been reported to blunt the hypotensive effects of systemic clonidine; it is not known whether or not the concomitant use of these agents with apraclonidine can reduce the intraocular pressure lowering effect.
    Aprepitant, Fosaprepitant: (Major) Use caution if clomipramine and aprepitant are used concurrently and monitor for an increase in clomipramine-related adverse effects for several days after administration of a multi-day aprepitant regimen. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Clomipramine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer; substitution of fosaprepitant 115 mg IV on day 1 of the 3-day regimen may lessen the inhibitory effects of CYP3A4. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold and 3.3-fold on days 1 and 5, respectively, when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively, when given on days 1, 4, 8, and 15. As a single 40-mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.2-fold; the midazolam AUC increased by 1.5-fold after a single 125-mg dose of oral aprepitant. After single doses of IV fosaprepitant, the midazolam AUC increased by 1.8-fold (150 mg) and 1.6-fold (100 mg); less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Moderate) Combination therapy with aripiprazole and tricyclic antidepressants should be approached with caution and close monitoring. Aripiprazole has a risk for QT prolongation and torsade de pointes, and tricyclics at elevated serum concentrations may produce clinically significant prolongation of the QTc interval. In addition, there is potential for other interactions, such as augmentation of anticholinergic effects.
    Armodafinil: (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as clomipramine during coadministration with armodafinil.
    Arsenic Trioxide: (Minor) If possible, drugs that are known to prolong the QT interval, such as tricyclic antidepressants, should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and the tricyclic antidepressants are substrates of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased tricyclic antidepressant concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval such as tricyclic antidepressants should be avoided. Consider ECG monitoring if tricyclic antidepressants must be used with or after artemether; lumefantrine treatment.
    Articaine; Epinephrine: (Major) Tricyclic antidepressants potentiate the effects of sympathomimetics including epinephrine. Enhanced cardiovascular effects including arrhythmias, severe hypertension, and/or hyperpyrexia are possible with combined use. Concomitant use of epinephrine with these agents should be avoided when possible; use caution when concomitant use cannot be avoided.
    Asenapine: (Moderate) Concurrent use of asenapine and tricyclic antidepressants should be avoided if possible. Asenapine has been associated with a risk for QT prolongation and torsade de pointes, and tricyclics at elevated serum concentrations may produce clinically significant prolongation of the QTc interval. In addition, there is a potential for other interactions, such as augmentation of CNS impairment or orthostatic hypotension. Further, in vitro studies indicate that CYP1A2 and CYP3A4 are involved in the metabolism of asenapine. Inhibitors of these isoenzymes such as imipramine may decrease the elimination of asenapine. During co-administration of a single 75 mg dose of imipramine and a single 5 mg dose of asenapine, the Cmax of asenapine was increased by 17% and the AUC was increased by 10%. No asenapine dose adjustments are required during combined use.
    Aspirin, ASA: (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed. (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed. (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed.
    Aspirin, ASA; Carisoprodol: (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed. (Moderate) Concomitant use of carisoprodol with tricyclic antidepressants can result in additive CNS depression (sedation and dizziness), which can impair the ability to undertake tasks requiring mental alertness.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed. (Moderate) Concomitant use of carisoprodol with tricyclic antidepressants can result in additive CNS depression (sedation and dizziness), which can impair the ability to undertake tasks requiring mental alertness.
    Aspirin, ASA; Dipyridamole: (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed.
    Aspirin, ASA; Omeprazole: (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed. (Minor) Coadministration may result in increased clomipramine exposure. Omeprazole is a CYP2C19 inhibitor and clomipramine is a CYP2C19 substrate.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed.
    Aspirin, ASA; Pravastatin: (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed.
    Atazanavir: (Moderate) According to the manufacturer, concurrent use of tricyclic antidepressants (TCAs) and atazanavir may result in elevated TCA plasma concentration, and could increase the potential for serious adverse effects. If these drugs are administered together, carefully titrate the TCA dose based on a clinical assessment of antidepressant response. Patients on a stable dose of TCA who start treatment with atazanavir should be monitored for TCA-associated anticholinergic effects (e.g., sedation, confusion, constipation). In addition to clinical monitoring, the manufacturer suggests obtaining TCA serum concentrations (where available) as an adjunct to assessing the potential for interactions.
    Atazanavir; Cobicistat: (Moderate) According to the manufacturer, concurrent use of tricyclic antidepressants (TCAs) and atazanavir may result in elevated TCA plasma concentration, and could increase the potential for serious adverse effects. If these drugs are administered together, carefully titrate the TCA dose based on a clinical assessment of antidepressant response. Patients on a stable dose of TCA who start treatment with atazanavir should be monitored for TCA-associated anticholinergic effects (e.g., sedation, confusion, constipation). In addition to clinical monitoring, the manufacturer suggests obtaining TCA serum concentrations (where available) as an adjunct to assessing the potential for interactions. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
    Atomoxetine: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with clomipramine include atomoxetine.
    Atropine: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer of clomipramine, treatment initiation with clomipramine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than clomipramine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving clomipramine and requiring urgent treatment with intravenous methylene blue, clomipramine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Clomipramine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Clomipramine, a tricyclic antidepressant, is the most selective and potent inhibitor of serotonin within its class. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report describes a patient receiving clomipramine who experienced jerky movements in all four limbs, as well as confusion and agitation after intravenous administration of methylene blue, with a return to her pre-operative state by day 4. Although the authors attribute this reaction to methylene blue toxicity, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenousely administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Atropine; Difenoxin: (Moderate) Concurrent administration can potentiate the CNS and respiratory depressant effects of diphenoxylate/difenoxin and the CNS depressant effects of the tricyclic antidepressant (TCA). Both TCAs and diphenoxylate/difenoxin may cause constipation. Use caution during coadministration. Cases of severe GI reactions including toxic megacolon and adynamic ileus have been rarely reported. In some cases, a dosage reduction of diphenoxylate or difenoxin might be needed to manage any noted side effects. (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration can potentiate the CNS and respiratory depressant effects of diphenoxylate/difenoxin and the CNS depressant effects of the tricyclic antidepressant (TCA). Both TCAs and diphenoxylate/difenoxin may cause constipation. Use caution during coadministration. Cases of severe GI reactions including toxic megacolon and adynamic ileus have been rarely reported. In some cases, a dosage reduction of diphenoxylate or difenoxin might be needed to manage any noted side effects. (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Atropine; Edrophonium: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants. (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as edrophonium, due to their anticholinergic activity.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants. (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including tricyclic antidepressants.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including tricyclic antidepressants.
    Azithromycin: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), azithromycin and tricyclic antidepressants (TCAs) should be used together cautiously. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).There have been case reports of QT prolongation and TdP with the use of azithromycin in postmarketing reports. Concurrent use may increase the risk of QT prolongation.
    Baclofen: (Moderate) Concomitant use of baclofen with other CNS depressants, such as tricyclic antidepressants, can result in additive CNS depression. In addition, simultaneous use of baclofen and tricyclic antidepressants may cause muscle hypotonia.
    Barbiturates: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
    Bedaquiline: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with tricyclic antidepressants. Both bedaquiline and tricyclic antidepressants have been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants. (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
    Belladonna; Opium: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Benzodiazepines: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer of clomipramine, treatment initiation with clomipramine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than clomipramine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving clomipramine and requiring urgent treatment with intravenous methylene blue, clomipramine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Clomipramine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Clomipramine, a tricyclic antidepressant, is the most selective and potent inhibitor of serotonin within its class. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report describes a patient receiving clomipramine who experienced jerky movements in all four limbs, as well as confusion and agitation after intravenous administration of methylene blue, with a return to her pre-operative state by day 4. Although the authors attribute this reaction to methylene blue toxicity, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenousely administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Benzphetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as amphetamines and tricyclic antidepressants (TCAs). Both TCAs and amphetamines inhibit the reuptake of serotonin and amphetamines also increase central serotonin release. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The MAOI and sympathomimetic activity of amphetamines may also be of concern. Theoretically, the cardiovascular effects of TCAs or amphetamines may be potentiated through the stimulation of norepinephrine release. Although combination therapy with amphetamines and TCAs is used clinically, further study is needed to fully evaluate the severity and frequency of adverse effects that may occur. If serotonin syndrome is suspected, all serotonergic agents should be discontinued and appropriate medical management should be initiated. If the patient experiences changes in heart rate or rhythm, an ECG may be indicated. A dose reduction of one or both agents may be needed if side effects occur.
    Benztropine: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Bepridil: (Severe) Bepridil is contraindicated for use with other drugs that might prolong the QT interval, as bepridil is associated with an established risk for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Bethanechol: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Coadministration of metronidazole with tricyclic antidepressants (TCAs) may increase the risk for QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering clomipramine with boceprevir due to an increased potential for clomipramine-related adverse events. If clomipramine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of clomipramine. Clomipramine is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated clomipramine plasma concentrations.
    Bretylium: (Severe) The use of bretylium in conjunction with drugs associated with QT prolongation is not advised due to the potential risk for ventricular tachycardia, including torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP have been described with TCA and related compounds, but rarely occur when the drugs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of these antidepressants in combination with other QT-prolonging drugs. Because of the potential for TdP, use of bretylium with TCAs is contraindicated.
    Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including tricyclic antidepressants. Sedation is generally more pronounced with tertiary agents such as amitriptyline, imipramine, doxepin, and clomipramine. Similar precautions apply to combination products such as amitriptyline; chlordiazepoxide.
    Brimonidine: (Moderate) Tricyclic antidepressants have been reported to decrease the antihypertensive effects of systemic clonidine. It is not known whether tricyclic antidepressants will affect the IOP-lowering efficacy of brimonidine eye solution. There are no data concerning the levels of systemic catecholamines after ophthalmic administration of brimonidine; however, monitor patients carefully who are taking brimonidine and tricyclic antidepressants.
    Brimonidine; Brinzolamide: (Moderate) Tricyclic antidepressants have been reported to decrease the antihypertensive effects of systemic clonidine. It is not known whether tricyclic antidepressants will affect the IOP-lowering efficacy of brimonidine eye solution. There are no data concerning the levels of systemic catecholamines after ophthalmic administration of brimonidine; however, monitor patients carefully who are taking brimonidine and tricyclic antidepressants.
    Brimonidine; Timolol: (Moderate) Tricyclic antidepressants have been reported to decrease the antihypertensive effects of systemic clonidine. It is not known whether tricyclic antidepressants will affect the IOP-lowering efficacy of brimonidine eye solution. There are no data concerning the levels of systemic catecholamines after ophthalmic administration of brimonidine; however, monitor patients carefully who are taking brimonidine and tricyclic antidepressants.
    Brivaracetam: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Brompheniramine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Brompheniramine; Carbetapentane; Phenylephrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including tricyclic antidepressants.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Brompheniramine; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Bupivacaine Liposomal: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    Bupivacaine: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient.
    Bupivacaine; Lidocaine: (Major) Coadminister bupivacaine and tricyclic antidepressants together with caution. If epinephrine is added to bupivacaine, severe and prolonged hypertension may occur in a patient taking a TCA. Tricyclic antidepressants can increase the sensitivity to epinephrine by inhibiting epinephrine reuptake or metabolism. If concurrent therapy is necessary, carefully monitor the patient. (Major) If epinephrine is added to lidocaine for the purpose of infiltration and nerve block or spinal anesthesia, receipt of the product to a patient taking tricyclic antidepressants (TCA) may lead to severe, prolonged hypertension. In general, concurrent use of a local anesthetic solution containing epinephrine and a TCA should be avoided. If coadministration is necessary, careful patient monitoring is essential.
    Buprenorphine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of tricyclic antidepressants (TCAs) and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of tricyclic antidepressants (TCAs) and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as TCAs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Lastly, concomitant use of buprenorphine with other CNS depressants, such as TCAs, can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. Consider a dose reduction of one or both drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Bupropion: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Bupropion; Naltrexone: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Buspirone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants (TCAs) with other drugs that have serotonergic properties such as buspirone. Buspirone increases the sensitivity of postsynaptic serotonin receptors and TCAs inhibit the reuptake of serotonin. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Butabarbital: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. In addition, pharmacokinetic interactions may occur. Barbiturates may increase TCA metabolism. Monitor patients during concurrent use.
    Butorphanol: (Moderate) Pain medications such as mixed opiate agonists/antagonists should be combined cautiously with tricyclic antidepressants due to the possibility of additive CNS depression, respiratory depression, hypotension, or decreased intestinal motility. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. If a CNS depressant needs to be used with butorphanol, use the smallest effective dose and the longest dosing frequency of butorphanol.
    Cabergoline: (Minor) The prolactin-lowering effect of cabergoline may be antagonized by medications that increase prolactin levels such as tricyclic antidepressants.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and tricyclic antidepressants. CNS depressants can potentiate the effects of cannabidiol.
    Capsaicin; Metaxalone: (Moderate) Concomitant use of metaxalone with tricyclic antidepressants can result in additive CNS depression.
    Carbamazepine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, carbamazepine may increase tricyclic antidepressant metabolism.
    Carbetapentane; Chlorpheniramine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including tricyclic antidepressants.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including tricyclic antidepressants.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including tricyclic antidepressants.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including tricyclic antidepressants.
    Carbetapentane; Guaifenesin; Phenylephrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including tricyclic antidepressants.
    Carbetapentane; Phenylephrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including tricyclic antidepressants.
    Carbetapentane; Phenylephrine; Pyrilamine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including tricyclic antidepressants.
    Carbetapentane; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including tricyclic antidepressants.
    Carbetapentane; Pyrilamine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including tricyclic antidepressants.
    Carbidopa; Levodopa: (Moderate) Tricyclic antidepressants exhibit antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
    Carbidopa; Levodopa; Entacapone: (Moderate) Catechol-O-methyltransferase (COMT) inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants (TCAs), due to the possibility of additive sedation, dizziness, and other CNS depressive effects. Pharmacokinetic interactions have not been reported. No pharmacokinetic interaction with the tricyclic antidepressant imipramine was shown in a single-dose study with entacapone. Tolcapone did not change the pharmacokinetics of desipramine in a drug interaction study. (Moderate) Tricyclic antidepressants exhibit antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
    Carbinoxamine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Carbinoxamine; Phenylephrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Carbinoxamine; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including tricyclic antidepressants. Sedation is generally more pronounced with tertiary agents such as amitriptyline, imipramine, doxepin, and clomipramine.
    Carisoprodol: (Moderate) Concomitant use of carisoprodol with tricyclic antidepressants can result in additive CNS depression (sedation and dizziness), which can impair the ability to undertake tasks requiring mental alertness.
    Ceritinib: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and clomipramine; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Cetirizine: (Moderate) Cetirizine and levocetirizine are considered low-sedating antihistamines. Additive drowsiness may occur if cetirizine or levocetirizine are administered with other drugs that depress the CNS, including the tricyclic antidepressants (TCAs). Antihistamines and TCAs may also exhibit additive anticholinergic effects, which may commonly result in dry mouth, constipation, and occasionally blurred vision or urinary retention.
    Cetirizine; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Cetirizine and levocetirizine are considered low-sedating antihistamines. Additive drowsiness may occur if cetirizine or levocetirizine are administered with other drugs that depress the CNS, including the tricyclic antidepressants (TCAs). Antihistamines and TCAs may also exhibit additive anticholinergic effects, which may commonly result in dry mouth, constipation, and occasionally blurred vision or urinary retention.
    Cevimeline: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlophedianol; Guaifenesin; Phenylephrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Chlorcyclizine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlordiazepoxide: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Chlordiazepoxide; Clidinium: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam. (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as tricyclic antidepressants (TCAs), with caution. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Chlorpheniramine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Phenylephrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpromazine: (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy including chlorpromazine, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. In addition, TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases and may increase the risk of side effects when coadministered with chlorpromazine. Chlorpromazine is specifically associated with an established risk of QT prolongation and torsades de pointes (TdP); case reports have included patients receiving therapeutic doses of chlorpromazine.
    Chlorthalidone; Clonidine: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Chlorzoxazone: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression.
    Cholinergic agonists: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
    Cimetidine: (Moderate) Cimetidine can inhibit the systemic clearance of tricyclic antidepressants that undergo oxidative metabolism, such as clomipramine, resulting in increased plasma levels of the antidepressant. Patients should be monitored for TCA-related side effects and toxicity if cimetidine is added; when possible, choose an alternative H2-blocker for treatment.
    Cinacalcet: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as tricyclic antidepressants.
    Ciprofloxacin: (Minor) Rare cases of QT prolongation and torsade de pointe (TdP) have been reported with ciprofloxacin during post-marketing surveillance. Ciprofloxacin should be used with caution in patients receiving drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ciprofloxacin include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Cisapride: (Severe) QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Because of the potential for TdP, use of tricyclic antidepressants (TCAs) with cisapride is contraindicated. In addition to adverse cardiac effects, the antimuscarinic effects of the TCAs may hinder the therapeutic actions of cisapride on GI motility.
    Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation and tricyclic antidepressants are associated with a possible risk of QT prolongation and torsade de pointes (TdP). According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended. In addition, because of the potential risk and severity of serotonin syndrome, caution should be observed when administering citalopram with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants (TCAs) and SSRIs. Citalopram is a weak inhibitor of CYP2D6, the isoenzyme responsible for metabolism of many of the tricyclic antidepressants. Coadministration of citalopram and imipramine did not significantly affect the plasma concentrations of either drug. However, the concentration of desipramine, the primary metabolite of imipramine, was increased by 50%. The clinical significance of the elevation in desipramine concentration is unknown. However, symptoms of toxicity, including seizures, have been reported when drugs from these 2 classes were used together. A decreased dosage of the TCA or the avoidance of concomitant SSRI therapy should be considered.
    Clarithromycin: (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clemastine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Clobazam: (Moderate) A dosage reduction of CYP2D6 substrates, such tricyclic antidepressants, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Additive CNS depressant effects are possible when clobazam is administered concurrently with tricyclic antidepressants.
    Clonazepam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Clonidine: (Major) Concurrent use of clonidine with tricyclic antidepressants (TCAs) should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by TCAs; occasionally, the hypertension will occur within the first few days of combined therapy. If coadministration of a TCA with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed. In addition, concurrent administration of a TCA and clonidine may result in additive CNS depression or other side effects; clonidine produces mental depression as a side effect in roughly 1% of patients. In rats, the coadministration of amitriptyline with clonidine resulted in corneal lesions, but the human implications of these animal study findings are unknown.
    Clorazepate: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Clozapine: (Moderate) Concurrent use of clozapine and tricyclic antidepressants should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Tricyclic antidepressants have a possible risk of QT prolongation (particularly with elevated concentrations). The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Depending on the specific agent, additive anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. Anticholinergic effects are most prominent with tertiary TCAs such as amitriptyline, clomipramine, imipramine, and doxepin.
    Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
    Cocaine: (Major) Cocaine-induced toxicities on the cardiovascular and nervous system appear to be mediated by serotonin and dopamine neurotransmission. The tricyclic antidepressants target these monoamine systems and may thus amplify the cardiovascular or convulsive effects of cocaine, particularly during cocaine abuse. In the medical use of cocaine as a local anesthetic, interactions with tricyclic antidepressants are not common, but special care must be taken since there may be an increased risk of cardiac arrhythmia. Lower doses of cocaine and/or electrocardiographic monitoring may be necessary in conjunction with close clinical monitoring.
    Codeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and sedation may also occur. Clinicians should note that additive anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Codeine; Promethazine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and sedation may also occur. Clinicians should note that additive anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    COMT inhibitors: (Moderate) Catechol-O-methyltransferase (COMT) inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants (TCAs), due to the possibility of additive sedation, dizziness, and other CNS depressive effects. Pharmacokinetic interactions have not been reported. No pharmacokinetic interaction with the tricyclic antidepressant imipramine was shown in a single-dose study with entacapone. Tolcapone did not change the pharmacokinetics of desipramine in a drug interaction study.
    Conjugated Estrogens: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Conjugated Estrogens; Bazedoxifene: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Crizotinib: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes if crizotinib is administered with a tricyclic antidepressant. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Cyclizine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Cyclobenzaprine: (Major) The concurrent use of cyclobenzaprine with tricyclic antidepressants should be avoided whenever possible due to the potential for adverse effects resulting from similar pharmacology; consider alternative agents for skeletal muscle relaxation. The administration of cyclobenzaprine with drugs that increase serotonin concentrations such as tricyclic antidepressants may cause serotonin syndrome.
    Cyproheptadine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Dacomitinib: (Moderate) Monitor for increased toxicity of tricyclic antidepressants, such as increased anticholinergic effects, if coadministered with dacomitinib. Coadministration may increase the serum concentration of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates; dacomitinib is a strong CYP2D6 inhibitor
    Dantrolene: (Moderate) Concomitant use of dantrolene with tricyclic antidepressants can result in additive CNS depression.
    Darifenacin: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
    Darunavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations.
    Dasatinib: (Major) Monitor for evidence of QT prolongation during concurrent use of dasatinib and a tricyclic antidepressant. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Degarelix: (Minor) Tricyclic antidepressants (TCAs) should be used cautiously and with close monitoring with degarelix. Since degarelix can cause QT prolongation, degarelix should be used cautiously with other drugs that are associated with QT prolongation. Prescribers need to weigh the potential benefits and risks of degarelix use in patients with prolonged QT syndrome or in patients taking other drugs that may prolong the QT interval.
    Delavirdine: (Major) Delavirdine inhibits CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as tricyclic antidepressants (TCAs). Monitor the patient for side effects associated with TCAs such as an increase in constipation, urinary difficulty, dizziness, or rarely, fast, irregular heartbeat. A dosage adjustment may be needed for TCAs when given concurrently with delavirdine.
    Desflurane: (Minor) Tricyclic antidepressants (TCAs) should be used cautiously and with close monitoring with halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, general anesthetics may produce additive CNS depression when used in patients taking tricyclic antidepressants.
    Desloratadine; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with SIADH including tricyclic antidepressants. Hyponatremia-induced convulsions have been rarely reported when imipramine and desmopressin are used concomitantly. Use these drugs together with caution, and monitor patients for signs and symptoms of hyponatremia.
    Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants (TCAs). Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, desvenlafaxine and concurrent serotonergic agents should be discontinued. Dosage adjustments of TCAs may be necessary during concurrent use of desvenlafaxine. Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that primary substrates of CYP2D6, such as desipramine, doxepin, clomipramine, and imipramine be dosed at the original level when co-administered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued. The dose of these CYP2D6 substrates should be reduced by up to one-half if co-administered with desvenlafaxine 400 mg/day.
    Deutetrabenazine: (Moderate) For patients taking a deutetrabenazine dosage more than 24 mg/day with a tricyclic antidepressant, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Additionally, concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as tricyclic antidepressants, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dexchlorpheniramine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Dexmethylphenidate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dexmethylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate, a racemic mixture containing dexmethylphenidate. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Dextroamphetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as amphetamines and tricyclic antidepressants (TCAs). Both TCAs and amphetamines inhibit the reuptake of serotonin and amphetamines also increase central serotonin release. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The MAOI and sympathomimetic activity of amphetamines may also be of concern. Theoretically, the cardiovascular effects of TCAs or amphetamines may be potentiated through the stimulation of norepinephrine release. Although combination therapy with amphetamines and TCAs is used clinically, further study is needed to fully evaluate the severity and frequency of adverse effects that may occur. If serotonin syndrome is suspected, all serotonergic agents should be discontinued and appropriate medical management should be initiated. If the patient experiences changes in heart rate or rhythm, an ECG may be indicated. A dose reduction of one or both agents may be needed if side effects occur.
    Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Dextromethorphan; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Dextromethorphan; Promethazine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued. (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as the tricyclic antidepressants. Additive drowsiness and sedation may also occur. Clinicians should note that additive anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Dextromethorphan; Quinidine: (Severe) Quinidine administration is associated with QT prolongation and torsade de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions. Quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Tricyclic antidepressants are associated with a possible risk of QT prolongation, particularly at high dosages or in overdose, and are substrates for CYP2D6. (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering tricyclic antidepressants with other drugs that have serotonergic properties such as dextromethorphan. Both trimipramine and dextromethorphan inhibit central serotonin reuptake. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
    Diazepam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Dicyclomine: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Dienogest; Estradiol valerate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Diethylpropion: (Major) Avoid the use of these agents together. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as diethylpropion. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable.
    Diethylstilbestrol, DES: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Dimenhydrinate: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Diphenhydramine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Diphenhydramine; Ibuprofen: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Diphenhydramine; Naproxen: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Diphenhydramine; Phenylephrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Disopyramide: (Major) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes tachycardia have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies. Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). The need to coadminister TCAs with any of these therapies should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA. In addition to effects on the EKG, disopyramide has significant anticholinergic effects that are additive to those of the TCAs.
    Disulfiram: (Moderate) Limited data suggest that the combination of tricyclic antidepressants with disulfiram can produce transient delirium. In addition, disulfiram may inhibit some of the CYP450 isoenzymes involved in tricyclic antidepressant metabolism, although the clinical significance is unknown.
    Dofetilide: (Severe) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of tricyclic antidepressants (TCAs) with dofetilide is contraindicated.
    Dolasetron: (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with dolasetron. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Use of dolasetron injection for the prevention of chemotherapy-induced nausea and vomiting is contraindicated because the risk of QT prolongation is higher with the doses required for this indication; when the injection is used at lower doses (i.e., those approved for post-operative nausea and vomiting) or when the oral formulation is used, the risk of QT prolongation is lower and caution is advised. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Dolutegravir; Rilpivirine: (Minor) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Donepezil: (Major) Concurrent use of tricyclic antidepressants and donepezil should be avoided if possible. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy, and tricyclic antidepressants have a possible risk for QT prolongation and TdP. In addition, donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Tricyclic antidepressants with significant anticholinergic activity, such as amitriptyline, imipramine, doxepin, and clomipramine, are more likely to interfere with the therapeutic effect of donepezil than other tricyclics.
    Donepezil; Memantine: (Major) Concurrent use of tricyclic antidepressants and donepezil should be avoided if possible. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy, and tricyclic antidepressants have a possible risk for QT prolongation and TdP. In addition, donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Tricyclic antidepressants with significant anticholinergic activity, such as amitriptyline, imipramine, doxepin, and clomipramine, are more likely to interfere with the therapeutic effect of donepezil than other tricyclics.
    Dopamine: (Major) Tricyclic antidepressants (TCAs) may potentiate the pressor response to parenteral sympathomimetic agents, such as dopamine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience side effects like hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat. Patients should be closely monitored if use together is unavoidable.
    Doxylamine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Doxylamine; Pyridoxine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with tricyclic antidepressants (e.g., amitriptyline, desipramine) is necessary. Concurrent use of dronabinol, THC with tricyclic antidepressants may result in additive drowsiness, hypertension, tachycardia, and possibly cardiotoxicity.
    Dronedarone: (Severe) Coadministration of dronedarone and tricyclic antidepressants is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants (TCAs) have pharmacologic properties like the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with droperidol. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. According to the revised 2001 labeling for droperidol, any drug known to have potential to prolong the QT interval should not be coadministered with droperidol.
    Drospirenone; Estradiol: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Drospirenone; Ethinyl Estradiol: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SNRIs. Duloxetine and venlafaxine are inhibitors of CYP2D6, and many TCAs are metabolized by this isozyme. Duloxetine increased the maximum plasma concentration (Cmax) of desipramine 1.7-fold and the AUC 2.9-fold in one study. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or other adverse effects. Patients should be informed of the possible increased risk of serotonin syndrome. If serotonin syndrome occurs, duloxetine and the concomitant serotonergic agent should be discontinued and symptomatic treatment should be initiated.
    Edrophonium: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as edrophonium, due to their anticholinergic activity.
    Efavirenz: (Major) Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Efavirenz; Emtricitabine; Tenofovir: (Major) Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Elbasvir; Grazoprevir: (Moderate) Administering clomipramine with elbasvir; grazoprevir may result in elevated clomipramine plasma concentrations. Clomipramine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Moderate) Coadminister tricyclic antidepressants (TCAs) and eliglustat cautiously and with close monitoring; there may be an increased risk of QT prolongation and/or antidepressant-associated adverse effects. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, coadministration may result in increased concentrations of the antidepressant. If eliglustat and a TCA are used together, consider reducing the dosage of the TCA and titrating to clinical effect. When available, monitoring antidepressant serum concentrations may be beneficial. Eliglustat is a CYP2D6 inhibitor, and tricyclic antidepressants are CYP2D6 substrates.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Minor) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Minor) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Encorafenib: (Major) Avoid coadministration of encorafenib and tricyclic antidepressants due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Enflurane: (Minor) Tricyclic antidepressants (TCAs) should be used cautiously and with close monitoring with halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, general anesthetics may produce additive CNS depression when used in patients taking tricyclic antidepressants.
    Entacapone: (Moderate) Catechol-O-methyltransferase (COMT) inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants (TCAs), due to the possibility of additive sedation, dizziness, and other CNS depressive effects. Pharmacokinetic interactions have not been reported. No pharmacokinetic interaction with the tricyclic antidepressant imipramine was shown in a single-dose study with entacapone. Tolcapone did not change the pharmacokinetics of desipramine in a drug interaction study.
    Ephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as ephedrine or ephedra. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Epinephrine: (Major) Tricyclic antidepressants potentiate the effects of sympathomimetics including epinephrine. Enhanced cardiovascular effects including arrhythmias, severe hypertension, and/or hyperpyrexia are possible with combined use. Concomitant use of epinephrine with these agents should be avoided when possible; use caution when concomitant use cannot be avoided.
    Eribulin: (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with eribulin. Eribulin has been associated with QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). If eribulin and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erythromycin: (Minor) The use of erythromycin with tricyclic antidepressants is rarely problematic. Tricyclic antidepressants may prolong the QT interval, particularly in overdose, and erythromycin has also been reported to have this effect in rare circumstances. Erythromycin is sometimes used to stimulate GI motility, for example, in patients with diabetic gastroparesis. In patients requiring erythromycin to enhance GI motility, some tricyclic antidepressants with substantial antimuscarinic properties may counteract erythromycin's effectiveness.
    Erythromycin; Sulfisoxazole: (Minor) The use of erythromycin with tricyclic antidepressants is rarely problematic. Tricyclic antidepressants may prolong the QT interval, particularly in overdose, and erythromycin has also been reported to have this effect in rare circumstances. Erythromycin is sometimes used to stimulate GI motility, for example, in patients with diabetic gastroparesis. In patients requiring erythromycin to enhance GI motility, some tricyclic antidepressants with substantial antimuscarinic properties may counteract erythromycin's effectiveness.
    Escitalopram: (Major) Use tricyclic antidepressants and escitalopram together with caution and careful monitoring because there is an increased risk of adverse effects, some of which can be life-threatening. Both tricyclic antidepressants and escitalopram are associated with a possible risk for QT prolongation and torsade de pointes (TdP); using the drugs together may increase this risk. In addition, because of the potential risk and severity of serotonin syndrome, caution should be observed when administering escitalopram with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants (TCAs) and SSRIs. Escitalopram is a modest inhibitor of CYP2D6, the isoenzyme responsible for metabolism of many of the tricyclic antidepressants. Co-administration of escitalopram and desipramine (a substrate for CYP2D6), resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine. The clinical significance of the elevation in desipramine concentration is unknown. However, symptoms of toxicity, including seizures, have been reported when drugs from these 2 classes were used together. A decreased dosage of the TCA or the avoidance of concomitant SSRI therapy should be considered. If serotonin syndrome is suspected, escitalopram and concurrent serotonergic agents should be discontinued.
    Eslicarbazepine: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Esomeprazole: (Minor) Esomeprazole may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as clomipramine.
    Esomeprazole; Naproxen: (Minor) Esomeprazole may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as clomipramine.
    Estazolam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Esterified Estrogens: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Esterified Estrogens; Methyltestosterone: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Estradiol: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Estradiol; Levonorgestrel: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Estradiol; Norethindrone: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Estradiol; Norgestimate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Estrogens: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Estropipate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Eszopiclone: (Moderate) A reduction in the dose of eszopiclone and concomitantly administered CNS depressants, such as tricyclic antidepressants, should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Tricyclics with a higher incidence of sedation, such as amitriptyline, imipramine, doxepin, and clomipramine, are more likely to interact with eszopiclone.
    Ethanol: (Moderate) Patients should be cautioned about using alcohol concurrently, since tricyclic antidepressants (TCAs) may exaggerate the CNS depressant response to alcohol, leading to an increase in sedation or psychomotor impairment. In some studies, alcohol has increased the unbound form of the TCA in the blood, which might be related to exagerrated clinical effect.
    Ethinyl Estradiol: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Desogestrel: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Etonogestrel: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Levonorgestrel: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Norelgestromin: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Norethindrone: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Norgestimate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethinyl Estradiol; Norgestrel: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
    Ethosuximide: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Etomidate: (Moderate) General anesthetics like etomidate may produce additive CNS depression when used in patients taking tricyclic antidepressants.
    Everolimus: (Moderate) Monitor for an increase in clomipramine-related adverse reactions if coadministration with everolimus is necessary. Clomipramine is a CYP2D6 substrate and everolimus is a weak CYP2D6 inhibitor; concomitant use may increase plasma concentrations of clomipramine.
    Ezogabine: (Moderate) Ezogabine has been associated with QT prolongation. The manufacturer of ezogabine recommends caution during concurrent use of medications known to increase the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with ezogabine include tricyclic antidepressants (TCAs). In addition, coadministration can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Felbamate: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as clomipramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of clomipramine during coadministration with fenofibric acid.
    Fentanyl: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Fexofenadine; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Fingolimod: (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with fingolimod. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flavoxate: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Flecainide: (Minor) Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias. Drugs with a possible risk for QT prolongation that should be used cautiously with flecainide include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and TdP have been described with TCA use, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies.
    Fluconazole: (Minor) Fluconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP). Tricyclic antidepressants have been associated with a possible risk of QT prolongation. Fluconazole should be administered together with TCAs with caution. In addition, fluconazole has been reported to increase the effects of amitriptyline, perhaps through inhibition of the hepatic microsomal CYP2C19 or CYP3A4 isoenzymes. In at least one case, the interaction resulted in an increased incidence of TCA-related side effects, like dizziness and syncope. Monitor for an increased response to amitriptyline if fluconazole is coadministered. Doxepin is primarily metabolized by CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. Fluconazole potently inhibits the CYP2C9 isoenzyme in vivo and in vitro and the CYP2C19 isoenzyme in vitro. Concurrent administration of doxepin and fluconazole may result in increased doxepin plasma concentrations and subsequent adverse reactions. Because of similar metabolic pathways, other TCAs that may be affected include clomipramine and imipramine, but specific data are lacking.
    Flumazenil: (Major) Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially tricyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations; concurrent cyclic antidepressant poisoning is a risk factor for seizures. Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
    Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    Fluoxetine; Olanzapine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life. (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with drugs are known to possess relatively significant antimuscarinic properties, such as olanzapine. Amitriptyline has the greatest anticholinergic effects of the TCAs. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible. In addition, olanzapine therapy or TCA therapy, at elevated serum concentrations, may prolong the QTc interval. Olanzapine and TCAs should be used together cautiously.
    Fluphenazine: (Moderate) When prescribing tricyclic antidepressants (TCAs) to patients already receiving phenothiazine therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. TCAs may impair metabolism via the hepatic isoenzyme CYP2D6 at therapeutic doses and may result in increased serum phenothiazine concentrations, leading to side effects. Depending on the specific agent, additive anticholinergic effects may also be seen; clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur. TCAs may also cause additive cardiac effects (e.g., QT prolongation) in some cases.
    Flurazepam: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as tricyclic antidepressants, can potentiate the CNS effects of either agent. Tricyclic antidepressants may also lower the seizure threshold leading to pharmacodynamic interactions with anticonvulsant benzodiazepines (i.e., clobazam, clonazepam, diazepam, and lorazepam). The plasma concentrations of imipramine and desipramine may increase an average of 31% and 20%, respectively, when administered concurrently with alprazolam. The significance of this interaction has not been described; therefore, patients should be monitored closely for symptoms of tricyclic toxicity during coadministration of these agents with alprazolam.
    Fluvoxamine: (Major) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as clomipramine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Tricyclics share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with high dose therapy (elevated serum concentrations). QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, clomipramine is a primary substrate of CYP2D6 with a lesser contribution by CYP1A2. Fluvoxamine is a potent CYP1A2 inhibitor and a mild CYP2D6 inhibitor. At least one case report exists of a death thought to be due to impaired clearance of the TCA amitriptyline by fluoxetine. Patients receiving clomipramine should be monitored closely for toxicity if fluvoxamine is added.
    Food: (Major) Avoid administering marijuana and tricyclic antidepressants together as concurrent use may result in adverse cardiovascular effects, such as tachycardia and cardiac arrhythmias. Marijuana is known to produce significant increases in heart rate and cardiac output lasting for 2 to 3 hours. Further, rare case reports of myocardial infarction and cardiac arrhythmias have been associated with marijuana use. Tricyclic antidepressants have also been reported to produce a wide range of cardiovascular effects including cardiac arrhythmias, palpitations, hypertension, ventricular tachycardia, heart failure, and stroke. Coadministration of marijuana with tricyclic antidepressants may result in significant cardiovascular adverse events and thus, should be avoided.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as tricyclic antidepressants. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fospropofol: (Moderate) Fospropofol potentiates respiratory and CNS depression and may enhance the sedative, respiratory depressive, and hypotensive effects of tricyclic antidepressants. A reduced dose of fospropofol may be needed for sedation if it is used in conjunction with other medications that cause CNS depression.
    Gabapentin: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can enhance CNS depressant effects and may also lower the seizure threshold. Counsel patients to limit activity until they are aware of how coadministration affects them.
    Galantamine: (Moderate) The therapeutic benefits of galantamine may be diminished when coadministered with drugs known to exhibit anticholinergic properties including tricyclic antidepressants. When concurrent use cannot be avoided, monitor the patient for reduced galantamine efficacy. A population pharmacokinetic analysis showed that the clearance of galantamine was decreased by 25% to 33% during coadministration of certain CYP2D6 inhibitors including amitriptyline (n = 17). The CYP2D6 isoenzyme is partially involved in the metabolism of galantamine. The clinical relevance of this interaction is unknown; however, increased galantamine concentrations could potentially result in dose-related toxicity.
    Gemifloxacin: (Minor) Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with gemifloxacin include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Gemtuzumab Ozogamicin: (Minor) Use gemtuzumab ozogamicin and tricyclic antidepressants together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Glasdegib: (Major) Avoid coadministration of glasdegib with tricyclic antidepressants due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Glycopyrrolate: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Glycopyrrolate; Formoterol: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Goserelin: (Moderate) Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with goserelin include tricyclic antidepressants.
    Granisetron: (Minor) Both tricyclic antidepressants (TCAs) and granisetron are associated with a possible risk for QT prolongation and torsade de pointes (TdP); therefore, caution and close monitoring are recommended during co-administration of TCAs and granisetron. In addition, because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, granisetron and concurrent serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Guaifenesin; Phenylephrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Guaifenesin; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Guanabenz: (Major) Tricyclic antidepressants block the action of guanabenz, preventing or significantly reducing the expected antihypertensive effects.
    Guanfacine: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Guanidine: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
    Guselkumab: (Moderate) Clinically relevant drug interactions may occur when guselkumab is administered with sensitive substrates of CYP2D6, such as tricyclic antidepressants (TCA). Monitor TCA concentrations if guselkumab is initiated or discontinued; the TCA dose may need to be adjusted. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP2D6 could be normalized during guselkumab administration.
    Halofantrine: (Severe) Halofantrine is considered to have a well-established risk for QT prolongation and torsade de pointes (TdP). Halofantrine is contraindicated in patients receiving drugs that may induce QT prolongation; these drugs include tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Halogenated Anesthetics: (Minor) Tricyclic antidepressants (TCAs) should be used cautiously and with close monitoring with halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, general anesthetics may produce additive CNS depression when used in patients taking tricyclic antidepressants.
    Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants such as tricyclic antidepressants (TCAs). Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects. Limited data suggest that haloperidol may inhibit the metabolism of some tricyclic antidepressants, however, the clinical significance of this interaction is uncertain. Haloperidol is an inhibitor of hepatic CYP2D6, and coadministration with many TCAs (which are CYP2D6 substrates) may lead to elevated TCA serum concentrations, potentiating toxicity. Haloperidol has also been associated with a possible risk for QT prolongation and/or torsades de pointes, particularly when excessive doses are used or in overdose. Haloperidol should be used cautiously with other agents that may have this effect (e.g., tricyclic antidepressants).
    Halothane: (Minor) Tricyclic antidepressants (TCAs) should be used cautiously and with close monitoring with halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, general anesthetics may produce additive CNS depression when used in patients taking tricyclic antidepressants.
    Histrelin: (Minor) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tricyclic antidepressants is necessary; correct any electrolyte abnormalities. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Hydantoins: (Major) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Many references caution against the combined use of tricyclic antidepressants (TCAs) and methyldopa. Although reports exist of loss of blood pressure control when TCAs are added to methyldopa, the interaction is not well documented. Nevertheless, if use of these drugs together is not avoidable, monitor the patient's blood pressure for the desired response.
    Hydrocodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to parenteral direct-acting sympathomimetic agents such as norepinephrine and, to a lesser extent, epinephrine and phenylephrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Avoid prescribing opioid cough medications in patients taking tricyclic antidepressants. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Hydromorphone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and tricyclic antidepressants. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include tricyclic antidepressants. In addition, the anticholinergic effects of hydroxyzine are moderate and may be enhanced when combined with medications with anticholinergic effects, such as tricyclic antidepressants. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Hyoscyamine: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) According to the manufacturer of clomipramine, treatment initiation with clomipramine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than clomipramine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving clomipramine and requiring urgent treatment with intravenous methylene blue, clomipramine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Clomipramine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Clomipramine, a tricyclic antidepressant, is the most selective and potent inhibitor of serotonin within its class. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report describes a patient receiving clomipramine who experienced jerky movements in all four limbs, as well as confusion and agitation after intravenous administration of methylene blue, with a return to her pre-operative state by day 4. Although the authors attribute this reaction to methylene blue toxicity, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenousely administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Ibuprofen; Oxycodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Ibuprofen; Pseudoephedrine: (Major) Tricyclic antidepressants (TCAs) may markedly enhance the pressor response to certain sympathomimetic agents, such as pseudoephedrine. TCAs inhibit norepinephrine reuptake in adrenergic neurons, resulting in increased stimulation of adrenergic receptors. Clinically, the patient might experience hypertension, headache, tremor, palpitations, chest pain, or irregular heartbeat.
    Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ibutilide include tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). This pharmacologic property of the TCAs is of concern in patients with significant cardiac histories or treated with selected cardiac agents. Cases of long QT syndrome and torsade de pointes (TdP) have been described, but rarely occur when TCAs are used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of TCAs in combination with other QT-prolonging drugs. One study reported the common occurrence of overlapping prescriptions for 2 or more drugs with potential for QT-prolonging effects; antidepressants were involved in nearly 50% of the cases, but there are little data to document safety of the combined therapies.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with clomipramine, a CYP3A substrate, as clomipramine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Moderate) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as tricyclic antidepressants.
    Imatinib: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation.
    Indacaterol; Glycopyrrolate: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other anticholinergics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with tricyclic antidepressants.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with tricyclic antidepressants (TCAs) due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Iobenguane I 131: (Major) Discontinue tricyclic antidepressants for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart tricyclic antidepressants until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as tricyclic antidepressants, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with clomipramine may result in increased serum concentrations of clomipramine. Clomipramine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoflurane: (Minor) Tricyclic antidepressants (TCAs) should be used cautiously and with close monitoring with halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, general anesthetics may produce additive CNS depression when used in patients taking tricyclic antidepressants.
    Isoniazid, INH: (Major) Due to the risk of serotonin syndrome, concurrent use of tricyclic antidepressants and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, clomipramine and concurrent serotonergic agents should be discontinued.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of tricyclic antidepressants and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, clomipramine and concurrent serotonergic agents should be discontinued. (Moderate) It may be necessary to adjust the dosage of tricyclic antidepressants if given concurrently with rifampin. Rifampin may induce the metabolism of tricyclic antidepressants; coadmini