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    Compounding Kits Miscellaneous
    Tricyclic Antidepressants

    BOXED WARNING

    Children, suicidal ideation

    The safety and efficacy of amitriptyline for the treatment of depression have not been established in children less than 12 years of age. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of amitriptyline may be necessary in patients with emerging suicidality or worsening depression. Amitriptyline should be used with caution in children with a known family history of heart disease or who are taking medications that cause QT prolongation. QTc interval prolongation, tachycardias, and other side effects have been reported in children who have taken tricyclic antidepressants (TCAs); there are rare reports of deaths due to cardiovascular side effects. Routine cardiovascular monitoring has been suggested for children receiving TCAs due to the potential of these agents to produce adverse cardiac effects.

    DEA CLASS

    Rx

    DESCRIPTION

    Tertiary amine tricyclic antidepressant; amitriptyline is metabolized to nortriptyline, an active metabolite
    FDA-approved for use in adults for the treatment of depression; used off label for neuropathic pain and other uses
    Boxed warning for use in pediatric patients and young adults due to risk for suicidality

    COMMON BRAND NAMES

    Elavil, EnovaRX, Equipto Amitriptyline, Vanatrip

    HOW SUPPLIED

    Amitriptyline/Amitriptyline Hydrochloride/Elavil/Vanatrip Oral Tab: 10mg, 25mg, 50mg, 75mg, 100mg, 150mg
    EnovaRX/Equipto Amitriptyline Topical Pwd F/Recon: 1.2g, 2%, 2.4g

    DOSAGE & INDICATIONS

    For the treatment of major depression.
    Oral dosage
    Adults

    Initially, 75 mg/day PO, given in divided doses, or, 50 mg to 100 mg PO once daily at bedtime. Hospitalized patients may require 100 mg/day PO initially. Titrate if needed, up to 150 mg/day PO, by increasing the daily dose 25 to 50 mg at weekly intervals, depending on clinical need and response and tolerance. Max (hospitalized patients): 300 mg/day PO. The usual maintenance dosage in adults is 50 to 100 mg PO per day. In some patients, 40 mg/day PO is sufficient. For maintenance, the total daily dosage may be given in a single dose, preferably at bedtime. When satisfactory improvement occurs, use the lowest effective dose. It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse.

    Geriatric

    10 to 25 mg PO at bedtime initially. Titrate as needed and tolerated. Lower doses are used compared to younger adults; 10 mg PO 3 times per day with 20 mg PO at bedtime may be satisfactory. Max: 150 mg/day PO, but such doses are not usually tolerated in geriatric adults. Usual adult maintenance dosage: 50 to 100 mg PO per day. In some patients, 40 mg/day PO is sufficient. For maintenance therapy, the total daily dosage may be given in a single dose, preferably at bedtime. When satisfactory improvement occurs, reduce to lowest effective dose. It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse.

    Adolescents

    Begin at a low daily dosage, usually at bedtime, and titrate as needed and tolerated. Lower doses are used compared to young adults; 10 mg PO 3 times per day with 20 mg PO at bedtime may be satisfactory in adolescents who do not tolerate higher dosages. When satisfactory improvement has occurred, reduce to the lowest effective dose. It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse. Weight-based dosing has been used in clinical trials of amitriptyline in adolescents for other indications. Tricyclic antidepressants (TCAs) are not drugs of choice for pediatric patients with depression; there is lack of high-quality data to support efficacy and safety.

    For the treatment of social phobia (social anxiety disorder)† or panic disorder†.
    Oral dosage
    Adults

    25 mg PO 3 times per day initially. Titrate the dose up to 200 mg/day PO, as tolerated or needed, by increasing the daily dose 25 to 50 mg at weekly intervals, depending on response and adverse effects. Max (hospitalized patients): 300 mg/day PO.

    For the treatment of painful diabetic neuropathy†.
    Oral dosage
    Adults

    Initially, 25 mg PO given once daily 1 to 2 hours before bedtime. Titrate in 10 mg to 25 mg increments once or twice a week, if needed, until pain is controlled or side effects are limiting. The American Academy of Neurology (AAN) recommends a dosage range of 25 mg to 100 mg/day. The AAN considers amitriptyline probably effective in lessening the pain of peripheral diabetic neuropathy.

    For the treatment of postherpetic neuralgia†.
    Oral dosage
    Adults

    A median dose of 75 mg/day PO at bedtime (range 25 mg/day to 137.5 mg/day) after titration has provided good to excellent responses; patients rated as having a poor response took a median dose of 50 mg/day PO at bedtime (range 25 mg/day to 125 mg/day).

    For migraine prophylaxis†.
    Oral dosage
    Adults

    25 mg PO once daily at bedtime, initially; titrate as tolerated to efficacy. Usual effective target dose range: 75 to 100 mg PO once daily.[44244] [52577] [58269] Guidelines classify amitriptyline as probably effective for migraine prophylaxis.[57981] [64551]

    For the treatment of fibromyalgia†.
    Oral dosage
    Adults

    In one trial, amitriptyline 10 mg PO once daily at bedtime and titrated up to 50 mg PO at bedtime was superior to placebo at 1 month but not significantly better at 3 or 6 months. In another small study comparing amitriptyline to fluoxetine, placebo, or the combination of amitriptyline with fluoxetine, amitriptyline 25 mg PO once daily alone was superior to placebo.

    For the treatment of insomnia†.
    Oral dosage
    Adults

    10 to 50 mg PO once daily at bedtime.

    For the treatment of persistent singultus (hiccups)†.
    Oral dosage
    Adults

    10 mg PO 3 times per day has been reported as effective for relieving idiopathic intractable hiccups resistant to both chlorpromazine and metoclopramide.

    For the treatment of primary nocturnal enuresis†.
    Oral dosage
    Children and Adolescents 11 years and older

    50 mg PO at bedtime has been successful either alone or in combination with desmopressin.

    Children 6 to 10 years

    25 mg PO at bedtime has been successful either alone or in combination with desmopressin.

    For the adjunct treatment of bulimia nervosa†.
    Oral dosage
    Adults

    Initially, 25 mg PO 3 times per day. Titrate the dose to 150 mg/day PO once daily at bedtime by increasing the daily dose by 25 to 50 mg at weekly intervals, as tolerated or needed. Limited trial data indicate amitriptyline might reduce binge-eating episodes. Adverse effects often limit the usefulness of the tricyclic antidepressants (TCAs) relative to the selective serotonin reuptake inhibitors (SSRIs) for bulimia nervosa, and thus they are not commonly employed. Treatment for symptom control is adjunctive to cognitive behavioral interventions. Clinical trial data are of relatively low to moderate quality.

    For the improvement of global symptoms of diarrhea-predominant irritable bowel syndrome†.
    Oral dosage
    Adults

    Guidelines recommend a dose range of 50 to 100 mg PO per day. Start at a low dose (10 mg PO at bedtime) and titrate to therapeutic relief. Guidelines strongly recommend selected tricyclic antidepressants to treat global symptoms of IBS such as abdominal pain; patients with IBS-D may respond better because of the anticholinergic properties which may improve symptoms of urgency and diarrhea.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    150 mg/day PO in outpatients; 300 mg/day PO for hospitalized patients.

    Geriatric

    150 mg/day PO in outpatients.

    Adolescents

    150 mg/day PO in outpatients.

    Children

    < 12 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Amitriptyline should be used with caution in those with hepatic impairment; if the drug must be used, a lower initial dosage and caution in dose titration is recommended.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears no dose adjustment is needed. Little unchanged drug appears in the urine. Hemodialysis is reported as ineffective in removing amitriptyline from the body.

    ADMINISTRATION

    Oral Administration

    May administer without regard to meals.
    Administration of entire daily dose at bedtime may increase compliance and reduce daytime sedation. In the minority of patients that experience stimulation and insomnia with bedtime dosing, the dose should be given in the morning.

    Injectable Administration

    Intramuscular Administration

    STORAGE

    Elavil:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    EnovaRX:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a cool, dry place
    Equipto Amitriptyline:
    - Discard unused reconstituted product after 30 days
    - Prior to compounding, store at room temperature (between 59 to 86 degrees F)
    - Protect from light
    - Reconstituted product may be stored at controlled room temperature (68 to 77 degrees F)
    Vanatrip:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Carbamazepine hypersensitivity, tricyclic antidepressant hypersensitivity

    Amitriptyline is contraindicated in patients with a hypersensitivity to amitriptyline or any of its inactive ingredients. Patients with a hypersensitivity to amitriptyline may experience a tricyclic antidepressant hypersensitivity reaction to other tricyclics. In some case reports, cross-allergenicity did not occur in patients who experienced a rash from the primary tricyclic and were switched to an alternate tricyclic. However, because the data are too limited to be conclusive, it is generally advisable to substitute with an antidepressant from another class in patients with a known hypersensitivity to amitriptyline. When considering use of an alternate tricyclic, it is prudent to avoid other cyclic compounds if the patient has experienced a severe or life-threatening reaction to the primary agent. Cross-sensitivity is possible in patients with a carbamazepine hypersensitivity. The manufacturer of carbamazepine contraindicates use in patients with a hypersensitivity to tricyclic compounds. 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

    Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) simultaneously; use with MAOI therapy is contraindicated. When it is desired to replace MAOI therapy with amitriptyline, a minimum of 14 days should be allowed to elapse after the MAOI is discontinued. Amitriptyline should then be initiated cautiously with a gradual increase in dosage until optimum response is achieved.

    Acute myocardial infarction, apheresis, AV block, bradycardia, cardiac disease, cardiomyopathy, celiac disease, congenital heart disease, females, fever, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, long QT syndrome, myocardial infarction, orthostatic hypotension, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

    Amitriptyline is contraindicated in patients who are in the acute recovery phase following acute myocardial infarction; use of amitriptyline could cause sudden death. Amitriptyline may cause orthostatic hypotension, particularly in the initial dosing titration. 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 amitriptyline, 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. Use amitriptyline with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, adrenal gland tumors, sickle cell disease, decreased thyroid function, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Rarely, TCAs are used in pediatric patients for the treatment of attention-deficit hyperactivity disorder (ADHD). 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

    The safety and efficacy of amitriptyline for the treatment of depression have not been established in children less than 12 years of age. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of amitriptyline may be necessary in patients with emerging suicidality or worsening depression. Amitriptyline should be used with caution in children with a known family history of heart disease or who are taking medications that cause QT prolongation. QTc interval prolongation, tachycardias, and other side effects have been reported in children who have taken tricyclic antidepressants (TCAs); there are rare reports of deaths due to cardiovascular side effects. Routine cardiovascular monitoring has been suggested for children receiving TCAs 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, amitriptyline 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. Also use TCAs with caution in patients with psychotic disorders (e.g., schizophrenia). Psychotic symptoms may be precipitated in some individuals. 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. 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 amitriptyline is not approved for use in treating bipolar depression.

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

    Amitriptyline can induce significant sedation, particularly during the initiation of treatment. Amitriptyline 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

    Amitriptyline should be used with extreme 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 amitriptyline 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

    Tricyclic antidepressants (TCAs), such as amitriptyline, should be used with caution in patients with hepatic disease. Metabolism of tricyclic antidepressants may be altered in patients with hepatic impairment. Rarely, TCAs have caused hepatitis and jaundice, which are reversible on discontinuation. Liver function tests (LFTs) should be performed if symptoms occur and the drug discontinued if there is persistent elevation of enzymes.

    Surgery

    Amitriptyline should be discontinued several days before elective surgery because of the risk of adverse reactions during surgery, including increased sensitivity to catecholamines and potential cardiovascular reactions.

    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 amitriptyline may be significant and are 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 amitriptyline to patients with 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 amitriptyline 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

    Patients who develop a continued fever and a sore throat during therapy with a tricyclic antidepressant (TCA) should have leukocyte and differential blood counts performed. The TCA should be discontinued if there is evidence of pathological neutrophil depression. On rare occasions, there have been reports of leukopenia, agranulocytosis, neutropenia, thrombocytopenia, anemia, and pancytopenia in association with TCA use.

    Hyperthyroidism, hypothyroidism, thyroid disease

    Tricyclic antidepressants (TCAs) like amitriptyline should be used with caution in patients who have thyroid disease. Close supervision is required when amitriptyline is given to patients with hyperthyroidism or to patients with hypothyroidism who are receiving thyroid medication. Hypothyroidism may increase the risk for developing a prolonged QT interval when using amitriptyline.

    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, amitriptyline 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. Pheochromocytoma may also increase the risk for developing a prolonged QT interval when using amitriptyline.

    Radiographic contrast administration

    Tricyclic antidepressants lower the seizure threshold. Because of a potential increased risk of seizures, amitriptyline 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 amitriptyline. 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.

    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.

    Geriatric

    Amitriptyline dose selection should generally be cautious in the geriatric patient. Initiation at the low end of the dosage range with slow titration and careful observation is recommended. Geriatric patients are particularly sensitive to the peripheral and central anticholinergic side effects of amitriptyline and may be at increased risk for falls. Geriatric patients may also be at increased risk for developing a prolonged QT interval when using amitriptyline. According to the Beers Criteria, tricyclic antidepressants (TCAs) are considered potentially inappropriate medications (PIMs) in geriatric patients; avoid TCA use due to the potential for orthostatic hypotension, anticholinergic effects or toxicity (e.g., constipation, urinary difficulties, blurred vision, dry mouth, delirium), or sedation. Avoid TCA use in geriatric patients with the following conditions due to the potential for symptom exacerbation or adverse effects: syncope (increased risk of orthostatic hypotension or bradycardia), dementia/cognitive impairment (drug-induced CNS effects), delirium/high risk of delirium (new-onset or worsening delirium), or lower urinary tract symptoms/benign prostatic hyperplasia in men (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 amitriptyline 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; the duration of therapy should be in accordance with pertinent literature and 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. 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 and well-controlled studies of amitriptyline use in pregnant women; therefore, amitriptyline should only be used in pregnancy if the benefits to the mother outweigh the possible risks to the fetus. Adverse events, including CNS effects, limb deformities, and developmental delays have been reported in infants of mothers taking amitriptyline during pregnancy. Some studies in animals have shown teratogenic effects at amitriptyline doses ranging from 9 to 33 times the maximum recommended human dose (MRHD); however, other studies in animals at doses up to 13 times the MRHD have not shown teratogenicity. Tricyclic antidepressants (TCAs) cross the placenta. Neonatal complications after in utero exposure to TCAs including withdrawal symptoms, hypoglycemia, respiratory diagnoses, developmental delays, and jaundice have been reported. Withdrawal symptoms in neonates 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 pediatric patients 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 amitriptyline during labor and obstetric delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to amitriptyline; information about the registry can be obtained at womensmentalhealth.org/research/pregnancyregistry or by calling 1-866-961-2388.

    Breast-feeding

    Because tricyclic antidepressants (TCAs), including amitriptyline, are excreted into breast milk, the benefits and risks of breast-feeding should be carefully weighed if TCA therapy is needed in the mother. According to the manufacturer, because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug. The effects of TCAs on the nursing infant are not known but may be of concern, particularly with prolonged exposure. A pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants in breast-feeding mothers.

    Tobacco smoking

    Physiological changes resulting from tobacco smoking may alter the pharmacokinetics of certain concomitant medications, such as tricyclic antidepressants (TCAs). Doses of TCAs may need to be adjusted in patients who successfully quit smoking.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 11.2-11.2
    oliguria / Early / 0.5-0.5
    seizures / Delayed / 0-0.1
    suicidal ideation / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    stroke / Early / Incidence not known
    AV block / Early / Incidence not known
    tardive dyskinesia / Delayed / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    neuroleptic malignant syndrome-like symptoms / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known

    Moderate

    orthostatic hypotension / Delayed / 2.0-30.8
    memory impairment / Delayed / 17.3-17.3
    constipation / Delayed / 1.9-17.0
    blurred vision / Early / 13.5-13.5
    palpitations / Early / 5.8-5.8
    sinus tachycardia / Rapid / 5.8-5.8
    peripheral vasodilation / Rapid / 4.1-4.1
    urinary retention / Early / 4.0-4.0
    amblyopia / Delayed / 2.7-2.7
    delirium / Early / Incidence not known
    confusion / Early / Incidence not known
    depression / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    psychosis / Early / Incidence not known
    mania / Early / Incidence not known
    edema / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    QT prolongation / Rapid / Incidence not known
    PR prolongation / Rapid / Incidence not known
    ataxia / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    dysarthria / Delayed / Incidence not known
    involuntary movements / Delayed / Incidence not known
    EEG changes / Delayed / Incidence not known
    cycloplegia / Early / Incidence not known
    hepatitis / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    erythema / Early / Incidence not known
    eosinophilia / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    ejaculation dysfunction / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    galactorrhea / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    testicular swelling / Early / Incidence not known
    hyperthermia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    xerostomia / Early / 9.0-69.2
    drowsiness / Early / 4.0-36.0
    lethargy / Early / 3.8-33.0
    weight gain / Delayed / 2.5-15.4
    tremor / Early / 15.1-15.1
    dizziness / Early / 5.0-14.0
    hyperhidrosis / Delayed / 11.8-11.8
    insomnia / Early / 6.7-10.0
    asthenia / Delayed / 7.7-7.7
    dyspepsia / Early / 7.0-7.0
    anxiety / Delayed / 6.9-6.9
    paresthesias / Delayed / 6.9-6.9
    fatigue / Early / 5.9-5.9
    headache / Early / 4.8-5.0
    nausea / Early / 4.8-5.0
    diarrhea / Early / 3.8-3.8
    rhinitis / Early / 3.7-3.7
    anorexia / Delayed / 2.0-2.0
    abdominal pain / Early / 2.0-2.0
    pruritus / Rapid / 2.0-2.0
    syncope / Early / 1.8-1.8
    polydipsia / Early / 1.1-1.1
    agitation / Early / Incidence not known
    restlessness / Early / Incidence not known
    weakness / Early / Incidence not known
    nightmares / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    mydriasis / Early / Incidence not known
    tongue discoloration / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    dysgeusia / Early / Incidence not known
    increased urinary frequency / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known
    libido increase / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    purpura / Delayed / Incidence not known
    tinnitus / Delayed / 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 amitriptyline-related adverse reactions if coadministration with abiraterone is necessary; a dose reduction of amitriptyline may be necessary. Amitriptyline is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor. Patients who are stable on a given dose of amitriptyline may become abruptly toxic when given abiraterone is concomitant therapy.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants.
    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: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; 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. 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants.
    Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; 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. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Acetaminophen; Dextromethorphan; 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    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. 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants.
    Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    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.
    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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Alfuzosin: (Minor) Use caution when administering alfuzosin with tricyclic antidepressants due to the potential for QT prolongation. Alfuzosin may prolong the QT interval in a dose-dependent manner. 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.
    Amisulpride: (Minor) Monitor ECGs for QT prolongation when amisulpride is administered with tricyclic antidepressants. Amisulpride causes dose- and 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).
    Amlodipine; Celecoxib: (Moderate) A dosage adjustment may be warranted for amitriptyline if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of amitriptyline. Celecoxib is a CYP2D6 inhibitor, and amitriptyline is a CYP2D6 substrate.
    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: (Major) The use of a heterocyclic antidepressant, such as amoxapine, with tricyclic antidepressants (TCAs) is not generally recommended due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., tachycardia), CNS effects, or antimuscarinic effects may occur. Additive dry mouth, constipation, drowsiness, bladder difficulties, or changes in heart rate might be possible.
    Amoxicillin; Clarithromycin; Omeprazole: (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: (Moderate) Use of amphetamines with tricyclic antidepressants may increase the risk for serotonin syndrome or have effects on blood pressure or heart rate. Monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Also monitor blood pressure and heart rate. 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: (Moderate) Use of amphetamines with tricyclic antidepressants may increase the risk for serotonin syndrome or have effects on blood pressure or heart rate. Monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Also monitor blood pressure and heart rate. 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: (Moderate) Use of amphetamines with tricyclic antidepressants may increase the risk for serotonin syndrome or have effects on blood pressure or heart rate. Monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Also monitor blood pressure and heart rate. 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) Use apomorphine and tricyclic antidepressants together with caution due to the risk of additive QT prolongation. Tricyclic antidepressants have been associated with QT prolongation, primarily in overdosage or when excessive plasma concentrations are encountered. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Additive sedation is also possible during combined use of these agents.
    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: (Moderate) Use caution if amitriptyline and multi-day regimens of oral aprepitant are used concurrently and monitor for an increase in amitriptyline-related adverse effects, including QT prolongation and torsade de pointes (TdP), for several days after administration. Amitriptyline 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 and may increase plasma concentrations of amitriptyline. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Aprepitant is also a CYP2C9 inducer and amitriptyline is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
    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.
    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 may potentiate the pressor effects of epinephrine. Monitor blood pressure and heart rate closely and carefully adjust dosages as required. Avoid decongestants and local anesthetics that contain epinephrine.
    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; 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.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking 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.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Orphenadrine should be combined cautiously with tricyclic antidepressants due to the potential for additive anticholinergic and CNS depressant effects. Antimuscarinic effects might be seen on GI smooth muscle, bladder function, the eye, and temperature regulation. Consider an alternative skeletal muscle relaxant.
    Aspirin, ASA; 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.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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; Oxycodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    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) Atomoxetine should be used cautiously with tricyclic antidepressants (TCAs) such as amitriptyline as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. 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).
    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: (Contraindicated) Per the manufacturer, treatment initiation with amitriptyline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than amitriptyline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving amitriptyline and requiring urgent treatment with IV methylene blue, amitriptyline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Amitriptyline 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. 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 patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV 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. Published interaction reports between IV 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; 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.
    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) Avoid coadministration of azithromycin with tricyclic antidepressants (TCAs) due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. 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).
    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.
    Benzhydrocodone; Acetaminophen: (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.
    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: (Contraindicated) Per the manufacturer, treatment initiation with amitriptyline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than amitriptyline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving amitriptyline and requiring urgent treatment with IV methylene blue, amitriptyline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Amitriptyline 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. 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 patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV 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. Published interaction reports between IV 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: (Moderate) Use of amphetamines with tricyclic antidepressants may increase the risk for serotonin syndrome or have effects on blood pressure or heart rate. Monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Also monitor blood pressure and heart rate. 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: (Contraindicated) 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).
    Berotralstat: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
    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) QT/QTc prolongation can occur with concomitant use of tricyclic antidepressants and metronidazole although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) QT/QTc prolongation can occur with concomitant use of tricyclic antidepressants and metronidazole although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering amitriptyline with boceprevir due to an increased potential for amitriptyline-related adverse events. If amitriptyline 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 amitriptyline. Amitriptyline is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated amitriptyline plasma concentrations.
    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 (TCAs). Sedation is generally more pronounced with tertiary TCAs such as amitriptyline, imipramine, doxepin, and clomipramine.
    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. 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. 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: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Brompheniramine; Dextromethorphan; 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Brompheniramine; 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. 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Budesonide; 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.
    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.
    Bupivacaine; Meloxicam: (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.
    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.
    Butalbital; Acetaminophen: (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.
    Butalbital; Acetaminophen; 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.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking 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.
    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.
    Cabotegravir; Rilpivirine: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused 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).
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and amitriptyline. Concurrent use may result in additive CNS depression.
    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. 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. 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. 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. 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. 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: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them. (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. 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) 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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. 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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. 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. 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. 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.
    Celecoxib: (Moderate) A dosage adjustment may be warranted for amitriptyline if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of amitriptyline. Celecoxib is a CYP2D6 inhibitor, and amitriptyline is a CYP2D6 substrate.
    Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
    Ceritinib: (Minor) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and amitriptyline; 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) Concurrent use of cetirizine/levocetirizine with tricyclic antidepressants should generally be avoided. Coadministration may increase the risk of anticholinergic and CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive anticholinergic effects, sedation, and somnolence.
    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) Concurrent use of cetirizine/levocetirizine with tricyclic antidepressants should generally be avoided. Coadministration may increase the risk of anticholinergic and CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive anticholinergic effects, sedation, and somnolence.
    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. 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. 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; Amitriptyline: (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) Avoid coadministration of chloroquine with tricyclic antidepressants (TCAs) due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. 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).
    Chlorpheniramine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; Dextromethorphan: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Dextromethorphan; 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Dextromethorphan; 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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. 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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. 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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. 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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. 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpheniramine; 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. (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. 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. 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Chlorpromazine: (Moderate) During coadministration of tricyclic antidepressants (TCAs) and chlorpromazine, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Chlorpromazine is associated with an established risk of QT prolongation and torsades de pointes (TdP); case reports have included patients receiving therapeutic doses of chlorpromazine. TCAs may cause cardiac effects (e.g., QT prolongation) in some cases. Additive anticholinergic effects, hypotension, and sedation may also occur.
    Chlorthalidone; Clonidine: (Moderate) If a patient receiving clonidine is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose. Concurrent administration of a tricyclic antidepressant (TCA) and clonidine may also result in additive sedation. 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 hepatic clearance of some tricyclic antidepressants that undergo oxidative metabolism, including amitriptyline. Choose an alternate H2-blocker when possible; alternatively, observe patients closely for TCA-induced side effects or toxicity if the concurrent use of cimetidine is unavoidable.
    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: (Contraindicated) 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. 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.
    Clofazimine: (Minor) Monitor ECGs for QT prolongation when clofazimine is administered with tricyclic antidepressants. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. 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).
    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: (Moderate) If a patient receiving clonidine is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose. Concurrent administration of a tricyclic antidepressant (TCA) and clonidine may also result in additive sedation. 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. Anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like tricyclic antidepressants. 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, trimipramine, 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.
    Cocaine: (Moderate) Monitor patients for increased CNS stimulation during coadministration of cocaine and tricyclic antidepressants (TCAs). Concurrent use of cocaine and TCAs may increase the risk for excessive sympathetic CNS activity leading to symptoms such as tachycardia, hypertension, diaphoresis, agitation, cardiac arrythmias, or convulsions.
    Codeine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants.
    Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants.
    Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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 anticholinergic effects may also occur. 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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 anticholinergic effects may also occur. Anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    COMT inhibitors: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    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. 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 and chemical structures; consider alternative agents for skeletal muscle relaxation. Additive anticholinergic, cardiovascular, and serotonergic activity may occur. The administration of cyclobenzaprine with drugs that increase serotonin concentrations, such as tricyclic antidepressants, may cause serotonin syndrome. Postmarketing cases of serotonin syndrome have been reported during combined use of cyclobenzaprine and other drugs, such as the TCAs,
    Cyproheptadine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. 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: (Major) Coadministration of darunavir and amitriptyline may result in increased amitriptyline plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope, and consider a lower dose of amitriptyline with concurrent use. Amitriptyline is metabolized by CYP2D6 and also partially metabolized by CYP3A4.
    Darunavir; Cobicistat: (Major) Coadministration of darunavir and amitriptyline may result in increased amitriptyline plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope, and consider a lower dose of amitriptyline with concurrent use. Amitriptyline is metabolized by CYP2D6 and also partially metabolized by CYP3A4. (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: (Major) Coadministration of darunavir and amitriptyline may result in increased amitriptyline plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope, and consider a lower dose of amitriptyline with concurrent use. Amitriptyline is metabolized by CYP2D6 and also partially metabolized by CYP3A4. (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: (Major) Concurrent administration of amitriptyline with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated amitriptyline plasma concentrations; however, the clinical implications of this interaction have not been clearly defined. Amitriptyline is a substrate of the hepatic isoenzymes CYP3A4 and CYP2D6 and uridine glucuronyltransferase (UGT). Ritonavir inhibits CYP3A4 and CYP2D6, while dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. Hepatic isoenzymes CYP1A2, CYP2C9, and CYP2C19 also contribute to amitriptyline's metabolism, and these isoenzymes do not appear to be inhibited by the 4-drug regimen. Caution and close monitoring are advised if these drugs are administered together. (Major) Concurrent administration of amitriptyline with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated amitriptyline plasma concentrations; however, the clinical implications of this interaction have not been clearly defined. Amitriptyline is a substrate of the hepatic isoenzymes CYP3A4 and CYP2D6 and uridine glucuronyltransferase (UGT). Ritonavir inhibits CYP3A4 and CYP2D6, while dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. Hepatic isoenzymes CYP1A2, CYP2C9, and CYP2C19 also contribute to amitriptyline's metabolism, and these isoenzymes do not appear to be inhibited by the 4-drug regimen. Caution and close monitoring are advised if these drugs are administered together. (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: (Minor) 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) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents like amitriptyline. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    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: (Moderate) 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.
    Desogestrel; 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.
    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 coadministered 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 coadministered with desvenlafaxine 400 mg/day.
    Deutetrabenazine: (Moderate) The risk of QT prolongation may be increased with coadministration of deutetrabenazine and tricyclic antidepressants (TCAs). Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. 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). Monitor for excessive sedation and somnolence during coadministration of TCAs and deutetrabenazine. Concurrent use may result in additive CNS depression.
    Dexbrompheniramine; 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.
    Dexchlorpheniramine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. 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) 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextroamphetamine: (Moderate) Use of amphetamines with tricyclic antidepressants may increase the risk for serotonin syndrome or have effects on blood pressure or heart rate. Monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Also monitor blood pressure and heart rate. 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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; 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. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Quinidine: (Contraindicated) 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. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with tricyclic antidepressants. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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. 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. 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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. 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. 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. 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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Diphenoxylate; Atropine: (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.
    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: (Minor) Coadministration of dofetilide and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). 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).
    Dolasetron: (Minor) Administer dolasetron with caution in combination with 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). Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused 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).
    Donepezil: (Moderate) Use donepezil with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also be reduced. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. 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 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: (Moderate) Use donepezil with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also be reduced. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. 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 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. 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. 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: (Contraindicated) 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; Estetrol: (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; 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: (Moderate) Consider alternatives to efavirenz when coadministering with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the 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: (Moderate) Consider alternatives to efavirenz when coadministering with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the 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: (Moderate) Consider alternatives to efavirenz when coadministering with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the 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).
    Elagolix; 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.
    Elbasvir; Grazoprevir: (Moderate) Administering perphenazine; amitriptyline with elbasvir; grazoprevir may result in elevated amitriptyline plasma concentrations. Amitriptyline 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.
    Elvitegravir; 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.
    Elvitegravir; Cobicistat; 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.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused 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).
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused 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).
    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: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including tricyclic antidepressants, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Entrectinib: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT 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).
    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.
    Ephedrine; Guaifenesin: (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 may potentiate the pressor effects of epinephrine. Monitor blood pressure and heart rate closely and carefully adjust dosages as required. Avoid decongestants and local anesthetics that contain epinephrine.
    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: (Moderate) Use tricyclic antidepressants (TCAs) and escitalopram together with caution as concurrent use may increase the risk of QT prolongation and serotonin syndrome; a decreased dosage of the TCA or the avoidance of concomitant SSRI therapy should be considered. Elevated concentrations of the tricyclic antidepressant may occur. Symptoms of toxicity, including seizures, have been reported when drugs from these 2 classes were used together. If serotonin syndrome is suspected, discontinue all serotonergic agents. Escitalopram is a moderate inhibitor of CYP2D6 that has been associated with a risk of QT prolongation and torsade de pointes (TdP). CYP2D6 is responsible for metabolism of many of the 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).
    Esketamine: (Major) Closely monitor patients receiving esketamine and a tricyclic antidepressant for sedation and other CNS depressant effects. Patients who receive a dose of esketamine should not drive or engage in other activities requiring alertness until the next day after a restful sleep.
    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.
    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.
    Estradiol; Progesterone: (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; 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; 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.
    Ethynodiol Diacetate; 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.
    Etomidate: (Moderate) General anesthetics like etomidate may produce additive CNS depression when used in patients taking tricyclic antidepressants.
    Etonogestrel; 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.
    Everolimus: (Moderate) Monitor for an increase in amitriptyline-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of amitriptyline if clinically appropriate. Amitriptyline is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of amitriptyline.
    Ezogabine: (Minor) Use caution during concurrent use of ezogabine and tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Ezogabine 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). In addition, tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Fedratinib: (Moderate) Monitor for an increase in amitriptyline-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of amitriptyline may be necessary. Amitriptyline is a CYP2D6 and CYP2C19 substrate and fedratinib is a moderate inhibitor of CYP2D6 and CYP2C19.
    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.
    Fenfluramine: (Moderate) Use fenfluramine and tricyclic antidepressants with caution due to an increased risk of serotonin syndrome and additive CNS depression. Monitor for excessive sedation, somnolence, and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Fentanyl: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    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) Exercise caution when administering fingolimod concomitantly with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. 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. 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).
    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 should be administered together with TCAs with caution. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). 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, fluconazole has been reported to increase the effects of amitriptyline, likely via 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.
    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: (Moderate) Coadministration of fluoxetine and amitriptyline may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
    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 amitriptyline 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, several isoenzymes have been identified in the metabolism of amitriptyline including CYP2D6 (primary), CYP2C19, CYP1A2, CYP3A4, and CYP2C9. Fluvoxamine is a potent inhibitor of CYP1A2 and 2C19 and a moderate inhibitor of CYP3A4. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by the SSRI fluoxetine. Patients receiving a TCA should be monitored closely for toxicity if fluvoxamine is added.
    Food: (Major) Avoid concurrent use of marijuana and tricyclic antidepressants as 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.
    Fosamprenavir: (Moderate) An increased plasma concentration of amitriptyline is seen when coadministered with fosamprenavir; therapeutic concentration monitoring is recommended when coadministered.
    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: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and tricyclic antidepressants. Concomitant use of gabapentin with tricyclic antidepressants may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
    Galantamine: (Moderate) The therapeutic benefits of galantamine may be diminished when coadministered with drugs known to exhibit anticholinergic properties including tricyclic antidepressants (TCAs). When concurrent use cannot be avoided, monitor the patient for reduced galantamine efficacy, and consider use of secondary TCAs (e.g., desipramine, nortriptyline), which generally have less potent anticholinergic effects than tertiary TCAs (e.g., amitriptyline, clomipramine).
    Gemifloxacin: (Minor) Coadministration of gemifloxacin and tricyclic antidepressants should be done with caution due to increased risk of QT prolongation and torsade de pointes (TdP). 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. 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).
    Gilteritinib: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and a tricyclic antidepressant is necessary. Gilteritinib 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).
    Givosiran: (Major) Avoid concomitant use of givosiran and amitriptyline due to the risk of increased amitriptyline-related adverse reactions. If use is necessary, consider reducing the amitriptyline dose. Amitriptyline is a CYP2D6 substrate. Givosiran may moderately reduce hepatic CYP2D6 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
    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: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving amitriptyline. 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). Androgen deprivation therapy may also prolong the QT/QTc interval.
    Granisetron: (Moderate) Use granisetron with caution in combination with tricyclic antidepressants due to increased risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. Discontinue all serotonergic agents and initiate supportive therapy if serotonin syndrome is suspected. Granisetron 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).
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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: (Contraindicated) 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 whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). 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). Androgen deprivation therapy may also prolong the QT/QTc interval.
    Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking tricyclic antidepressants. (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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydroxychloroquine: (Major) Avoid coadministration of tricyclic antidepressants and hydroxychloroquine due to an increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs 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).
    Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with tricyclic antidepressants due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, additive anticholinergic effects and CNS depression may also occur. Postmarketing data indicate that hydroxyzine causes QT prolongation and 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).
    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: (Contraindicated) Per the manufacturer, treatment initiation with amitriptyline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than amitriptyline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving amitriptyline and requiring urgent treatment with IV methylene blue, amitriptyline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Amitriptyline 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. 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 patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV 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. Published interaction reports between IV 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 and somnolence. 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, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    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 amitriptyline, a CYP3A substrate, as amitriptyline 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 amitriptyline may result in increased serum concentrations of amitriptyline. Amitriptyline 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 amitriptyline 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, amitriptyline and concurrent serotonergic agents should be discontinued.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of amitriptyline 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, amitriptyline 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; coadministration may result in decreased tricyclic antidepressant plasma concentrations.
    Isoniazid, INH; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of amitriptyline 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, amitriptyline 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; coadministration may result in decreased tricyclic antidepressant plasma concentrations.
    Itraconazole: (Minor) Use itraconazole with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; itraconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope has occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with tricyclic antidepressants due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. 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).
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (Pgp). Amitriptyline is a Pgp substrate, and concomitant use of ixabepilone with a Pgp substrate may cause an increase in amitriptyline concentrations. Use caution if ixabepilone is coadministered with a Pgp substrate.
    Ketamine: (Moderate) General anesthetics, including ketamine, may generally produce additive CNS depression when used in patients taking tricyclic antidepressants (TCAs). Specific interactions between ketamine and TCAs are not certain.
    Ketoconazole: (Minor) Use ketoconazole with caution in combination with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation and increased TCA-related 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). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Labetalol: (Moderate) An increased incidence of labetalol-induced tremor has been reported in patients being treated concurrently with tricyclic antidepressants (TCAs). the mechanism of the increase in tremor is not clear. In one study, labetalol caused a significant decrease (22% mean decrease) in the amount of imipramine metabolized to 2-hydroxyimipramine and from desipramine to 2-hydroxydesipramine (8% mean decrease). The AUCs of imipramine and desipramine were increased. Since these metabolic processes are dependent on the CYP2D6 isozyme, these data suggest that labetalol decreases the oral clearance of some TCAs by inhibiting this system.
    Lacosamide: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Lamotrigine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Lansoprazole; Amoxicillin; 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).
    Lapatinib: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. 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).
    Lasmiditan: (Moderate) Monitor for excessive sedation, somnolence, and serotonin syndrome during coadministration of lasmiditan and tricyclic antidepressants. Inform patients taking this combination of the risks and symptoms of excessive CNS depression and serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Lefamulin: (Minor) Coadministration of lefamulin and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. 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).
    Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and tricyclic antidepressants. Dosage adjustments of lemborexant and the tricyclic antidepressant may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. 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).
    Leuprolide: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). 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). Androgen deprivation therapy may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving tricyclic antidepressants (TCAs). 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). Androgen deprivation therapy may also prolong the QT/QTc interval.
    Levetiracetam: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with tricyclic antidepressants should generally be avoided. Coadministration may increase the risk of anticholinergic and CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive anticholinergic effects, sedation, and somnolence.
    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.
    Levofloxacin: (Minor) Levofloxacin should be used cautiously with other agents, such as tricyclic antidepressants, that may prolong the QT interval or increase the risk of torsade de pointes (TdP). Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythm